Table Of ContentHandbook of Experimental Pharmacology 248
Kathleen A. Grant · David M. Lovinger
Editors
The
Neuropharmacology
of Alcohol
Handbook of Experimental Pharmacology
Volume 248
Editor-in-Chief
J.E.Barrett,Philadelphia
EditorialBoard
V.Flockerzi,Homburg
M.A.Frohman,StonyBrook
P.Geppetti,Florence
F.B.Hofmann,Mu¨nchen
M.C.Michel,Mainz
C.P.Page,London
W.Rosenthal,Jena
K.Wang,Qingdao
Moreinformationaboutthisseriesathttp://www.springer.com/series/164
Kathleen A. Grant (cid:129) David M. Lovinger
Editors
The Neuropharmacology
of Alcohol
Editors
KathleenA.Grant DavidM.Lovinger
DepartmentofBehavioralNeuroscience LaboratoryforIntegrativeNeuroscience
OregonHealth&ScienceUniversity NationalInstitutesofHealth
Portland,Oregon Bethesda,Maryland
USA USA
ISSN0171-2004 ISSN1865-0325 (electronic)
HandbookofExperimentalPharmacology
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Preface
ThisvolumeoftheHandbookofExperimentalPharmacology,“TheNeuropharma-
cology of Alcohol,” was an exciting and challenging editorial effort. Our under-
standingofthepharmacologyofthesimpleorganiccompoundethanol(referredto
asalcoholinthisvolume)hasflourishedinthepast40years.Thisvolumefocuses
on the alcohol’s central nervous system (CNS) effects and its behavioral pharma-
cologyrelatedtoabusepotential.Manyofalcohol’sinitialactionsonbraintargets
thatwereidentifiedinthelate1980sandearly1990shavestoodthetestoftimeand
technologicaldevelopments;however,farmoredepthandbreadthhasbeenadded
toourunderstandingofalcohol’spharmacologyinthepasttwodecades.Withthis
realityinmind,itwasdifficulttoassemble20ofthemostimportanttopicsforthis
volume.Thereareregrettablegapsintheneurotransmittersystemscoveredandthe
extent of phenotypic outcomes related to chronic alcohol exposure. Nevertheless,
representativemechanismsofalcohol’sneuropharmacologyarepresented,wehope
to the satisfaction of the interested reader. We have organized the volume by
generalemphasisonneurotransmittersystems,neuropeptides,andionchannelsas
wellasnewertopicsincludingneuroimmunesystems,genomicmechanisms,anda
currentreviewofpreclinicalanimalandhumanclinicalstudiesofpharmacotherapy
developments.
The gamma-aminobutyric acid (GABA) and glutamatergic systems were argu-
ablythefirstreceptorsystemsfoundtohavethesensitivityandselectivityexpected
forreceptor-mediatedalcoholoutcomes.Theseaminoacidneurotransmitterscon-
tinue to be the most studied in alcohol neuropharmacology. Furthermore, as the
fieldcontinuestodefinebothpre-andpostsynapticmechanisms,neuroanatomical
specificity and GABA–glutamate interactions are becoming prominent
explanations of alcohol’s behavioral effects. Therefore, we highlight these recent
developments with five chapters. A general overview of GABA -gated chloride
A
channelsasatargetofalcoholisprovidedbyChandler,Overton,Ruedi-Bettschen,
and Platt. This is complemented by a chapter by Lovinger on presynaptic release
mechanisms implicated in G-protein coupled receptor actions on GABAeric
synapses. Notable is the range of brain areas where alcohol’s effects appear to
alter synaptic efficacy and the potential cross talk with other drugs of abuse. The
importance of alcohol’s interaction with neurosteroid GABA networks is
A
reviewed by Finn and Jimenez. The chapter by Cuzon Carlson emphasizes the
v
vi Preface
striatumasabrainareawherealcoholalterstheexcitatoryandinhibitorybalanceof
GABAergic and glutamatergic transmission. The contribution from Rossi and
Richardson also emphasizes anatomical specificity, in this case recent data
implicating the cerebellum as a site for alcohol’s abuse liability through effects
on GABA channels. Next, the chapter by Hopf and Mangieri focuses on AMPA
A
glutamate receptor (AMPAR)-mediated effects of alcohol, where advances in
selective antagonists have helped illuminate subunit-specific aspects of ethanol
sensitivity. Finally, another ionotropic receptor system that is prominent in the
abuse aspects of alcohol is the nicotinic acetylcholine receptors. The chapter by
Klenowski and Tapper provides an excellent overview of separate and common
targets of alcohol and nicotine, particularly in the mesolimbic pathways with an
emphasisontheapparentsynergisticeffectsleadingtocomorbidaddiction.
We selected two monoaminergic systems to highlight in this volume. The
dopaminergic system has long occupied a predominant place in
neuropharmacologicalaspectsofaddictivedrugs,includingalcohol.Inthereview
bySiciliano,Karkhanis,Holleran,Melchior,andJones,dopaminergicmechanisms
that are determined under similar experimental conditions and translate across
speciesareemphasizedasawayofdisentanglingacomplexliterature.Inaddition
to dopamine, the monoamine norepinephrine (NE) is also implicated in alcohol
reinforcementmechanisms,particularlyinrelationtoarousal,emotionalregulation,
andstressprocesses.ThereviewbyVazey,denHartog,andMoormanemphasizes
recent findings and provides new directions for better understanding how the NE
systemismaladaptivelyalteredbyalcohol.
Theinteractionofalcoholandvoltage-dependentionchannelsisrepresentedby
onereview oncalciumchannelsand two reviews on potassiumchannels.As with
the GABA and glutamate systems, alcohol research has a relatively long history
with voltage-sensitive calcium channels, particularly with neurophysiological
disturbances such as tremors and seizures. The review by N’Gouemo takes this
complexsubjectandemphasizestheroleofneuronalhomeostasisanditsdisruption
by chronic alcohol exposure. The large conductance voltage- and calcium-depen-
dentpotassiumchannel(BK)andchannelinteractionswithalcoholarereviewedby
Dopico,Bukiya,andBettinger,withanemphasisonadaptationsunderlyingtoler-
ance to alcohol. Comparatively new to the neuropharmacology of alcohol is
disruptions in intrinsic neuronal excitability by alcohol-induced adaptations in
small-conductance calcium-activated (SK), voltage-dependent, and G-protein-
activated inwardly rectifying potassium channels. These potassium channel
mechanismsrelatedtoalcoholandimpairedneuronalfiringarereviewedelegantly
byCannady,Rinker,Nimitvilai,Woodward,andMulholland.
The aspect of alcohol’s pharmacology that is receiving renewed attention is
alcohol-induced neuroinflammation involving immune signaling molecules. For
thissubject,wehaveincludedthreereviews.ThefirstreviewbyKim,McCullough,
Poulson, Sanz-Garcia, Sheehan, Stravitsky, and Nagy provides the important per-
spective of how alcohol interferes with the hepatic immune system. The second
reviewbyColemanandCrewsfocusesoninnateimmunesignalsasmodulatorsof
neurocircuitry involved in the addiction to alcohol and possibilities for new
Preface vii
treatmentapproaches.ThisisfollowedbyareviewfromRoberto,Patel,andBajo
ontheeffectsofkeycytokinesonmolecularpropertiesandsynaptictransmission,
particularly in the extended amygdala and hippocampus. From this collection of
reviews,itisclearthattargetsandpharmacotherapiesthatemergefromthecancer
biologyfieldcanberepurposedtoaddresswidespreadorgandysfunction,including
neuroinflammation,associatedwithheavyalcoholdrinking.
The final set of reviews on neuropharmacological mechanisms of alcohol
includesareview bySchreiberandGilpinontheextended amygdalaandcortico-
tropin-releasing factor as a basic allosteric mechanism propagating excessive
drinking. This is followed by a review of alcohol’s interaction with dynorphin
and orexin neuropeptide systems by Anderson, Moorman, and Becker. These two
systems are closely interrelated and underlie homeostatic mechanisms that likely
become dysfunctional under chronic alcohol exposure, leading to changes in
motivationalstatesthatincreasefurtheralcoholconsumption.Thefinalmechanistic
review is by Savarese and Lasek on genomic factors induced by alcohol that can
change signal transduction mechanism and gene expression integral to long-term
adaptations in chronic alcohol drinking. The emergence of new pharmacological
agents that target transcriptional factors promises new directions in alcohol
pharmacotherapy.
We conclude this volume with highly informative, comprehensive, and timely
reviews on the practical side of alcohol neuropharmacology: approaches and
outcomes of preclinical and human clinical studies of alcohol
pharmacotherapeutics. The review by Egli provides background on the role of
animal models as sensitive and efficient for rapid screening, but emphasizes that
better translational approaches are needed to have potential pharmacotherapies
retain efficacy in the arena of human outpatient treatment. The final review, by
Litten,Falk,Ryan,Fertig,andLeggio,providesahistoryandcurrentemphasison
developingefficaciousandsafecompoundsfortreatingalcoholusedisorder.
Wesincerelybelievethatthisvolumeprovidesavaluableandinstructiveview
onthestateoftheartinourunderstandingofthedepthandbreadthofpast,present,
andfutureneuropharmacologicalresearchonalcohol.Itremainsawonderthatthis
simple 2-carbon alcohol can result in such complex neuropharmacology. There is
nodoubtthataswelearnmoreaboutreceptorsystems,theircircuitry,co-modula-
tion, adaptive capacities, and underlying functions, we will learn more about the
complex processes that result in alcohol use disorders. We hope you find this
volumehelpfulindefiningimportantdirectionsofthisexcitingresearch.
Portland,OR,USA KathleenA.Grant
Bethesda,MD,USA DavidM.Lovinger
Contents
PartI NeurotransmitterSystems
GABA ReceptorSubtypeMechanismsandtheAbuse-Related
A
EffectsofEthanol:GeneticandPharmacologicalEvidence. . . . . . . . . . 3
CassieM.Chandler,JohnS.Overton,DanielaRüedi-Bettschen,
andDonnaM.Platt
PresynapticEthanolActions:PotentialRolesinEthanolSeeking. . . . . 29
DavidM.Lovinger
DynamicAdaptationinNeurosteroidNetworksinResponse
toAlcohol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
DeborahA.FinnandVanessaA.Jimenez
GABAandGlutamateSynapticCoadaptationstoChronicEthanol
intheStriatum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
VerginiaC.CuzonCarlson
TheCerebellarGABA RSystemasaPotentialTarget
A
forTreatingAlcoholUseDisorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
DavidJ.RossiandBenD.Richardson
DoAlcohol-RelatedAMPA-TypeGlutamateReceptorAdaptations
PromoteIntake?. .. . . . . .. . . . . . .. . . . . . .. . . . . .. . . . . . .. . . . . . .. 157
F.WoodwardHopfandReginaA.Mangieri
Molecular,Neuronal,andBehavioralEffectsofEthanolandNicotine
Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
PaulM.KlenowskiandAndrewR.Tapper
Cross-SpeciesAlterationsinSynapticDopamineRegulation
AfterChronicAlcoholExposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
CodyA.Siciliano,AnushreeN.Karkhanis,KatherineM.Holleran,
JamesR.Melchior,andSaraR.Jones
CentralNoradrenergicInteractionswithAlcoholandRegulation
ofAlcohol-RelatedBehaviors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
ElenaM.Vazey,CarolinaR.denHartog,andDavidE.Moorman
ix
x Contents
PartII IonChannels
Voltage-SensitiveCalciumChannelsintheBrain:Relevance
toAlcoholIntoxicationandWithdrawal. . . . . . . . . . . . . . . . . . . . . . . . 263
ProsperN’Gouemo
Voltage-SensitivePotassiumChannelsoftheBKType
andTheirCodingGenesAreAlcoholTargetsinNeurons. . . . . . . . . . . 281
AlexM.Dopico,AnnaN.Bukiya,andJillC.Bettinger
ChronicAlcohol,IntrinsicExcitability,andPotassiumChannels:
NeuroadaptationsandDrinkingBehavior. . . . . . . . . . . . . . . . . . . . . . . 311
ReginaldCannady,JenniferA.Rinker,SudaratNimitvilai,
JohnJ.Woodward,andPatrickJ.Mulholland
PartIII NeuroimmuneSystem
HepaticImmuneSystem:AdaptationstoAlcohol. . . . . . . . . . . . . . . . . 347
AdamKim,RebeccaL.McCullough,KyleL.Poulsen,CarlosSanz-Garcia,
MeganSheehan,AbramB.Stavitsky,andLauraE.Nagy
InnateImmuneSignalingandAlcoholUseDisorders. . . . . . . . . . . . . . 369
LeonG.Coleman,Jr.andFultonT.Crews
EthanolandCytokinesintheCentralNervousSystem. . . . . . . . . . . . . 397
MarisaRoberto,ReeshaR.Patel,andMichalBajo
PartIV NeuropeptidesandGenomics
Corticotropin-ReleasingFactor(CRF)Neurocircuitry
andNeuropharmacologyinAlcoholDrinking. . . . . . . . . . . . . . . . . . . . 435
AllysonL.SchreiberandNicholasW.Gilpin
ContributionofDynorphinandOrexinNeuropeptideSystems
totheMotivationalEffectsofAlcohol. . . . . . . . . . . . . . . . . . . . . . . . . . 473
RachelI.Anderson,DavidE.Moorman,andHowardC.Becker
TranscriptionalRegulatorsasTargetsforAlcohol
Pharmacotherapies. . . .. . . .. . . . .. . . .. . . . .. . . . .. . . .. . . . .. . . .. 505
AntoniaM.SavareseandAmyW.Lasek
PartV Pharmacotherapy
AdvancingPharmacotherapyDevelopmentfromPreclinicalAnimal
Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
MarkEgli
AdvancesinPharmacotherapyDevelopment:HumanClinical
Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
RayeZ.Litten,DanielE.Falk,MeganL.Ryan,JoanneFertig,
andLorenzoLeggio
