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VOLUME ONE HUNDRED AND THIRTY SEVEN
PROGRESS IN
MOLECULAR BIOLOGY
AND TRANSLATIONAL
SCIENCE
The Molecular Basis of Drug
Addiction
VOLUME ONE HUNDRED AND THIRTY SEVEN
PROGRESS IN
MOLECULAR BIOLOGY
AND TRANSLATIONAL
SCIENCE
The Molecular Basis of Drug
Addiction
Edited by
SHAFIQUR RAHMAN
Department of Pharmaceutical Sciences,
South Dakota State University,
Brookings, South Dakota, USA
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ISBN: 978-0-12-803786-7
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CONTRIBUTORS
Richard L. Bell
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
Thomas P. Beresford
Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational
Research in Psychiatry, Denver, Colorado, USA
Department of Psychiatry, School of Medicine, University of Colorado, Denver,
Colorado, USA
Patrick Chan
Department of Pharmacy and Pharmacy Administration, Western University of Health
Sciences, College of Pharmacy, Pomona, California, USA
Howard J. Edenberg
Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics,
Indiana University School of Medicine, Indianapolis, Indiana, USA
Eric A. Engleman
Sheketha R. Hauser
Simon N. Katner
Kabirullah Lutfy
Department of Pharmaceutical Sciences,College of Pharmacy, Western University of Health
Sciences, Pomona, California, USA
William J. McBride
Jeanette McClintick
Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics,
Indiana University School of Medicine, Indianapolis, Indiana, USA
Bethany S. Neal-Beliveau
Department of Psychology, Purdue School of Science, Indiana University-Purdue University
Indianapolis, Indianapolis, Indiana, USA
Pamela M. Quizon
Department of Drug Discovery and Biomedical Sciences, South Carolina College
of Pharmacy, University of South Carolina, Columbia, South Carolina, USA
ix
x Contributors
Shafiqur Rahman
Department of Pharmaceutical Sciences, South Dakota State University, Brookings,
South Dakota, USA
Patrick J. Ronan
Research Service, Sioux Falls VA Health Care System, Sioux Falls, South Dakota, USA
Department of Psychiatry and Division of Basic Biomedical Sciences, Sanford School
of Medicine at the University of South Dakota, Sioux Falls, South Dakota, USA
Wei-Lun Sun
Department of Drug Discovery and Biomedical Sciences, South Carolina College of
Pharmacy, University of South Carolina, Columbia, South Carolina, USA
Karen K. Szumlinski
Department of Psychological and Brain Sciences, University of California Santa Barbara,
Santa Barbara, California, USA
Joachim D. Uys
Department of Cellular and Molecular Pharmacology and Experimental Therapeutics,
Medical University of South Carolina, Charleston, South Carolina, USA
Jacqueline S. Womersley
Department of Cellular and Molecular Pharmacology and Experimental Therapeutics,
Medical University of South Carolina, Charleston, South Carolina, USA
Narin Wongngamnit
Department of Psychiatry, School of Medicine, University of Colorado, Denver,
Colorado, USA
Substance Abuse Treatment Program, Department of Veterans Affairs, Denver, Colorado, USA
Nurulain T. Zaveri
Astraea Therapeutics, LLC, Mountain View, California, USA
Jun Zhu
Department of Drug Discovery and Biomedical Sciences, South Carolina College
of Pharmacy, University of South Carolina, Columbia, South Carolina, USA
PREFACE
Drug addiction is the most complex and costly neuropsychiatric disorder

affecting millions of people in the world. Recent surveys indicate that
approximately 250 million people are illegal drug users which represent
~4% of the global population. Acute and chronic exposure to drugs of abuse
produces numerous neurobiological effects, but the cellular and molecular
processes involved are only partially understood. Neuroscientists around
the world are searching for clues that underlie the molecular basis of
drug addiction. While current scientific breakthroughs have increased the
understanding on molecular determinants of drug addiction, limitations
exist on effective treatment strategies for many forms of drug addiction.
Thus, there is a need to translate the current knowledge regarding molecular
mechanisms of drug addiction derived from neurobiological research into
the discovery of new therapeutics.
This volume,The Molecular Basis of Drug Addiction, consists of eight chapters
written by eminent experts in the field. The volume covers important
aspects of neuroscience research on drug addiction associated with the
neurotransmitter receptors, signaling molecules, and relevant mechanisms
implicated in drug addiction. The chapters in this volume describe some of
the latest concepts in emerging and innovative research, discuss new break-
through findings, define innovative strategies, and target multiple signaling
pathways and genes. The primary molecular targets discussed in this volume
include extracellular signal-regulated kinase, glutamate-associated genes
or proteins, S-glutathionylated proteins, cannabinoid receptor mediated
signaling pathways, adenylyl cyclase/cyclic adenosine 3,5-monophosphate
protein kinase A, neuronal nicotinic receptors, and nociceptin receptors
involved in many forms of drug addiction. The first chapter presents and
discusses the role of the extracellular signal-regulated kinase and its related
intracellular signaling pathways in drug-induced neuroadaptive changes
that are associated with drug-mediated psychomotor activity, rewarding
properties, and relapse of drug-seeking behaviors (Zhu et al.). The second
chapter reviews the role of glutamate neurotransmitter receptor system in
mediating the development of alcohol dependence. The chapter discusses the
expression levels of glutamate-associated genes and/or proteins, including
metabotropic and ionotropic receptor subunits and glutamate transporters
xi
xii Preface
in a genetic animal model of alcoholism and highlights the changes in

glutamate receptors, transporters, enzymes, and scaffolding proteins involving
alcohol dependence (Bell etal.). The third chapter presents and highlights the
evidence for S-glutathionylation as a redox-sensing mechanism and how this
may be involved in the response to drug-induced oxidative stress. The
function of S-glutathionylated proteins involved in neurotransmission,
dendritic spine structure, and drug-induced behavioral outputs are reviewed
with specific reference to alcohol, cocaine, and heroin (Uys and Reissner). The
fourth chapter provides a comprehensive account of the state of knowledge
regarding mechanisms of Cannabis signaling in the brain and the modulation
of key brain neurotransmitter systems involved in addiction and psychiatric
disorders (Ronan et al.). The fifth chapter reviews the existing literature
on the roles of nociception receptors and associated mechanisms in the
rewarding and addictive actions of cocaine (Lutfy and Zaveri). The sixth
chapter presents recent insights on the rewarding effects of alcohol as they
pertain to different brain nicotinic receptor subtypes and associated signaling
pathways that contribute to the molecular mechanisms of alcoholism and/or
comorbid brain disorders (Rahman etal.). The seventh chapter focuses on and
reviews the adenylyl cyclase and cyclic adenosine 3,5-monophosphate/
protein kinase A system as a central player in mediating the acute and chronic
effects of opioids in opiate abusers (Chan and Lutfy). The eighth chapter
concentrates on Caenorhabditis elegans, a nonvertebrate model, to study the
molecular and genetic mechanisms of drug addiction and to identify potential
targets for medication development (Engleman et al.).
Together, this body of work not only provides a deeper understanding
of our current knowledge on specific neurotransmitter systems, functional
proteins, signaling molecules, genes, and additional targets for drug addiction,
but also indicates complex interactions between drugs of abuse, endogenous
neuromodulators, signaling molecules, and the mechanisms underlying the
structural and functional plasticity in the brain. I hope that the molecular basis
of drug addiction research summarized in this volume will generate new ideas
on diverse targets and stimulate translational research for further mechanistic
understanding and insight into effective strategies for novel therapeutics in
the management of drug addiction.
I would like to thank all the authors for their outstanding contributions to
this volume. I am very thankful to Dr. P. Michael Conn, the Editor-in-Chief
of the Book Series, for his guidance. Finally, I also thank Ms. Mary Ann
Preface xiii
Zimmerman, the Senior Acquisitions Editor and Ms. Helene Kabes, Senior
Editorial Project Manager of Elsevier, for their assistance and support in
bringing this volume together. A special thanks to my wife and daughters
for their understanding and love.
SHAFIQUR RAHMAN
Editor
CHAPTER ONE
Molecular Mechanism: ERK

Signaling, Drug Addiction,
and Behavioral Effects
Wei-Lun Sun, Pamela M. Quizon, Jun Zhu1
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University
of South Carolina, Columbia, South Carolina, USA
1
Corresponding author: e-mail address: [email protected].
Contents
1. Introduction 3
2. ERK Signaling Pathway 4
3. ERK Signaling and Drug Addiction 5
3.1 Cocaine 6
3.2 Amphetamine 14
3.3 Methamphetamine 16
3.4 Marijuana 18
3.5 Nicotine 20
3.6 Alcohol (Ethanol) 21
4. Conclusions and Future Directions 23
Acknowledgment 25
References 25
Abstract
Addiction to psychostimulants has been considered as a chronic psychiatric disorder
characterized by craving and compulsive drug seeking and use. Over the past two
decades, accumulating evidence has demonstrated that repeated drug exposure
causes long-lasting neurochemical and cellular changes that result in enduring neu-
roadaptation in brain circuitry and underlie compulsive drug consumption and
relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling
in the rewarding circuitry that contributes to the neuroplasticity of learning and
memory associated with addiction. Here, we review the role of the extracellular
signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase,
and its related intracellular signaling pathways in drug-induced neuroadaptive
changes that are associated with drug-mediated psychomotor activity, rewarding
properties and relapse of drug seeking behaviors. We also discuss the neurobiological
Progress in Molecular BiologyandTranslational Science, Volume 137

ISSN 1877-1173 © 2016 Elsevier Inc.
http://dx.doi.org/10.1016/bs.pmbts.2015.10.017 All rights reserved. 1
2 Wei-Lun Sun et al.
and behavioral effects of pharmacological and genetic interferences with ERK-associ-

ated molecular cascades in response to abused substances. Understanding the
dynamic modulation of ERK signaling in response to drugs may provide novel molec-
ular targets for therapeutic strategies to drug addiction.
ABBREVIATIONS
AC Adenylyl cyclase
AMPH Amphetamine
Amy Amygdala
BDNF Brain-derived neurotrophic factor
BNST Bed nucleus of the striatal terminals
Ca2+ Calcium
CaM Calcium/calmodulin
CaMK CaM kinase
CB1-R Cannabinoid receptor 1
CB2-R Cannabinoid receptor 2
CPP Conditioned place preference
CPu Caudate putamen
CREB cAMP response element-binding protein
DA Dopamine-regulated phosphoprotein-32
D1-R Dopamine D1 receptor
D2-R Dopamine D2-Receptor
ERK Extracellular signal-regulated kinase
Glu Glutamate
HIPP Hippocampus
IEG Immediate early gene
MAPK Mitogen-activated protein kinase
MEK MAPK kinase
METH Methamphetamine
mGluR1/5 Metabotropic glutamate receptor-1/5
MKP-1/3 MAPK phosphatases 1 and 3
MSK Mitogen- and stress-activated protein kinase
NAc Nucleus accumbens
nAChRs Nicotinic acetylcholine receptors
pCREB Phosphorylated CREB
pERK Phosphorylated ERK
PFC Prefrontal cortex
pGluN2B Phosphorylation of glutamate receptor, ionotropic, N-methyl
D-aspartate 2B
PKA Protein Kinase A
PKC Protein Kinase C
pMEK Phosphorylation of MEK
PP2A Protein phosphatase 2A
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects 3
PP2B Protein phosphatase 2B

pSTEP Phosphorylation of STEP
pThr75 DARPP-32 Phosphorylation of DARPP-32 at threonine 75
Ras-GRF-1 Ras-guanine nucleotide-releasing factors 1
RSK Ribosomal S6 kinase
SA Self-administration
STEP Striatal-enriched protein tyrosine phosphatase
THC Δ9-Tetrahydrocannabinol
VTA Ventral tegmental area
1. INTRODUCTION
Drug addiction is a chronic brain disease characterized by high relapse

rates and compulsive drug use despite negative consequences. To date, there
is no effective treatment for drug addiction. Understanding the neurobio-
logic aspects underlying substance abuse provide a basis for developing
potential therapeutic strategies targeting to drug addiction. Accumulating
evidence demonstrates that drugs of abuse alter dopamine (DA) and gluta-
mate (Glu) neurotransmission in the mesocorticolimbic system to exert their
molecular and behavioral effects.1–3 DA neurons in the ventral tegmental
area (VTA) and their descending projections to the nucleus accumbens,
prefrontal cortex (PFC) and other limbic regions, including the hippocam-
pus (HIPP) and amygdala (Amy), comprise the mesocorticolimbic system,4
which is crucial for reward and reinforcement processing, motivation, and
goal-directed behavior.5,6 The NAc and VTA also receive Glu output from
the PFC. In addition, a reciprocal Glu connection is found between the PFC
and Amy. The nigrostriatal pathway containing the DA projection from the
substantia nigra to the caudate putamen (CPu/dorsal striatum) has also been
implicated in molecular events, rewarding effects, and habitual behavior of
drug addiction.7,8
The extracellular signal-regulated kinases (ERK1/2 or p44/p42 MAPK)
cascade, one of the isoforms of mitogen-activated protein kinases (MAPK), is
associated with the pathology of diseases due to its role in cell proliferation,
differentiation, survival, and death.9,10 Since the identification the activation
of ERK by chronic morphine and cocaine administration in the VTA in
1996,11 several lines of studies have focused ERK-mediated molecular
signaling in response to various drugs of abuse during the last two decades.
Herein, we review the alterations of ERK signaling induced by abused

substances including cocaine, amphetamine (AMPH), methamphetamine,
marijuana, nicotine, and alcohol. In addition, most of these drugs have been
shown to induce psychomotor changes, the ERK-associated molecular
changes underlying drug-induced behaviors are also discussed. Further,
due to the critical role of ERK in the neuroplasticity of learning and memory
associated with addiction,12 its influence on the reinforcing, rewarding, and
relapse/reinstatement of drug addiction is also described.
2. ERK SIGNALING PATHWAY
Initially, intracellular ERK signaling has been characterized to respond

to extracellular stimuli and regulate cell proliferation and differentiation.13
For example, once ERK is activated by growth factors or neurotrophins, the
tyrosine kinase receptors recruit Ras family G-proteins and lead to sequential
activation of Raf (MAPK kinase kinase), MEK (MAPK kinase), and ERK.
Once ERK is activated, the phosphorylated ERK (pERK) protein can
translocate to the nucleus,14 where they phosphorylate the ternary complex
factor Elk-1.15,16 The activated Elk-1 and other ternary complex factors
associate with serum response factor, bind to the serum response element
site, and promote immediate early gene (IEG) transcription related to neu-
roadaptation.17–19 In addition to Elk-1, through phosphorylating ribosomal
S6 kinases and mitogen- and stress-activated protein kinases (pRSKs and
pMSKs, respectively), ERK has been shown to indirectly result in cAMP
response element-binding protein phosphorylation (pCREB), a transcription
factor that has been shown to regulate gene expression.20–24 Increasing
evidence shows a Glu linkage to ERK signaling in neurons both in vivo
and in vitro. For instance, through the elevation of intracellular calcium
(Ca2+)/calmodulin (CaM)/CaM kinases (CaMK), the activation of the Glu
NMDA receptor can increase the phosphorylation of MEK (pMEK)/ERK/
Elk-1 in hippocampal slices, neuronal culture,25–27 cortical cultured neurons,28
and striatal cultured neurons.29–31 Inhibition of ERK activation attenuates Glu-
mediated pElk-1 in the striatal slice,32 striatum,33–35 and in the HIPP.17
Alternatively, in PC12 cells, Ca2+ may increase the intracellular cAMP through
Ca2+/CaM-sensitive adenylyl cyclase (AC) leading to the activation of
PKA. Increase of cAMP and PKA induces pMEK via the activation of
Rap1/Raf.36,37 Consistent with these studies, pharmacologic activation of
D1-R or the AC markedly stimulates ERK activity and its phosphorylation
in various neuronal cells.33,38–41 In addition, activation of group 1 metabotropic

Glu receptors (mGluR1/5) has been shown to increase the intracellular Ca2+
and activate ERK signaling.42–45 Although the activation of DA D2 receptor
(D2-R) inhibits PKA activity, D2-R stimulation also increases ERK signaling
through PKC activation.46
There are several families of ERK-related phosphatases. Among these,
protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phos-
phatase (STEP) are the best characterized. PP2A is a major serine/threonine
phosphatase containing two regulatory subunits and one catalytic subunit.
PP2A mediates a rapid inactivation of pERK in vitro. STEP is another
phosphatase that regulates ERK activation. Although it is enriched in
the striatum, STEP is expressed abundantly in the mesocorticolimbic
system.47,48 Through direct interaction of a kinase-interacting motif,
STEP and its nonneuronal homologues have been shown to dephosphory-
late pERK and prevent its nuclear translocation.49,50 Phosphorylation of
STEP (pSTEP) reduces its activity and its capacity to inhibit pERK.49
STEP is regulated through D1-R/PKA/DARPP-32 signaling.51 In vitro,
D1-R activation has been shown to activate pThr34 and inhibit pThr75
DARPP-32 via PKA-activated PP2A,52 which inhibits protein phosphatase
1 and thereby increasing pSTEP.53 In addition, stimulation of NMDA-R has
been reported to induce Ca2+-activated PP2A and protein phosphatase 2B
(PP2B), which inhibit DARPP-32 signaling52,54,55 and indirectly modulate
ERK activity. Therefore, the protein phosphatases of pERK are regulated by
DA- and Glu-mediated transmission. Further, dual specificity MAPK pho-
phatases 1 and 3 (MKP-1/3) are also implicated in pERK deactivation. Both
in vitro and in vivo studies indicated that MKP-1/3 expression and activation
is dependent on ERK signaling. Once induced and activated, MKP-1/3
reduces the ERK activation as an inhibitory feedback loop.34,56–61
Furthermore, there is evidence demonstrating that MKP-1 is phosphory-
lated (pMKP-1) by pERK leading to MKP-1 protein stabilization without
altering its ability to dephosphorylate pERK.62
3. ERK SIGNALING AND DRUG ADDICTION
ERK signaling is responsive to various abused drugs in the mesocorti-

colimbic system. Both acute and chronic exposure to drugs results in
alteration of ERK-mediated signaling in specific brain regions underlying
neuronal plasticity and drug-induced behavioral changes. Therefore, we
focus on the effects of the most prevalent abused substances on ERK signal-
ing and its relationship of drug-mediated behavioral changes across different
paradigms including locomotor activity/sensitization, conditioned place
preference (CPP), and self-administration (SA), if applicable. Since pharma-
cologic and genetic approaches have been used to interfere with the ERK
signaling cascade, their effects on abused drug-mediated behaviors were
summarized in Table 1 and Table 2, respectively.
3.1 Cocaine
Numerous studies have demonstrated that acute cocaine administration
increases pERK in the CPu, NAc, PFC, central and basolateral Amy (CeA
and BLA, respectively), HIPP, and bed nucleus of the striatal terminals
(BNST).98–112 The increased pERK and its downstream targets including
pMSK-1, pElk-1, pCREB, phosphorylation of GluN2B (pGluN2B) and
IEGs by acute cocaine, are dependent on the activation of MEK, D1-R/
DARPP-32, and NMDA-R.51,69,71,97–99,102,103,106,107,111 In addition to
pMSK-1 induction, the pRSKs in the striatum are also increased by acute
cocaine leading to the indirect activation of CREB by pERK.97,112 In terms
of protein phosphatases of pERK, acute cocaine has been shown to result in
an increase of MKP-1 mRNA in the striatum and cortex.113 In addition,
depending on D1- and NMDA-Rs, the phosphorylation of MKP-1 was also
enhanced in the CPu and NAc 45–60 min after acute cocaine, contributing
to the transient pERK induction.111 Further, the pSTEP was also down-
regulated after acute cocaine in the CPu with corresponding pERK induc-
tion.112 Together, in a time-dependent manner, the activation and inactiva-
tion of protein phosphatases are critical for controlling the acute cocaine–
augmented pERK. Behaviorally, the acute cocaine–induced locomotor
activity was not affected by MEK inhibitor, SL327 (30 or 40 mg/kg), but
partially inhibited or not altered with a higher dose injection (50 mg/kg),
which has nonspecific sedative effect on basal locomotion.51,69,71,75,114
Similar to acute cocaine, MEK/ERK activation is necessary for the chronic
cocaine-induced IEG expression in the CPu, NAc, and Amy in a time-
dependent manner.102,103 In cocaine-sensitized animals, 7–21 days but not 1
day withdrawal resulted in increased AMPA-R subunit surface insertion
and NDMA-R subunit expression with paralleled pERK induction in the
NAc.115–119 AMPA-R expression in the NAc after prolonged withdrawal
from repeated cocaine injection is dependent on the activation of both
GluN2B and pERK, which contributes to the development of behavioral
sensitization.117 This conclusion is further supported by a study that D1-R/Src
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects
Table 1 Effects of MEK Inhibitors on Drug-Induced Behaviors
Drugs MEK Inhibitors (Dose, Area) Behavioral Effects References
None SL327 (50 mg/kg, i.p.) ↑ Basal locomotor activity [63]
SL327 (50–100 mg/kg, i.p.) ↓ Basal locomotor activity [64–67]
PD98059 (50 μM, continuous infusion ↑ Basal locomotor activity↓ [68]
into the PFC)
Cocaine SL327 (50 mg/kg, i.p.) ↓ Acute cocaine–induced locomotion [69]
SL327 (30 mg/kg, i.p.); PD98059 ↓ Development of locomotor sensitization (inhibitors were [64,70]
(10 μM, VTA) injected/infused before each cocaine injection)
SL327 (40 mg/kg, i.p.); PD98059 ↓ Expression of locomotor sensitization (inhibitors were [71,72]
(2 μg) or U0126 (1 μg, NAc) injected/infused before cocaine challenge)
SL327 (30 mg/kg, i.p.) ↓ Conditioned locomotor response (inhibitor was injected [64]
before each cocaine injection during conditioning)
SL327 (50 mg/kg, i.p.); U0126 ↓ Development of CPP (inhibitors injected/infused before [69,73]
(0.1 μg, VTA) each cocaine injection during conditioning)
U0126 (1 μg, NAc core) ↓ Expression of CPP (inhibitor was infused before CPP test) [74]
SL327 (30 mg/kg, i.p.); PD98059 (2 μg) ↓ Context- and cocaine priming-induced expression of CPP [74–77]
or U0126 (1 μg, NAc core); U0126 and ↓ context-induced reinstatement after SA by impairing
(1 μg, BLA) memory reconsolidation (inhibitors were injected/infused
either before or after reconsolidation phase)
U0126 (1 μg, CeA) ↓ Context + cues-induced relapse after abstinence from SA [78]
(inhibitor was infused before relapse testing)
U0126 (1 μg, VTA) ↓ BDNF/GDNF-enhanced relapse by context + cues after [79,80]
abstinence from SA (infusions were conducted
immediately after the end of the last SA session)
U0126 (0.5 μg, dmPFC) ↓ BDNF’s inhibitory effect on context-, cues-, and cocaine [81]
priming-induced drug seeking after abstinence/extinction
7
(Continued )
8
Table 1 Effects of MEK Inhibitors on Drug-Induced Behaviors—cont'd.
Drugs MEK Inhibitors (Dose, Area) Behavioral Effects References
of SA (infusions were conducted immediately after the end
of the last SA session)
Amphetamine SL327 (50–100 mg/kg, i.p.) ↓ Acute AMPH–induced locomotion [69,82,83]
PD98059 (50 μM, continuous infusion ↑ Acute AMPH–induced locomotor activity [68]
into the PFC)
SL327 (40 mg/kg, i.p.) ↓ Expression of locomotor sensitization (inhibitors were [71]
injected/infused before AMPH challenge)
SL327 (30 mg/kg, i.p.) ↓ Conditioned locomotor response (inhibitor was injected [64]
before each AMPH injection during conditioning)
PD98059 (2.5 μg, NAc) ↓ Development of intra-NAc AMPH-induced CPP [84]
(inhibitor was infused before or after each intra-NAc
AMPH infusion during conditioning)
PD98059 (2 μg, NAc) ↓ Expression of AMPH-CPP (inhibitor was infused before [85]
CPP testing)
Marijuana SL327 (50 mg/kg, i.p.) ↓ Development of THC-induced locomotion tolerance [86]
(THC) (inhibitor was injected before each THC administration)
SL327 (50 mg/kg, i.p.) ↓ Development of THC-CPP (inhibitor was injected before [87]
each conditioning session)
Alcohol PD98059 (30 or 90 μg, i.c.v.) ↓ Development of ACD-CPP (inhibitor was infused before [88]
each conditioning session)
SL327 (30 mg/kg, i.p.) ↑ Ethanol SA (inhibitor was injected before SA session) [67]
Wei-Lun Sun et al.

U0216 (0.5 μg, VTA) ↓ GDNF’s inhibitory effect on ethanol SA (infusions were [89]
conducted before SA session)
i.p., intraperitoneal injection; i.c.v., intracerebroventricular infusion; ↑, enhancing effect; ↓, inhibiting effect.
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects
Table 2 Effects of Interfering ERK Signaling-Related Genes/Proteins on Drug-Induced Behaviors
Target Genes/Proteins Behavioral Effects References
2+
Ca -stimulated AC1/AC8 (KO) ↑ Acute cocaine–induced locomotion [90]
↓ Development of cocaine locomotor sensitization
Ras-GRF-1 (KO) ↓ Development and expression of cocaine locomotor sensitization [86,91,92]
↓ Cocaine-CPP
↓ Repeated THC-induced behavioral tolerance
Ras-GRF-1 (OE) ↑ Development and expression of cocaine locomotor sensitization [91]
↑ cocaine-CPP
Ras-GRF-2 (KO) ↓ Ethanol intake and preference (two bottle-free choice task) [93]
ERK1 (KO) ↑ Basal locomotor activity [34,63,94,95]
↑ AMPH-induced locomotion
↑ Development of cocaine locomotor sensitization
↑ cocaine-CPP
ERK1 (KD in the PFC) ↑ Basal locomotor activity [68]
↑ AMPH-induced locomotion
ERK2 (OE in the VTA) ↑ development and expression of cocaine locomotor sensitization [96]
↑ Cocaine-CPP
ERK2 (KD in the VTA) ↓ Development and expression of cocaine locomotor sensitization [96]
↓ Cocaine-CPP
MSK-1 (KO) ↓ Development and expression of cocaine locomotor sensitization [97]
↑ Cocaine-CPP
Inhibition of pElk-1 ↓ Development and expression of cocaine locomotor sensitization [98]
↓ The establishment of cocaine-CPP
KO, knockout; KD, knockdown; OE, overexpression; ↑, enhancing effect; ↓, inhibiting effect.
9
kinase-mediated pGluN2B is necessary for the pERK induction in response to

repeated cocaine administration.106 In addition, cocaine challenge after
withdrawal from repeated cocaine administration also resulted in sensitized
pERK in the NAc and CPu compared to the acute cocaine effect.108,120,121
The cocaine behavioral sensitization-induced pERK and pCREB in the
NAc is dependent on ERK activation.122 Further, the induction and
expression of cocaine behavioral sensitization can be inhibited by systemic
SL327 injection or intra-NAc MEK inhibitor infusion.64,71,72 Similarly
through MEK activation, the pERK induction in the VTA is required for
the development of behavioral sensitization to cocaine.11,70 Lastly, studies
have indicated that, in response to D1- and NMDA-R activation, pERK
induced by cocaine is responsible for the chronic cocaine-enhanced
dendritic spine density and dendritic length in the CPu and NAc123,124
providing the morphologic evidence mediated by ERK signaling after
repeated cocaine administration.
Repeated pairing of a specific environment with drug administration
leads to a memory association between contextual cues and the drug reward-
ing effect. Subsequently, the context itself directly motivates drug-seeking
behavior as a measurement of the reinforcing effect of the drug,125,126 which
is associated with ERK signaling. For example, the acquisition of cocaine-
CPP is accompanied by pERK induction in the NAc and PFC in a D1-R-
dependent manner.127 Systemic preadministration of SL327 (50 mg/kg) and
a GluN2B antagonist inhibited the development of cocaine-CPP,69,106
indicating the requirement of NMDA-R-mediated ERK activation in the
formation of context–drug association memory. ERK activation in the VTA
is necessary for the development of cocaine-CPP.73 Cocaine challenge in the
drug-paired environment resulted in pERK and pCREB induction in the
subset of neurons of the NAc.128 In animals with repeated cocaine admin-
istration, the saline challenge enhanced pERK induction in the D1-positive
neurons in NAc and CPu, indicating context conditioning-induced ERK
activity.108 Similarly, after the establishment of CPP, CPP testing or
re-exposure to the cocaine-associated context induced pERK, pCREB,
and/or ΔFosB in the CPu, HIPP, VTA, and NAc as well as in D1-R-
containing neurons of the NAc.73,129–133 The CPP test-induced pERK
expression in the VTA is dependent on mGluR1 activation and protein
synthesis.133 Further, Miller and Marshall demonstrated that CPP test-ele-
vated pERK and drug-seeking behavior were blocked by intra-NAc core
infusion of U0126 (2 μg/side).74 In the cocaine SA paradigm, context-
induced relapse is also associated with enhanced pERK in the NAc core
and CPu.134 Altogether, these results imply that, through ERK signaling, the
NAc core and VTA are important for the memory formation of context–
drug association. pERK in the NAc core and CPu also involve the retrieval
of CPP memory and a general motor activation driven by drug-associated
context, respectively.
Memory reconsolidation occurs when well-established drug-associated
memories are recalled by re-exposure to drug-associated context, cues, or
the drug itself during which memories can be destabilized by adding new
information or subjected to manipulation.135–137 The ability to disrupt
drug-related memories provides an opportunity to promote treatment out-
come and prevent relapse. The general procedure to test the memory
reconsolidation on drug-seeking behavior contains two phases: re-exposing
animals to drug-associated context (phase 1) followed by testing drug-seek-
ing behavior after withdrawal (phase 2). A previous study demonstrated that,
before or immediately after phase 1, intra-NAc core MEK inhibition
through U0126 (1 μg/side) or PD98059 (2 μg/side) reduced cocaine-CPP
during the phase 2. The protein expression of pERK, pCREB, pElk-1, and
c-Fos induced by phase 2 is also attenuated with inhibiting ERK
during phase 1.74 Systemic SL327 injection after phase 1 also decreased
subsequent context-induced CPP in animals conditioned by escalating doses
of cocaine.76 Similar to reactivation of CPP memory by context, the mem-
ory reconsolidation in response to cocaine is also accompanied by ERK
activation in the PFC, NAc, and CPu. With or without cocaine priming,
the systemic SL327 (20 mg/kg) pretreatment before phase 1 inhibits the
subsequent drug-seeking behavior.75 However, the effect of ERK on
cocaine-induced memory reconsolidation is still dependent on the presence
of context. Thus, the contribution of cocaine itself on memory reconsolida-
tion is still ambiguous. After the establishment of cocaine SA, U0126 (1 μg/
side) infusion into the BLA immediately after phase 1 inhibited context-
induced reinstatement and the pERK induction after phase 2.77 Taken
together, these studies indicate that ERK signaling activated during memory
reconsolidation is necessary for cocaine-seeking behavior. However, a critical
time window, 6 h after the reactivation of memories, has been documented
during which the memory is susceptible to alteration in the fear-conditioning
paradigm.138 The pretreatment before phase 1 may influence the memory
retrieval instead of reconsolidation. If the ERK signaling actually involves
drug-related memory reconsolidation, the difference should be found when
treatment is conducted within and beyond the critical time window in terms
of both behavioral and molecular aspects.
Unlike pERK sensitization in cocaine-induced behavioral sensitization,

immediately after the cessation of cocaine SA, there is a dissociation between
pERK induction and cocaine intake indicating the failure of developing
pERK sensitization or tolerance, although with enhanced pERK expression
in several brain regions.139 However, ERK activation has been implicated in
relapse after withdrawal. For example, the extinction test (conditioned cues +
context) significantly increased pERK in the CeA and cocaine-seeking
behavior after 30 days of withdrawal. Both enhanced pERK and relapse
are dependent on MEK and NMDA-R activation.78 Similarly, the pERK
induction in the ventromedial PFC has been shown to mediate extinction-
test-induced cocaine-seeking behavior after 1- or 30-day withdrawal from
cocaine SA.140 Through ERK activation, direct intra-VTA glial cell line-
derived neurotrophic factor (GNDF) or brain-derived neurotrophic factor
(BDNF) infusion immediately after the last session of cocaine SA induced
robust drug-seeking behavior after 3 or 10 days withdrawal.79,80 These results
demonstrated that the potentiated ERK signaling underlies relapse behavior
after cocaine SA. In contrast to augmented pERK induction in the PFC after
1-day abstinence of cocaine SA,140 2 h after the last cocaine SA session, we
have demonstrated a transient reduction of pERK in the PFC.81,141,142 The
reduction of pERK is associated with an increase of STEP but not PP2A
activity accompanied by decreased total GluN2B protein expression and
phosphorylation, suggesting the inhibitory effect of STEP on pERK and
NMDA-R.143 Through MEK activation and normalization of pERK in the
PFC, direct BDNF infusion into the dorsomedial PFC immediately after the
end of the last cocaine SA session resulted in a long-term inhibition on
context-, cue-, or cocaine-induced relapse.81 Thus, it indicated that rescuing
the ERK signaling or hypofunction in the PFC during early withdrawal
might provide a potential therapeutic strategy for preventing cocaine relapse.
Several animal models have been used to dissect the ERK signaling
cascade in cocaine-induced behavioral changes. For example, double knock-
out (KO) type 1 and type 8Ca2+-stimulated AC resulted in a reduction of
basal pERK in medium spiny neurons in the striatum with blunted acute
cocaine–induced pERK, pMSK-1, and pCREB. Behaviorally, these double
KO AC mice are supersensitive to low-dose acute cocaine–induced loco-
motion and fail to develop behavioral sensitization in response to repeated
cocaine administration.90 Ras-guanine nucleotide-releasing factors 1 (Ras-
GRF1), the upstream activator of Ras, can increase ERK signaling. In the
striatum, the protein expression of Ras-GRF-1 is increased by acute psy-
chostimulants including cocaine.144,145 D1-R agonist and Glu-induced
pERK is attenuated in the striatal slice of Ras-GRF-1 KO mice. The acute

cocaine–induced pERK is downregulated and upregulated in Ras-GRF-1
KO and overexpressing (OE) mice, respectively. In addition, the develop-
ment of cocaine behavioral sensitization and cocaine-CPP are attenuated in
Ras-GRF-1 KO mice accompanied by a reduction of FosB/ΔFosB in the
striatum. An opposite facilitation on behavior and FosB/ΔFosB was
observed in Ras-GRF-1 OE mice in response to repeated cocaine.91
ERK1 KO mice exhibit higher responsibility to morphine.94 Similarly, in
response to chronic cocaine exposure, ERK1 KO mice display enhanced
behavioral sensitization and cocaine-CPP as well as c-fos mRNA induction in
the CPu.34 This suggests that ERK1 acts as an inhibitor on ERK2 activation
and a heightened stimulus- or cocaine-induced ERK2 signaling after ERK1
KO.146 In addition, selective ERK2 OE in the VTA resulted in an increase of
sensitivity of cocaine-CPP and the repeated cocaine-mediated behavioral
sensitization.96 In contrast, inhibition of ERK2 activity in the VTA atten-
uated the cocaine-CPP and the development and expression of cocaine-
induced locomotor sensitization. Through activating MSKs, ERK leads to
the increase of CREB activity. The acute cocaine–induced pCREB and
IEGs as well as histone H3 phosphorylation were attenuated in the striatum
of MSK-1 KO mice, indicating the role of MSK-1 in chromatin remodeling
in response to cocaine. Although showing higher sensitivity to low-dose
cocaine-CPP, MSK-1 KO mice have reduced behavioral sensitization in
response to repeated cocaine administration.97 Finally, systemic injection
of the peptide-inhibiting pElK-1 significantly inhibited acute cocaine–
activated pElk-1, pElk-1 nuclear translocation, and histone H3 phosphory-
lation, as well as IEGs protein and mRNA expression in the CPu and
NAc.98,147 Further, the inhibition of pElk-1 also resulted in an attenuation
of repeated cocaine-induced dendritic plasticity in the NAc shell and pre-
vented repeated cocaine-induced behavioral sensitization and CPP.98
Together, these studies demonstrated that ERK-associated signaling is
important for the long-term cocaine-mediated behavioral alterations,
rewarding effects, and neuronal plasticity. Interestingly, the acute cocaine–
mediated locomotor activity was not altered in animal models with manip-
ulation of ERK1 or downstream molecular targets of ERK (e.g., MSK-1,
ElK-1), further supporting that ERK signaling is not required for the acute
cocaine–induced psychomotor effect.
Since both NMDA- and D1-Rs are implicated in cocaine-induced
pERK, the direct protein–protein interaction between both receptors may
underlie their effects on ERK activation.148–151 Previously, we have
demonstrated the protein–protein interaction between D1-R and GluN1 of

NMDA-R in the CPu. The D1-R/GluN1 complex is disrupted after acute
cocaine administration which may underlie transient pERK induction by
cocaine.152 The assumption is supported by a recent finding indicating that
interference of D1-R/GluN1 association in vitro decreases D1 agonist- and
NMDA-induced pERK induction. In addition, disrupting the protein–
protein interaction in the NAc also attenuates acute cocaine–induced
pERK induction and repeated cocaine-induced behavioral sensitization in
the two-injection protocol.153 Further, the receptor complex of sigma-1,
histamine H3, and D1-Rs has been found in the striatum. Through binding
to sigma-1-R, cocaine results in a disinhibitory effect of histamine H3
receptor on D1-Rs leading to pERK activation after either acute cocaine
injection or cocaine SA.154 However, the impact of these receptor–receptor
interactions on cocaine-induced behavioral alteration is still unknown.
3.2 Amphetamine
Acute AMPH has been shown to increase pERK in the CPu, NAc, PFC, and
VTA.51,64,71,82,83,155–157 Multiple upstream receptors and molecular activa-
tors have been implicated in acute AMPH–induced ERK signaling in a brain-
region-specific manner. For instance, acute AMPH–induced pMEK and
pERK in the striatum is regulated by D1-R/DARPP-32 and NMDA-R
activation.51 In contrast, pERK induction in the PFC by acute AMPH is
dependent on NMDA-R, adrenoceptors, and serotonin receptors but not
D1- or D2-Rs.158 Blockade of mGluR1/5 or mGluR5 specifically in the
CPu attenuates acute AMPH–induced pERK, pElk-1, pCREB, and Fos
immunoreactivity.159–161 The activation of Ca2+/CaM-dependent protein
kinases II (CaMK II) in the CPu is also necessary for acute AMPH–
augmented pERK, pElk-1, and pCREB.159 Direct MEK inhibition via
systemic SL327 (20–100 mg/kg) administration or intra-CPu U0216
(2 μg/side) infusion attenuated acute AMPH–elevated pERK and pCREB
protein expression in the CPu and NAc, and IEGs including preproenkephalin,
preprodynorphin, and c-fos mRNA in the CPu.71,82,83,162 However, the differ-
ential pERK induction profile in the striatum in response to acute psychos-
timulants is determined by the environment: acute AMPH and cocaine-
induced pERK expression mainly in D1-R-expressing neurons,51,108,163
whereas, in a novel environment, AMPH dominantly increases pERK in
D2-R-containing neurons of the striatum.162 In line with cocaine, protein
phosphatases have been shown to be induced by acute AMPH administration,
which may control ERK activity after AMPH stimulation. For example, in
the striatum, acute AMPH significantly increases pSTEP in a DARPP-32-

dependent manner.51 In addition, acute AMPH increases the gene encoding
PP2B in the striatum,164 relevant to MKP-1 mRNA expression and
DARPP-32/STEP activity.53,165
Behaviorally, similar to their enhanced response to the rewarding prop-
erties of morphine and cocaine, ERK1 KO mice exhibit higher hyperloco-
motion after acute AMPH injection.34,63,94 ERK1 KO mice display
increased basal locomotor activity accompanied by a reduction of pRSK
expression in the PFC and striatum,63,94,95 indicating a blunted ERK-
mediated signaling after ERK1 ablation. The increased basal and acute
AMPH–induced locomotion as well as the reduction of pRSK can be
replicated by chronic and continuous infusion of MEK inhibitor,
PD98059 (50 μM), and selective knockdown (KD) of ERK1 in the
PFC.68 Although the predominant hypothesis indicates that enhanced
stimuli-activated ERK2 signaling in the striatum in ERK1 KO mice is
responsible for increased behavioral responses to abused drugs,34,94 the
reduction of ERK-mediated molecular cascade, at least in the PFC, may
also contribute to both basal and drug-induced behavioral phenotype due to
a general inhibition of ERK1 and ERK2 activity by MEK inhibitor. The
latter assumption is supported by our recent finding demonstrating that rats
raised in enriched environment have an augmented basal pERK induction in
the PFC associated with lower basal and repeated nicotine-induced loco-
motion compared to control animals.166 The acute AMPH–induced hyper-
activity was not altered by SL327 (30–40 mg/kg) but attenuated by high
doses of SL327 (50–100 mg/kg) with a potentially inhibitory effect on basal
locomotion.64,65,71,82,83 Although inhibiting acute AMPH–induced loco-
motor activity, acute systemic MEK inhibition by SL327 (50 mg/kg)
resulted an enhancement to the basal locomotion.167 The discrepancy may
be accounted for experimental procedure, since a potentiated acute AMPH–
activated locomotor activity was documented after pERK suppression in the
CPu of rats without habituating to the behavioral apparatus.161
In a D1- and D2-Rs dependent manner, AMPH challenge after with-
drawal from repeated AMPH exposure resulted in behavioral sensitization,
which is associated with pERK and pCREB sensitization in the CPu.168,169
The chronic AMPH-augmented pERK and pCREB induction is attenuated
by D1- but not D2-Rs antagonist. Thus, although antagonism of both
D1- and D2-Rs can inhibit the expression of behavioral sensitization, only
D1-R-mediated ERK and CREB activation is critical for the expression of
behavioral sensitization of the AMPH challenge. In contrast to the CPu, the
expression of AMPH-induced behavioral sensitization is required for ERK’s

inhibitory effect on CREB activity modulated by Ca2+ voltage-gated chan-
nels in the NAc.71 However, in the VTA, withdrawal from repeated AMPH
exposure results in elevated MKP-1 and PP2B protein expression to down-
regulate the AMPH-mediated pERK induction.157 Systemic administration
of SL327 (30 or 40 mg/kg) dose-dependently prevents the development and
expression of behavioral sensitization as well as the acquisition of condi-
tioned locomotor response to AMPH administration.64,71 A previous study
demonstrated that intra-NAc AMPH infusion led to pERK and the estab-
lishment of CPP.84 The AMPH-CPP was prevented by direct intra-NAc
PD98059 (2.5 μg/side) infusion either before or after each conditioning
session, suggesting the role of ERK on memory acquisition and consolida-
tion of association of contextual rewarding effect of AMPH. However, the
enhanced locomotor response by intra-NAc AMPH infusion is not affected
by MEK inhibition. Altogether, it seems that ERK plays an important role in
chronic AMPH-induced behavioral alterations ranging from behavioral sen-
sitization, conditioned locomotor response to CPP. However, dynamic
molecular mechanisms underlying behaviors including ERK-mediated
downstream targets and the modulatory effect of ERK-related protein phos-
phatases should be further elucidated in specific brain regions associated to
AMPH.
3.3 Methamphetamine
Methamphetamine (METH) is a highly addictive psychostimulant causing a
serious and growing worldwide problem associated with medical, socioeco-
nomic, and legal domains.170,171 Although accumulating evidence has impli-
cated the Glu and DA neurotransmission in METH-induced behavioral
changes,172–176 a direct exploration of their downstream target, ERK signal-
ing, is limited. Acute METH (3 mg/kg) injection significantly increases
pERK in the striatum, which is attenuated in serine racemase KO mice.177
Serine racemase is an enzyme synthesizing D-serine, an endogenous coagonist
of NMDA-R, thereby, partially supporting the requirement of NMDA-R for
acute METH–induced pERK. In contrast, a recent study demonstrated that
acute METH (2 mg/kg) did not affect pERK in either CPu or NAc.178 The
dose of METH, routes of administration, or the timing of collecting tissue
may contribute to the discrepancy.
METH challenge after withdrawal from repeated METH exposure has
been shown to induce behavioral sensitization related to pERK induction in
both CPu and NAc as well as ΔFosB expression in the CPu.142,178,179 The
development and expression of METH behavioral sensitization and chal-

lenge-augmented pERK induction were inhibited by levo-tetrahydropal-
matine, an antagonist of D1- and D2-Rs,178,180,181 suggesting the involve-
ment of DA receptors in chronic METH-induced pERK and behavioral
sensitization. However, the METH challenge-elevated pERK is associated
to the consequences of acute stimulation, since the pERK protein expression
in the striatum is transiently increased during early withdrawal or not
altered after long-term abstinence.142,182 In agreement with the increase
of pERK induction in the NAc shell after 1-day withdrawal from METH
sensitization,142 2 h withdrawal from METH SA resulted in elevated D1-R,
pCREB, and ΔFosB protein expression as well as transcriptional regulating
genes including CREB, Elk-1, and Fos family in the striatum.183,184 Genes
associated with dual-specificity phosphatases 12 and protein tyrosine
phosphatase were also upregulated, implying an inhibitory mechanism to
dampen ERK signaling during the early phase of withdrawal from METH
SA.184–186 In both D1- and NMDA-Rs dependent manners, acute or
chronic METH administration results in increases of MKP-1 and MKP-3
mRNA in several brain regions including the PFC, orbital cortex, CPu,
NAc, and HIPP.187,188 Therefore, the ERK-driven MKPs expression and
other phosphatases represent a positive feedback to gate the transient ERK
activation in response to acute or chronic METH exposure.
The increase of pERK, pElk-1, pCREB, and/or ΔFosB protein expres-
sion in the CPu, NAc, or PFC is related to METH-induced CPP.85,189
Specifically, the acquisition of CPP and pERK induction in the NAc by
METH-CPP require D1-R but not NMDA-R activation. Intra-NAc infu-
sion of MEK inhibitor, PD98059 (2 μg/side), also prevents the expression of
METH-CPP and pERK induction.85 Therefore, this demonstrates the
importance of the activation of D1-R/MEK/ERK/pElk-1 in the NAc on
the development and expression of METH-CPP. In contrast, the METH-
CPP testing reduced pERK and pCREB in the NAc after a single pairing
session with 2 days withdrawal,190 suggesting either a compensatory reduc-
tion in response to overactivation of ERK signaling during conditioning and
withdrawal or other molecular cascades are required for the initial acquisition
of METH-CPP. Both assumptions should be further deciphered to identify
molecular mechanisms underlying the difference between single and mul-
tiple condition session-mediated METH-CPP.
Chronic METH use causes cognitive deficits associated with altered
neurotransmission.191–194 In animal studies, repeated METH administration
leads to spatial learning and memory impairment, which is associated with
reduced total ERK in the PFC.195 In addition, deficits in spatial working

memory and novel object recognition (NOR) are accompanied by an
inability of pERK induction in the HIPP and PFC by the learning process
or stimuli.196–199 Interestingly, intra-PFC infusion of PD98509 (2 μg/side)
mimics the METH-induced cognitive impairment in NOR,196 indicating
that a reduced pERK signaling is responsible for the cognitive dysfunction
after long-term METH exposure. Several drugs have been demonstrated to
ameliorate the cognitive deficit by METH through ERK signaling. For
example, depending on nicotinic acetylcholine receptors (nAChRs), D1-
R and MEK activation, galantamine, a drug used to treat Alzheimer’s disease
by inhibiting acetylcholinesterase and allosterically modulating nAChRs,
alleviates NOR impairment through pERK induction in the PFC.198
Similarly, modafinil, a cognitive enhancer with a weak DA-transporter-
inhibiting effect, also activates pERK in the PFC to rescue the NOR
deficit199,200 probably through increasing extracellular DA levels. Finally,
clozapine, an atypical antipsychotic medication, reverses dysfunctional
pERK signaling in the HIPP with an attenuating effect on spatial working
memory impairment induced by chronic METH.197 Taken together, these
results demonstrate that the cognitive impairment induced by chronic
METH is attributed to the downregulation of ERK signaling during learn-
ing and memory-a potential therapeutic molecular biomarker for future
drug development.
3.4 Marijuana
Δ9-Tetrahydrocannabinol (THC) is the main psychoactive component of
marijuana, which is one of the most used illicit drugs.201 Cannabinoid recep-
tors 1 and 2(CB1-R and CB2-R) have been identified and located mainly in
neuronal and peripheral tissues, respectively. Activation of the CB1-R leads to
the closing of calcium and the opening of potassium channel, subsequently
inhibiting AC and activating protein kinase including ERK.202 Acute low-
dose THC injection (1 mg/kg) has been demonstrated to increase pERK
expression in the mesocorticolimbic system.99,203 Specifically, in the striatum,
the THC-activated pERK is mediated by CB1-, D1-, D2-, and NMDA-Rs
indicating a synergistic action among cannabinoid, DA and Glu neurotrans-
mission. Acute THC–induced ERK downstream targets, pElk-1 and zif268
mRNA, were inhibited by D1-R antagonist and MEK inhibitor, SL327
(100 mg/kg). Further, in response to repeated low dose of THC injection,
the development of THC-CPP was attenuated by SL327 (50 mg/kg), sug-
gesting that ERK-regulated signaling is involved in THC-rewarding effect.87
Similarly, acute THC (1 mg/kg) induced transient pERK induction in the

HIPP was dependent on the activation of CB1- and NMDA-Rs. SL327
(100 mg/kg) pretreatment also inhibited the acute THC–induced IEG
expression (c-Fos protein, Zif268, and BDNF mRNAs) in the HIPP.204
However, the relevance between acute THC–induced behavioral changes
and ERK signaling should be further elucidated, since there is no significant
locomotor activity alteration by low-dose THC.205
In contrast to the low dose of THC, high dose of THC (≥10 mg/kg)
acutely resulted in hypolocomotor activity in the striatum and cerebellum
with pERK, pCREB, and c-fos induction depending on CB1-R and Ras-
GRF1.86,92,203 Although the ERK signaling in both brain regions is distinct
from the acute THC–induced hypolocomotor, it is necessary for the
development of behavioral tolerance, a gradual behavioral recovery
from the initial hypolocomotor by acute THC, after repeated THC
injection.86,92,206 In an ERK-dependent manner, the behavioral tolerance
is mediated by recruiting G-protein-coupled receptor kinases and β-arrestins
to desensitize and internalize CB1-R in the striatum and cerebellum. The
chronic THC-mediated cerebellar synaptic transmission and plasticity as well
as reduced sensitivity of CB1-R activation were also prevented in
Ras-GRF1 KO mice.207 In addition, chronic THC-exposure-induced
pCREB and FosB protein expression in the PFC and HIPP is inhibited by
either SL327 (50 mg/kg) or in Ras-GRF1null mice.206 Taken together, the
results demonstrated that, in response to a high dose of THC, the activation
of pERK-mediated signaling in the striatum and cerebellum is critical for the
development of behavioral tolerance. In the PFC and HIPP, the ERK-
associated molecular cascade may underlie the addicted state for THC.
However, the latter assumption needs to be examined due to a similar
analgesic tolerance effect after a chronic high dose of THC. Since THC-
induced behavioral sensitization and SA have been documented,208–210 it
will be worthwhile to determine the role of ERK on reinforcing/rewarding
effects of THC in specific brain region(s).
In addition to the THC action on CB-1R, DA agonists and psychosti-
mulants have been shown to increase endocannabinoid release.211–213 A
previous study has indicated that acute cocaine–induced pERK and c-Fos
in the CPu and NAc was inhibited by CB1-R antagonist pretreatment, and
mice with CB1-R KO or conditional deletion in the forebrain neurons.104
In addition, the elevated pERK protein expression-induced by chronic
cocaine in the VTA is dependent on CB1-R activation. The development
of cocaine-CPP and underlying pERK induction were also inhibited by
intra-VTA CB1-R antagonist infusion,73 implicating the role of CB1-R and

endocannabinoids in regulating the rewarding effect of cocaine mediated by
ERK signaling activation.
3.5 Nicotine
Cigarette smoking is the largest preventable cause of death and diseases
worldwide with an estimated 6 million deaths each year.214 It has
been shown that nicotine, through activation of the DA- and Glu-related
signaling in the mesocorticolimbic system, exerts its reinforcing
effects.215–217 Several in vitro studies have demonstrated that activation of
ERK and CREB by acute and chronic administration of nicotine depends
on nAChRs, CaMKs, PKA, and MEK activity.218–222 A genome-wide
expression analysis revealed acute nicotine exposure, through activation
of ERK signaling, induced alterations of gene expression.223 Similarly,
acute nicotine–induced transient ERK activation through nAChRs,
Ca2+ voltage-gated channels, CaMKs, and MEK in primary cortical and
hippocampal neurons;224,225 however, only PKA is required for pERK
induction by nicotine in the hippocampal neurons, suggesting differential
upstream activators for ERK activity in distinct neuronal types. Chronic
nicotine exposure in mesencephalic dopaminergic neuronal culture
resulted in increases of dendritic length and soma size through nAChRs-
and D3-R-recrutied ERK signaling,226 demonstrating that ERK involves
nicotine-mediated structural neuronal plasticity. In vivo, acute nicotine
administration increases pERK levels in the NAc, CPu, PFC, Amy, and
BNST.51,99,227,228 In the striatum, acute nicotine–induced pERK is medi-
ated by D1-R/PKA/DARPP-32 signaling pathways,99,100 indicating the
relevance of dopaminergic neurotransmission in response to nicotine.
After chronic oral consumption of nicotine,the levels of pERK and
pCREB were increased in the PFC, but pCREB was decreased in
the NAc,227 suggesting an increase of PFC excitatory output into the
NAc. Indeed, pERK was increased in the NAc of nicotine-induced
CPP animals,228 supporting the role of PFC-NAc projection in the
conditioned rewarding effect of nicotine. Interestingly, a direct protein–
protein interaction between α7nAChR and GluN2A has been identified in
the HIPP, which can be upregulated by chronic nicotine exposure.229
After nicotine SA, disruption of the α7nAChR–NMDAR complex
decreased ERK activity and blocked cue-induced reinstatement of nico-
tine-seeking behavior.229 Taken together, these results demonstrate that
the ERK signaling pathway is a key integrator of the DA/D1 receptor and
Glu/NMDA receptor signaling that induces long-term cellular alterations

and behavioral adaptation in response to nicotine exposure. However, a
direct manipulation on ERK is warranted to examine its effect on nico-
tine-induced behavioral changes.
Environment is an important factor affecting the vulnerability for drug
abuse.230–232 Exposure to an environmental enrichment paradigm results
in neurobiologic adaptations, particularly in the PFC of the mesocortico-
limbic dopaminergic system.166,233–235 Our recent study has demonstrated
that the basal level of pERK was higher in animals housing in an enriched
environmental condition compared to animals housing in an impoverished
condition, which was negatively correlated with their respective baseline
locomotor activities.166 After nicotine sensitization or nicotine SA, the
pERK induction was significantly increased in the PFC of rats raised in
either impoverished or standard condition. In contrast, due to their higher
basal ERK activity in the PFC, nicotine did not alter pERK protein levels
in animals raised in an enriched environmental condition with a decreased
sensitivity in response to chronic nicotine.166 Regardless of raising condi-
tions, the pERK induction is positively correlated to the amount of nic-
otine intake during nicotine SA. Thus, these results suggest that pERK
induction in the PFC may underlie the rewarding effect of nicotine, which
is consistent with a previous study demonstrating a preference for ERK-
mediated signaling pathway activation in the PFC after nicotine SA.236
3.6 Alcohol (Ethanol)

In a time-dependent manner, acute injection with higher doses of ethanol
(EtOH 2.5–4.7 g/kg) reduced pERK and pCREB in the PFC, NAc, CPu,
Amy, HIPP, cerebellum, and BNST in various ages of rodents.237–240 In
contrast, acute administration of a lower dose of EtOH (1 g/kg) significantly
increased pERK in various regions including the NAc and CeA in theD1-R
and neuropeptide S receptor dependent manner.241,242 The acute
EtOH–induced c-fos induction in the medial Amy was inhibited by the
MEK inhibitor, U0126.243 Similarly, acute acetaldehyde (ACD), the first
and main metabolite of EtOH, enhanced pERK in the NAc, CeA, and
BNST through activation of D1-R and opioid receptors.244,245
Behaviorally, the low dose of acute EtOH (1 mg/kg) is associated to an
anxiolytic response accompanied by the rapid increase of spine density in
the CeA and MeA through the BDNF-mediated TrkB phosphorylation and
pERK/pElk-1/pCREB and Arc induction.246 In addition to the acute
EtOH–mediated pERK signaling, its intrinsic activation state may
Another random document with
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magnificent Englishmen who occupied high commercial positions on
the shores of the Mediterranean, I got a central forwarding station for
information fixed up privately in Switzerland; and it so happened,
through a most Providential state of circumstances, that I was thus
able to obtain all the cypher messages passing from the various
Foreign Embassies, Consulates and Legations through a certain
central focus, and I also obtained a key to their respective cyphers.
The Chief man who did it for me was not in Government employ; and
I’m glad to think that he is now in a great position—though not
rewarded as he should have been. No one is. But as to any
information from an official source reaching me, who was so vastly
interested in the matter, in the event of war where the Fleet should
strike first—all our Diplomats and Consuls and Intelligence
Departments might have been dead and buried. And how striking the
case in the late War—the Prime Minister not knowing at the Guildhall
Banquet on November 9th, 1918, that the most humiliating armistice
ever known would be accepted by the Germans within thirty-six
hours, and one of our principal Cabinet Ministers saying the Sunday
before that the Allies were at their last gasp. And read now
Ludendorff, Tirpitz, Falkenhayn, Liman von Sanders, and others—
they knew exactly what the Allies’ condition was and what their own
was. And if the Dardanelles evidence is ever published, it will be
found absolutely ludicrous how the official spokesmen gravely give
evidence that the Turks had come to their last round of ammunition
and that the roofs of the houses in Constantinople were crowded
with people looking for the advent of the approaching British Fleet.
Why! it took our Admiral, on the conclusion of the Armistice, with the
help of the Turks and all his own Fleet, several weeks to clear a
passage through the mines, on which Marshal Liman von Sanders
so accurately based his reliance against any likelihood of the
Dardanelles being forced.
[Photo Press Portrait Bureau
Admiral of the Fleet Lord Fisher, G.C.B.,
O.M., etc., 1917.
CHAPTER VII
A JEU D’ESPRIT
BOWS AND ARROWS—SNAILS AND

TORTOISES—FACILE DUPES AND SERVILE
COPYISTS
“Not the wise find salvation.”—St. Paul.
One of the charms of the Christian religion is that the Foolish

confound the Wise. The Atheists are all brainy men. Myself, I hate a
brainy man. All the brainy men said it was impossible to have
aeroplanes. No brainy man ever sees that speed is armour. Directly
the brainy men got a chance they clapped masses of armour on the
“Hush-Hush” ships. They couldn’t understand speed being armour,
and said to themselves: “Didn’t she draw so little water she could
stand having weight put on her? Shove on armour!” and so bang
went the speed, and the “Hush-Hush” ships, whose fabulous beauty
was their forty shore-going miles an hour, were slowed down by
these brainy men. Don’t jockeys have to carry weights? Isn’t it called
handicapping? Isn’t it the object to beat the favourite—the real
winner? There really is comfort in the 27th verse of the 1st chapter of
i Corinthians, where the Foolish are wiser than the Wise.
What!—A battle cruiser called the “Furious” going 40 shore-
going miles an hour with 18-inch guns reaching 26 miles! “Take the
damn guns out and make it into an aeroplane ship!” (And I’m not
sure they could ever get the aeroplanes to land on her, owing to the
heat of the funnels causing what they call “Air pockets” above the
stern of the ship.)
Yes! and we still have ancient Admirals who believe in bows and
arrows. There’s a good deal to be said for bows and arrows. Our
ancestors insisted on all churchyards being planted with yew trees to
make bows. There you are! It’s a home product! Not like those damn
fools who get their oil from abroad! And I have now the
Memorandum with me delivered to me when I was Controller of the
Navy by a member of the Board of Admiralty desiring to build 16
sailing ships! Again, didn’t the Board of Admiralty issue a solemn
Board Minute that wood floated and iron sank? So what a damnable
thing to build iron ships! Wasn’t there another solemn Board Minute
that steam was damnable and fatal to the supremacy of the British
Navy? Haven’t we had Admirals writing very brainy articles in
magazines to prove that there was nothing like a tortoise? You could
stand on the tortoise’s back; you weren’t rushed by the tortoise,
whereas these “Hush-Hush” ships, they were flimsy, and speed was
worshipped as a god. One mighty man of valour (only “he was a
leper” as regards sea fighting) told me at his luncheon table that
when one of these “Hush-Hush” ships encountered at her full
strength of nearly a hundred thousand horse power a gale of wind in
a mountainous sea she was actually strained! It’s all really too lovely;
but of course the humour of it can’t be properly appreciated by the
ordinary shore-going person. Yes, the brainy men, as I said before,
crabbed the “Hush-Hush” ships; they couldn’t understand that speed
was armour when associated with big guns because the speed
enabled you to put your ship at such a distance that she couldn’t be
hit by the enemy, so it was the equivalent of impenetrable armour
although you had none of it, and you hit the enemy every round for
the simple reason that your guns reached him when his could not
reach you. Q.E.D. as Euclid says. What these splendid armour
bearers say is “Give me a strong ship which no silly ass of a Captain
can hurt.” Of course this implies that if it’s Buggins’s turn to be
Captain of a ship he gets it; it’s his turn, even if he is a silly ass. The
phase of mind they have is this: “None of your highly strung
racehorses for me, give me a good old cart-horse!” So we build huge
costly warships which will last a hundred years, but become obsolete
in five.
It all really is very funny—if it wasn’t disastrous and ruinous! And
they are such a motley crew, these discontented ones who come
together in John Bright’s cave of Adullam; and the Poor Dear Public
read an interview in a newspaper with some Commander Knowall;
and then a magazine article by Admiral Retrograde; and some old
“cup of tea” writes to The Times (wonderful paper The Times
—“Equal Opportunity for All”) and there you are! Lord Fisher is a
damned fool; and if he isn’t a damned fool he’s a maniac. Oh! very
well then, if he isn’t a maniac, then he’s a traitor. Wasn’t Sir Julian
Corbett very seriously asked if he (Sir John Fisher) hadn’t sold his
country to Germany? Sir Julian thought the report was exaggerated,
and that satisfied the Searcher after Truth. But I ask my listeners,
however should we get on without these people? How dull life would
be without their dialectical subtleties and “reasoned statements” (I
think they call them) and “considered judgments”!
My splendid dear old friend, who could hardly write his name, the
Chief Engineer of the first ironclad, the “Warrior,” told me, when I was
Gunnery Lieutenant of her in 1861, that he had arranged for his
monument at death being of “malleable” iron. No cast iron for him, he
said! It played you such pranks. So it is with these carbonised cranks
who wield the pen, actuated by the wrong kind of grey matter of their
brain, and, their tongues acidulated with lies, sway listening Senates
and control our wars. It requires a Mr. Disraeli to deal with these
victims of their own verbosity, who are the facile dupes of their
vacuous imaginations and the servile copyists of the Billingsgatean
line of argument!
CHAPTER VIII
NAVAL WAR STAFF AND ADMIRALTY CLERKS
“A wise old owl lived in an oak;

The more he heard, the less he spoke;
The less he spoke, the more he heard;
Why can’t we be like that wise old bird?”
Lord Haldane with his “art of clear thinking” elaborated the

Imperial War Staff to its present magnificent dimensions. If any man
wants a thing advertised, let him take it over there to the Secret
Department. Only Sir Arthur Wilson and myself, when I was First
Sea Lord of the Admiralty, knew the Naval plan of war. He was the
man, so head-and-shoulders above all his fellows, who in his time
was our undoubted, indeed our incomparable, Sea Leader. No one
touched him; and I am not sure that even now, though getting on for
Dandolo’s age, he would not still achieve old Dandolo’s great deeds.
What splendid lines they are from Byron:
“Oh for one hour of blind old Dandolo,

Th’ Octogenarian Chief, Byzantium’s Conquering Foe!”
I loved Sir Arthur Wilson’s reported reply to the maniacs who think
the Navy is the same as the Army. If it is not true it is ben trovato. He
said the Naval War Staff at the Admiralty consisted of himself—
assisted by every soul inside the Admiralty, and he added, “including
the charwomen”—they emptied the waste-paper baskets full of the
plans of the amateur strategists—Cabinet and otherwise.
No such rubbish has ever been talked as about the Navy War
Staff and also, in connexion therewith, the Admiralty clerks who are
supposed to have wrecked its first inception in the period long ago
when my great friend the late Admiral W. H. Hall was introduced into
the Admiralty to form a Department of Naval Intelligence. I give my
experience. I have been fifteen or more years in the Admiralty—
Director of Ordnance and Torpedoes, Controller of the Navy, Second
Sea Lord and First Sea Lord. Inside the Admiralty, for conducting
administrative work, the Civil Service clerk is incomparably superior
to the Naval Officer. The Naval Officer makes a very bad clerk. He
hasn’t been brought up to it. He can’t write a letter, and, as you can
see from my dictation, he is both verbose and diffuse. The Clerk is
terse and incisive.
I’ll go to instances. My Secretary, W. F. Nicholson, C.B., was
really just as capable of being First Sea Lord as I was, when
associated with my Naval Assistant. I often used to say that the First
Sea Lord was in commission, and that I was the facile dupe of these
two; and I was blessed with a succession of Naval Assistants who
knew so exactly their limitations as regards Admiralty work as
allowed the Admiralty machine to be, as was officially stated, the
best, most efficient, and most effective of all the Government
Departments of the State. I have a note of this, made by the highest
authority in the Civil Service. I would like here to name my Naval
Assistants, because they were out and away without precedent the
most able men in the Navy: Admirals Sir Reginald Bacon, Sir
Charles Madden, Sir Henry Oliver, Sir Horace Hood, Sir Charles de
Bartolomé, Captain Richmond and Captain Crease—I’ll back that set
of names against the world.
I was the originator of the Naval War College at Portsmouth—
that’s quite a different thing from an Imperial General Staff at the War
Office. The vulgar error of Lord Haldane and others, who are always
talking about “Clear thinking” and such-like twaddle, is that they do
not realise that the Army is so absolutely different from the Navy.
Every condition in them both is different. The Navy is always at war,
because it is always fighting winds and waves and fog. The Navy is
ready for an absolute instant blow; it has nothing to do with strategic
railways, lines of communication, or bridging rivers, or crossing
mountains, or the time of the year, when the Balkans may be
snowed under, and mountain passes may be impassable. No! the
ocean is limitless and unobstructed; and the fleet, each ship
manned, gunned, provisioned and fuelled, ready to fight within five
minutes. The Army not only has to mobilize, but—thank God! this
being an island—it has to be carried somewhere by the Navy, no
matter where it acts. I observe here that when Lord Kitchener went
to Australia to inaugurate the scheme of Defence, he forgot Australia
was an island. What Australia wants to make it impregnable is not
Conscription—it’s Submarines. However, I fancy Kitchener was sent
there to get him out of the way. They wanted me to go to Australia,
11
but I didn’t. Jellicoe has gone there. But then, Jellicoe hasn’t
always sufficient foresight; exempli gratia, he was persuaded to take
the deplorable step of giving up command of the Grand Fleet and
going as First Sea Lord of the Admiralty. Never was anything so
regrettable. I told the War Council that I am very glad Nelson never
went to the Admiralty, and that Nelson would have made an awful
hash of it. Nelson was a fighter, not an administrator and a snake
charmer—that’s what a First Sea Lord has to be.
Gross von Schwartzhoff told me on the sands of
Scheveningen:—
“Your Navy can strike in thirteen hours; Our Army can’t

under thirteen days.”
Frau von Pohl tells us the Germans did expect us so to strike, but
Nelson was in heaven (Dear Reader, look again at what Frau von
Pohl said, you’ll find it in Chapter III.). On one occasion I got into a
most unpleasant atmosphere. I arrived at a country house late at
night, and at breakfast in the morning, I not knowing who the guests
were, a Cabinet Minister enunciated the proposition that sea and
land war were both in principle and practice alike. At once getting up
from the breakfast table, in the heat of the moment, and not knowing
that distinguished military officers were there, I said, “Any silly ass
could be a General.” I graphically illustrated my meaning. I gave the
contrast between a sea and a land battle. The General is
somewhere behind the fighting line, or he ought to be. The Admiral
has got to be in the fighting line, or he ought to be. The Admiral is
indeed like the young Subaltern, he is often the first “Over the top.”
The General, at a telescopic distance from the battle scene and
surrounded by his Kitcheners, and his Ludendorffs, and his Gross
von Schwartzhoffs, has plenty of time for the “Clear thinking” à la
Lord Haldane; and then, acting on the advice of those surrounding
him, he takes his measures. So far as I can make out from the
Ludendorff extracts in The Times, Hindenburg, the Generalissimo,
was clearly not in it. He was “the silly ass”! Ludendorff did it all as
Chief of the Staff.
Now what’s the corresponding case at sea? The smoke of the
enemy, not even the tops of his funnels, can be seen on the horizon.
(I proved this myself with the great Mediterranean fleet divided into
two portions.) Within twenty minutes the action is decided! Realise
this—it takes some minutes for the Admiral to get his breeches on, to
get on deck and take in the situation; and it takes a good many more
minutes to deploy the Fleet from its Cruising Disposition into its
Fighting Disposition. In the Cruising Disposition his guns are
masked, one ship interfering with the fire of another. The Fleet for
Battle has to be so disposed that all the guns, or as many as
possible, can concentrate on one or a portion of the enemy’s fleet.
Each fleet pushes on at its utmost speed to meet the other, hoping to
catch the other undeployed. Every telescope in the fleet (and there
are myriads) is looking at the Admiral as he goes to the topmost and
best vantage spot on board his flag ship to see the enemy, and sees
him alone outlined against the sky—neither time nor room for a staff
around him, and if there were they’d say, “It’s not the Admiral who is
doing it,” and be demoralized accordingly—fatal to victory. In the
fleet the Admiral’s got to be like Nelson—“the personal touch” so that
“any silly ass can’t be an Admiral”; and the people of the Fleet watch
him with unutterable suspense to see what signal goes up to alter
the formation of the fleet—a formation on which depends Victory or
Defeat. So it was that Togo won that second Trafalgar; he did what is
technically known as “crossing the T,” which means he got the guns
of his fleet all to bear, all free to fire, while those of the enemy were
masked by his own ships. One by one Rozhdestvensky’s ships went
to the bottom, under the concerted action of concentrated fire. What
does it? Speed. And what actuates it? One mind, and one mind only.
Goschen was right (when First Lord of the Admiralty); he quoted that
old Athenian Admiral who, when asked what governed a sea battle,
replied, “Providence,” and then with emphasis he added: “and a
good Admiral.” Which reminds me too of Cromwell—a pious man,
we all know; when asked a somewhat similar question as to what
ruled the world, he replied “The Fear of the Lord,” and he added with
an emphasis equal to that of the Athenian Admiral—“And a
broomstick.” No one votes more for the Sermon on the Mount than I
do; but I say to a blithering fool “Begone!”
A Naval War Staff at the Admiralty is a very excellent
organisation for cutting out and arranging foreign newspaper
clippings in such an intelligent disposition as will enable the First Sea
Lord to take in at a glance who is likely amongst the foreigners to be
the biggest fool or the greatest poltroon, who will be opposed to his
own trusted and personally selected Nelson who commands the
British Fleet. The First Sea Lord and the Chief Admiral afloat have
got to be Siamese twins. And when the war comes, the Naval War
Staff at the Admiralty, listening every moment to the enemy’s
wireless messages (if he dare use it), enables the First Sea Lord to
let his twin at sea know exactly what is going on. He takes in the
wireless, and not necessarily the Admiral afloat, on account of the far
greater power of reception in a land installation as compared with
that on a ship. When you see that spider’s web of lines of wire on the
top of the Admiralty, then thank God this is more or less a free
country, as it got put up by a cloud of bluejackets before a rat was
smelt! An intercepted German Naval letter at the time gave me
personally great delight, for it truly divined that wireless was the
weapon of the strong Navy. For the development of the wireless has
been such that now you can get the direction of one who speaks and
go for him; so the German daren’t open his mouth. But if he does, of
course the message is in cypher; and it’s the elucidation of that
cypher which is one of the crowning glories of the Admiralty work in
the late war. In my time they never failed once in that elucidation.
Yes, wireless is the weapon of the strong. So also is the Submarine
—that is if they are sufficiently developed and diversified and
properly applied, but you must have quantities and multiplicity of
species.
What you want to do is to fight the enemy’s fleet, make him
come out from under the shelter of his forts, where his ships are
hiding like rabbits in a hole—put in the ferrets and out come the
rabbits, or they kill ’em where they are. Nelson blockading Toulon, as
he told the Lord Mayor of London in one of his most characteristic
letters, didn’t want to keep the French fleet in; he wanted them to
come out and fight. But he kept close in for fear they should evade
him in darkness or in fog.
But the mischief of a Naval War Staff is peculiar to the Navy. I
understand it is quite different in the Army—I don’t know. The
mischief to the Navy is that the very ablest of our Officers, both
young and old, get attracted by the brainy work and by the shore-
going appointment. I asked a splendid specimen once whatever
made him go in for being a Marine Officer. He said he wanted to be
with his wife! Well, it’s natural. I know a case of a Sea Officer whose
long absence caused his children not to recognise him when he
came home from China and, indeed, they were frightened of him.
The land is a shocking bad training ground for the sea. I once heard
one bluejacket say to another the reason he believed in the Bible
was that in heaven there is “no more sea.” I didn’t realise it at the
time, but I looked up “Revelations” and found it was so. A shallower
spirit observed: “Britannia rules the waves, but the mistake was she
didn’t rule them straight.” A very distinguished soldier who came to
see me when I was Port Admiral at Portsmouth said that the Army,
as compared with the Navy, was at a great disadvantage. In the
Army, or even in the country, he said, anyone who had handled a
rifle laid down the law as if he were a General; but the Navy, he said,
was “A huge mystery hedged in by sea-sickness.”
So far as the Navy is concerned, the tendency of these “Thinking
Establishments” on shore is to convert splendid Sea Officers into
very indifferent Clerks. The Admiralty is filled with Sea Officers now
who ought to be afloat; and the splendid civilian element—
incomparable in its talent and in its efficiency—is swamped. Before
the war, when I was First Sea Lord, when I left the Admiralty at 8
p.m., prior to some approaching Grand Manœuvres, I left it to my
friend Flint, one of the Higher Division Clerks, to mobilize the fleet by
a wireless message from the roof of the Admiralty; and the deciding
circumstances having arisen, he did it off his own bat at 2 a.m. A
weaker vessel, knowing of the telephone at my bedside, might have
rung me up; but Flint didn’t. Good old Flint! Always one of the Clerks
was on watch, all the year round, night and day; and that obtained in
the Admiralty long before any other Department adopted it.
Now for such work as I have described you don’t want sea art;
you want the Craven scholar, and I had him. A Sea Officer can never
be an efficient clerk—his life unfits him. He can’t be an orator; he’s
always had to hold his tongue. He can’t argue; he’s never been
allowed. Only a few great spirits like Nelson are gifted with the
splendid idiosyncrasy of insubordination; but it’s given to a few great
souls. I assure you that long study has convinced me that Nelson
was nothing if not insubordinate. This is hardly the place to describe
his magnificent lapses from discipline, which ever led to Victory. It’s
only due on my part, who have had more experience than anyone
living of the civilian clerks at the Admiralty, to vouch for the fact that
Sir Evan Macgregor, the ablest Secretary of the Admiralty since
Samuel Pepys, Sir Graham Greene, Sir Oswyn Murray, Sir Charles
Walker and my friends V. W. Baddeley, C.B., and J. W. S. Anderson,
C.B., W. G. Perrin, J. F. Phillips, and many others have done work
which has never been exceeded as regards its incomparable
efficiency. I can’t recall a single lapse.
The outcome of this expanded Naval War Staff beyond its real
requirements, such as I have indicated, and which were provided for
while I was First Sea Lord, was that a Chief of the Staff, in imitation
of him at the War Office, was planked into the Admiralty and
indirectly supplanted the First Sea Lord. I won’t enlarge on this
further. It’s many years before another war can possibly take place,
and it’s now a waste of educated labour to discuss it further. All I
would ask is for anyone to take up the last issue of the Navy List and
see the endless pages of Naval Officers at the Admiralty or holding
shore appointments. There has never been anything approaching
these numbers in all our Sea History! It is deplorable!
The Naval War College, which I established at Portsmouth, is
absolutely a different affair. There it can be arranged that all the
Officers go to sea daily and work as if with the fleet, with flotillas of
Destroyers that are there available in quantities. These Destroyers
would represent all the items of the fleet; and the formations of war
and the meetings of hostile fleets could be practised and so
constitute the Naval War College a real gem in war efficiency.
Aged 14. Midshipman.

H.M.S. “Highflyer,” China.
CHAPTER IX
RECAPITULATION OF DEEDS AND IDEAS
“Friends, Romans, Countrymen, lend me your ears!”
We have arranged that in this book you (to whom I am dictating)

are to insert a réchauffé of my fugitive writings and certain extracts from
the three bulky volumes of my letters to Lord Esher, which he has so
very kindly sent me.
All, then, that I have to say in this chapter will be a summing up of
all that is in my opinion worth saying, and you are going to be
responsible for the rest. My judgment is that the British Public will be
sick of it all long before you come to the end of your part. One can have
too much jam. Nor do you seem inclined to put in all the “bites.” For
instance, it was told King Edward, who warned me of what was being
said, that my moral character was shocking. No woman will ever
appear against me at the Day of Judgment. One dear friend of mine
attributed all his life’s disasters to kissing the wrong girl. I never even
did that. However, there is no credit in my morality and early piety. For I
ever had to work from 12 years old for my daily bread, and work hard,
so the Devil never had a “look in.” I love Dr. Watts, he is so practical.
“And Satan finds some mischief still.

For idle hands to do.”
Bishop Jeremy Taylor, who wrote that Classic, “Holy Living and
Dying,” who had a nagging wife who made him flee from home and
youthful lusts, said “That no idle rich healthy man could possibly go to
Heaven.” No doubt it is difficult for such a one. You will remember the
Saviour told us that the Camel getting through the eye of a needle is
more likely. Usually, earthly judgments on heavenly subjects are wrong.
Observe Mary Magdalene, and the most beautiful Collect for her Saint’s
Day which was in our First Prayer Book of 1540. This was later
expunged by the sacerdotal, pharisaic, self-righteous mandarins of that
period. The judgments of this world are worse than the judgments of
God. When David was offered three forms of punishment—Famine or
the Sword or Pestilence—he chose the pestilence, saying, “Let us now
fall into the hands of the Lord; for his mercies are great; and let me not
fall into the hand of man.” At the moment of making this note of which I
am speaking I am looking at two very beautiful old engravings I rescued
from the room here allotted to the Presbyterian Minister! One of them is
the “Woman Taken in Adultery” and the other is “Potiphar’s Wife”! My
host tells me it was a pure accident that these pictures came to be in
the Minister’s room; but such events happen to Saints. Wasn’t there
“The Scarlet Letter”—that wonderful book by Hawthorne?
I observe in passing how wonderfully well these Presbyterians do
preach. Our hosts have a beautiful Chapel in the house, and they have
got a delightful custom of selecting one from the Divines of Scotland to
spend the week-end here. Their sermons so exemplify what I keep on
impressing on you—that the printed word is a lifeless corpse. Can you
compare the man who reads a sermon to the man who listens to one
saturated with holiness and enthusiasm speaking out of the abundance
of the heart? No doubt there is tautology, but there’s conviction. Two
qualities rule the world—emotion and earnestness. I have said
elsewhere, with them you can move far more than mountains; you can
move multitudes. It’s the personality of the soul of man that has this
immortal influence. Printed and written stuff is but an inanimate picture
—a very fine picture sometimes, no doubt, but you get no aroma out of
a picture. Fancy seeing the Queen of Sheba herself, instead of only
reading of her in Solomon’s print! And those Almug trees—“And there
came no such Almug trees, nor were seen until this day.”
To a friend I was once adoring St. Peter (I love his impetuosity)—I
am illustrating how earthly judgments are so inferior to heavenly
wisdom. St. John, who was a very much younger man, out-ran Peter.
Up comes Peter, and dashes at once into the Sepulchre. Those men in
war who get there and then don’t do anything—Cui bono? A fleet
magnificent, five times bigger than the enemy, and takes no risks! A
man I heard of—his wife, separated from him, died at Florence. He was
on the Stock Exchange. They telegraphed, “Shall we cremate, embalm,
or bury?” “Do all three,” he replied, “take no risks!” Some of our great
warriors want the bird so arranged as to be able to put the salt on its
tail. But I was speaking of my praising St. Peter. What did my friend
retort (the judgment of this world, mind you!)? “Peter, Sir! he would be
turned out of every Club in London!” So he would! Thank God, we have
a God, so that when our turn comes we shall be forgiven much
because we loved much.
From this Christian homily I return to what I rather vainly hope is my
concluding interview.
Before beginning—one of my critics writes to The Times saying I
am not modest—I never said I was. However, next day, Sir Alfred
Yarrow mentions perhaps the most momentous thing I ever did—that is
the introduction of the Destroyer; and the day following Sir Marcus
Samuel writes that I am the God-father of Oil—and Oil is going to be
the fuel of the world. Sir George Beilby is going to turn coal into Oil. He
has done it. Thank God! we are going to have a smokeless England in
consequence, and no more fortified coaling stations and peripatetic
coal mines, or what coal mines were. And then, I was going to give
some more instances, but that’s enough “to point the moral and adorn
the tale.”
“Seekest Thou Great Things for Thyself?

Seek them not!” (The Prophet Jeremiah.)
You have given me a list of subjects which you think require
elucidation in regard to my past years—a résumé especially of the
incidents which claim peculiar notice between 1902 and 1910; and you
ask me to add thereto such episodes from the past as will enlighten the
reader as to how it came about that those big events between 1902
and 1910 were put in motion.
It’s a big order, in a life of some sixty years on actual service—with
but three weeks only unemployed, from the time of entry into the Navy
to the time of Admiral of the Fleet.
I begin by being heartfelt in my thankfulness to a benign
Providence for being capable yesterday, September 13th, 1919, of
enjoying suet pudding and treacle with a pleasure equal to that which I
quite well remember, of having suet pudding and treacle on July 4th,
1854, when I went on board H.M.S. “Victory,” 101 guns, the flagship at
Trafalgar of Admiral Lord Viscount Nelson. Yes! my thankfulness, I
hope, is equal to but hardly as wonderful as that of the almost toothless
old woman who, being commiserated with, replied: “Yes, I only ’as two
left; but thank God they meet!” So I say, to express the same
thankfulness with all my heart for the years that remain to me, though I
have all my teeth—or nearly all—notwithstanding that I have not had
even one single “thank you” for anything that I have done since King
Edward died. Nevertheless, I thank that same God as the old woman
thanked, Who don’t let a sparrow fall without a purpose and without
knowledge.
I have no doubt the slight has done me a lot of good!
I thought at the age of nineteen, when I was Acting Captain of
H.M.S. “Coromandel,” that I never could again be so great. Please look
at my picture then. It’s a very excellent one—rather pulled down at the
corners of the mouth even then. (The child is father to the man.) And
though now nearly as old as Dandolo I don’t feel any greater than at
19. Dandolo after an escapade at the Dardanelles similar to mine,
became conqueror of Byzantium at 80 years of age. And Justinian’s
two Generals, Belisarius and Narses, were over 70. Dolts don’t realise
that the brain improves while the body decays—provided of course that
the original brain is not that of a congenital idiot, or of an effete poltroon
who never will run risks.
“Risks and strife” are the bread of Life to a growing brain.
I beg the reader of this dictation to believe that, whatever he may
hear to the contrary (and he probably will), though swaggering as I did
just now at suet-puddening at 79 as efficiently as at nineteen, yet I do
daily realise what that ancient monk wrote in the year 800, when he
studied the words of Job—that “Man that is born of a woman hath but a
short time” compared to eternity, and death may be always near the
door; and no words are more beautiful in connection therewith than
when a parting friend at the moment of departure makes us say: “Teach
us who survive in this and other like daily spectacles of mortality to see
how frail and uncertain our own condition is.”
First of all in this Recapitulation comes back to me a prophecy I
ventured at that age of 19 I have just mentioned—that the next great
war that we should have at sea would be a war of young men. And how
beautifully this is illustrated by the letter received only a few days ago
from that boy in Russia (see Chapter IV) where two battleships were
sent to the bottom and the British sailors in command were only
Lieutenants. And in passing one cannot help paying a tribute to the
Subalterns on shore. General Sir Henry Rawlinson said lately: “Those
who really won the war were the young Company Leaders and the
Subalterns,” and pathetic was the usual Gazette notice of those killed:
“Second Lieutenants unless otherwise mentioned.”
There was little “otherwise!” So has it been in the Navy, at Zeebrugge
and elsewhere.
There is, however, a very splendid exception—when all hands, old
and young, went to the bottom; and that is in the magnificent Merchant
Navy of the British Nation. Seven million tons sank under these men,
and the record of so many I’ve seen who were saved was: “Three times
torpedoed.” And remember! for them no Peerage or Westminster
Abbey. They didn’t even get paid for the clothes they lost, and their pay
stopped the day the ship was sunk. Except in the rare cases where the
shipowner was the soul of generosity, like my friend Mr. Petersen, who
paid his men six months or a year to do nothing after such a
catastrophe. But we go with Mr. Havelock Wilson: “We hope to change
all that.” For who is going to deny, when we all stand up for them, that
the Merchant Navy shall be incorporated in the Navy of the Nation and
with all the rights and money and rank and uniform and widows’
pensions and pensions in old age? All this has to come; and I am Mr.
Havelock Wilson’s colleague in that matter, as he was mine in that
wonderful feeding and clothing of our thousands of British Merchant
sailor prisoners, who didn’t, for some damned red tape reason, come
within the scope of the millions of money in that enormous Prince of
Wales’s Fund, and the Red Cross.
Somebody will have to be a martyr, perhaps it’s me. And I expect I
am going to be burnt at the stake for saying these things; but in those
immortal words of the past “I shall light the candle!” Isn’t it just too
lovely—when Bishop Latimer, as the flames shot up around him at the
stake in Oxford in a.d. 1555, cried to his brother Bishop, equally
burning:
“Play the man, Master Ridley! We shall this day light such a
candle by God’s Grace in England as I trust shall never be put out.”
So may it be in our being burnt for the sake of the great Merchant
Navy that saved our country!
* * * * *
As regards the years 1902 to 1910, the first conceptions of these
great changes stole upon me when I perceived in that great Fleet in the
Mediterranean how vague were the views as to fighting essentials. For
instance, in one of the lectures to the Mediterranean Fleet Officers I set
forth a case of so dealing with a hostile fleet that we should ourselves
first of all deliberately and in cold blood sacrifice several of our fastest
cruisers. Why?
To delay the flying enemy by the wounding of his hindermost ships.
Possibly a ruthless German Admiral might leave a “Blücher” to her fate;
but not so our then probable and chivalrous foe! The most shocking
description I have ever read of the horrors of war was that detailed by
one of the crew of the “Blücher” as he describes Beatty’s salvoes
gradually approaching the “Blücher” and falling near in the water, and
then the hell when these salvoes arrived, immediately extinguishing the
electric light installation, till all below between decks was pitchy
darkness only lighted up by the bursting shells as they penetrated and
massacred the crew literally by hundreds, who, huddled up together in
the “Blücher’s” last moments, were hoping behind the thickest armour
to escape destruction.
I saw that the plan of sacrificing vessels in the pursuit of an enemy
seemed a new feature to my hearers; and yet it was as old as the hills.
And another “eye-opener” I had—in the inability to realise so obvious a
fact as, alas! was somewhat the case in the North Sea recently—that
you need not be afraid of a mine field; for where the enemy goes you
can go, if you keep in his wake, that is. In close regard with this matter,
I am an apostle of “End-on Fire,” for to my mind broadside fire is
peculiarly stupid. To be obliged to delay your pursuit by turning even
one atom from your straight course on to a flying enemy is to me being
the acme of an ass. And, strange to say, in connection with this I, only
yesterday, September 13th, 1919, got a letter from Admiral Weymouth
—a most excellent letter, delightfully elaborating with exceptional
acuteness this very idea, which came along so long ago as 1900, when
the first thought of the “Dreadnought” came into my brain, when I was
discussing with my excellent friend, Mr. Gard, Chief Constructor of
Malta Dockyard, the vision of the “Dreadnought.”
I greatly enjoyed years ago overhearing a lady describe to another
lady, when crossing over to Ryde, a passing Ryde passenger steamer
(just built and differing very greatly from the one we were on board of)
as a Battleship. And she wasn’t far out as to what a battleship should
be. The enterprise of the Ryde Steam Packet Company had just
produced that vessel, which went just as fast astern as she did ahead.
In fact, she had no stern. There was a bow at each end and a rudder at
each end and screws at each end; so they never had any bother to turn
round. Now when you go to Boulogne or Folkestone, I don’t know how
much time you don’t waste fooling around to go in stern first, so as to
be able to come out the right way; and having escaped sea-sickness so
far, I myself have found that the last straw. Let us hope every ship now
built after this Chapter will be a “Double-Ender.” But in this world you
are a lunatic if you go too fast.
Take now the submarines. They began by diving head first to get
below water; and in the beginning some stuck their noses in the mud
and never came up again, and in the shallow waters of the North Sea
this limited the dimension of the submarine. But now there’s no more
diving. A lunatic hit by accident on the idea of sinking the ship
horizontally; so there is no more bother about the metricentric
problems, and all the vagaries of Stabilities. No limit to size!
This sort of consideration brought into one’s mind that a great
“Education” was wanted; and that we wanted “Machinery Education,”
both with officers and men; and also that the education should be the
education of common sense. My full idea of Osborne was, alas!
emasculated by the schoolmasters of the Nation; but it is yet going to

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“Seekest Thou Great Things for Thyself?

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