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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
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
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
Sheketha R. Hauser
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
Simon N. Katner
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
Kabirullah Lutfy
Department of Pharmaceutical Sciences,College of Pharmacy, Western University of Health
Sciences, Pomona, California, USA
William J. McBride
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
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
Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational
Research in Psychiatry, Denver, Colorado, USA
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 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
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
xi
xii Preface
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
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
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
1. INTRODUCTION
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]
9
10 Wei-Lun Sun et al.
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.
12 Wei-Lun Sun et al.
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
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects 15
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
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects 17
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
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects 19
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
Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects 21
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:—
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.
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.”
“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