Neurobiology of Alcohol and the Brain

357 Pages·2020·38.969 MB·English

by  Ashok K. Singh

Neurobiology of Alcohol
and the Brain
Neurobiology of Alcohol
and the Brain
Ashok Singh
Associate Professor, Veterinary Population
Medicine, University of Minnesota, St. Paul,
MN, USA
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Preface
Alcoholistheanesthesiabywhichweenduretheoperationoflife.
G.BernardShaw(1932)
Shaw’sviewof1932societymayberelevanttopresentsocietiesbecausemillionsof
peoplearoundtheworlddrinkalcoholicbeveragestocopewiththestressofmodern
lifestyle.Althoughmoderatealcoholdrinkingmayhavesomerelaxingandeuphoric
effects,uncontrolleddrinkingexacerbatestheproblemsassociatedwithalcoholabuse
thatareincreasinginnumberandintensityintheUnitedStatesandaroundtheworld.
Almost 30 million people in the United States are unable to control their alcohol
intake,aremarkable50percentincreasefrom2003.Adolescentsandthose65years
or older showed the largest increase in alcohol use disorder. In addition, approxi-
mately17%ofmenand8%ofwomenmaydevelopdependence onalcoholintheir
lifetime, adding substantial cost to society. Thus, alcohol abuse and ensuing health
consequenceshavedevastatedmanylivesandaffectedpatients,families,andsociety.
It is important to understand that “alcohol” is a generic term used to represent a
group of substances such as methanol (CH OH), ethanol (CH CH OH), propanol
3 3 2
(CH CH CH OH), and isopropanol (CH CH(OH)CH ) that are chemically similar
3 2 2 3 3
but pharmacologically different. Ethanol is usually found in alcoholic beverages.
The othertypesofalcohol are notmeant tobeconsumed,butthey may beingested
accidentallyorintentionally,resultinginserioustoxiceffectsincluding,butnotlim-
ited to,blindness, brain damage, and severe ketosis/acidosis.
Althoughresponsibleethanol(alsoreferredtoasalcoholinthisbook)drinkinghas
transient pleasant/beneficial effects, uncontrolled drinking may lead to addiction
whenabstinencecausessevereadverseeffectsincludingseizuresand,insomecases,
death.Thewithdrawalsymptomssubsideupontheresumptionofalcoholintake.As
alcoholiswidely available globally, the vulnerable population such aschildren, the
elderly,andthosesufferingfromvariousdiseasesmaybeseverelyaffectedbyalcohol
drinkingandmaysufferfromitstoxiceffects.Oneoftheaimsofthisbookistostudy
the effects of alcohol drinking in patients suffering from mental disorders such as
bipolar disorder, schizophrenia, and PTSD.
Mixingalcoholwithotherdrugshasbecomeanemergingtrend,exacerbatingpub-
lichealthconcerns.Mixingalcoholwithotherdrugssuchasopioidsmaysynergisti-
callyaugmenttheseriousnessoftheadverseeffectssuchasthewithdrawalsymptoms,
cardiovascular disorders, liver damage, reproductive abnormalities, and behavioral
abnormalities.Despitetheseriousnessofthesituation,possiblemechanismsunderly-
ingaddictionandthewithdrawalsymptomsarenotyetunderstood.Thishasbeenone
of the keyhindrances indeveloping effective treatment.
viii Preface
The National Institutes of Health (NIH), recognizing the seriousness of alcohol
abuse,hasinvestedmillionsofdollarsintheareaofaddiction, resulting inprolifer-
ation research articles describing novel mechanistic and therapeutic approaches (a
search conducted using “drug abuse” resulted in over 700,000 research papers and
over200,000reviewarticlespublishedwithinthespanofthelast65years).However,
eachresearchpaperdealswithanarrowareaofdrugabuseandaddiction.Therefore,
there is an urgent need to collate the published information and propose a unified
hypothesis for mechanisms of alcohol addiction and interactions that will facilitate
the development ofnovel treatmentapproaches.
Theoverallaimofthisbookistodiscussthemechanismsofpharmacologicaland
toxicologicaleffectsofacuteandchronicalcoholexposure,interactionofalcoholwith
otherdrugs,alcohol–mentaldisordercomorbidity,currentlyusedmethods,andappli-
cationofnanoparticlesinthedevelopmentofnoveltherapies.Thebookconsistsofsix
chapters:
Chapter1:JourneyFromResponsibleAlcoholDrinkingtoAlcoholism.
Chapter2:InteractionofAlcoholWithDrugsofAbuseandMedicines.
Chapter3:MentalHealthandAlcoholUseDisorderComorbidity.
Chapter4:TraditionalTreatmentStrategiesforAlcoholismandtheWithdrawalSymptoms.
Chapter5:NovelNanoparticle-BasedTreatmentApproaches.
Chapter6:Conclusions.
Theinformationpresentedinthisbookisbasedonacomprehensiveliteraturesearch
describedbyGonza´lez-Castroetal.[1]andshowninFig.1.Theinclusionandexclu-
sion criteria were established as described by Singh [2]. Initial searches were per-
formed on the following literature databases: MEDLINE, Google Scholar, and
Fig.1 (A)Flowdiagramusedfortheliteraturesearchforeachchapter.(B)Atypicalsearch
conductedforalcoholmetabolismresearch[2].
Preface ix
Web of Science using search words either alone or tagged with qualifying words.
Some examples are listed below:
1. Alcoholdrinkingtaggedwithstatistics,social,abnormal,gender,age,tolerance,addiction,
bloodalcoholconcentrations(BAC),etc.
2. AlcoholdehydrogenasesorADHtaggedwithgeneticpolymorphism,alcoholism,tolerance,
demographic (Asians, Indians, Caucasians, Africans, etc.), acetaldehyde, acetaldehyde
dehydrogenase—ALDH,bloodalcoholconcentration—BAC,etc.
3. Alcoholism or alcohol addiction tagged with uncontrolled drinking, statistics, demo-
graphics,tolerance,brainpathways(dopamine,opiates,GABA,glutamate,NMDA,seroto-
nin,adenosine),brainregions,abstinence,withdrawalsyndrome,etc.
Othersearchwordsweretolerance,dependence,craving,genomics,epigenetics,and
hangover. The initial results were subjected to certain inclusion and exclusion
criteria[2].
References
[1] T.B.Gonza´lez-Castro,I.Jua´rez-Rojop,M.L.Lo´pez-Narva´ez,etal.,AssociationofTPH-1
and TPH-2 gene polymorphisms with suicidal behavior: a systematic review and meta-
analysis.BMCPsychiatry14(2014)196,https://doi.org/10.1186/1471-244X-14-196.
[2] A.K.Singh,Alcohol,alcoholismandthewithdrawalsymptomsI.Causesandmechanisms,
Arch.Addict.Rehabil.1(1)(2017)31–50.
1
Journey from responsible alcohol
drinking to alcoholism
1 Scope of alcohol abuse
Ethanol(also referred toas alcohol inthis book) is the principalpsychoactive com-
ponentofalcoholicdrinks[1].Unliketheillegalpsychoactivedrugssuchascocaine,
amphetamine,andLSD,alcoholicbeveragesarelegalandsociallyacceptedinmany
partsoftheworld(Europe>America>AsiaandAfrica>theMiddleEast,andother
countrieswherealcoholisbanned)(Fig.1.1,[2]).IntheUnitedStates,heavydrinking
ismorecommonin(i)MiddleAtlanticStatesorNewEngland,(ii)morehighlyurban-
ized areas, and (iii) certain national or ethnic origins. Although responsible alcohol
drinking induces euphoria and provides relaxation with some medicinal benefits,
chronicdrinkingisassociatedwiththedevelopmentofaddiction,aconditioninwhich
alcoholabstinenceresultsinseverewithdrawalsymptomsthatsubsideuponresump-
tionofalcoholconsumption[3,4].Accordingtoa2014WHOreport,about7%ofthe
globalpopulation(approximately500million)and10%oftheUSpopulationsuffer
fromalcoholismanddrugaddiction.Unfortunately,intheUnitedStates,anestimated
88,000peopledieperyearduetoalcoholabuse,andonlyabout11%ofthoseaddicted
toalcoholreceivetreatmentfortheirabusedisorder[5].Thissuggestsalackofacom-
prehensivepreventionstrategytocombataddiction,possiblybecausethepublicmay
not understand its seriousness toindividuals and society.
Considerableindividualdifferenceshavebeenreportedin(i)alcoholconsumption
and ensuing intoxication and (ii) development of addiction (defined as a cluster of
behavioral, cognitive, and physiological abnormalities as well as the development
ofphysicalwithdrawalstateuponabstinence)[6].Studieshaveshownthatonlyabout
6% (9.8 million, 5.3 million women and 623,000 adolescents aged 12–17 years) of
alcohol drinkers in the United States aged 18 and above developed alcoholism and
otheralcohol-relateddisorders(NIAAA2008).Thisisbecauseonlygeneticallypre-
disposed people experiencing socioenvironmental cues develop an addiction in
responsetopersistentdrinking[2,3].Althoughpossiblecausesfortheglobalandindi-
vidualdifferencesinalcoholuseandrateofaddictionarenotyetknown,akeyroleof
genetic predisposition, socioenvironmental factors (SEFs), and characteristics and
formulation of the drug have been implicated (Fig. 1.2)[1].
Manyriskfactors(definedasthefactorsthatincreaseaperson’schancesofdevel-
opingadisease)suchasage,sex,hormonalstatus,impulsivity,sweet-liking,novelty,
reactivity, exercise, environmental impoverishment, mental disorders, aggression,
stress,andreliefofwithdrawalsymptomsincreasevulnerabilitytoalcoholandother
drugabuse[7–10].Often,differentriskfactorsinteractwitheachother,resultinginan
additivevulnerability,thusincreasingthepredictabilitythatdrugabusewilloccur.In
additiontotheriskfactors,comorbidityisanotherfactorincreasingthevulnerability
NeurobiologyofAlcoholandtheBrain.https://doi.org/10.1016/B978-0-12-819680-9.00001-9
©2021ElsevierInc.Allrightsreserved.
2 NeurobiologyofAlcoholandtheBrain
Fig.1.1 Globalalcoholdrinkingstatistics.
Age, Mood, Body style,
Experience, Sex ratio,
Personality, Food Intake,
Expectations
Person
Drug effects
Drug Socio-environment
Drug structure, Purity and Post-drug activities, Place
Strength, Formulation, Company, Occasion,
Poly-drug exposure, Supervision, Pollution,
Exposure duration. Social constrains
Fig.1.2 Thedegreeofresponsecausedbydrugusedependsonmanyfactorsthatrelate
theinformationaboutthepersontakingthedrug.
to alcohol. Comorbidity is the presence of two or more illnesses, simultaneously or
sequentially,inthesameperson.Fig.1.3showstheriskfactorsforalcoholdrinking
and alcoholism andensuingcomorbid diseases.
Alcoholabuse,inadditiontocausingaversivereinforcementandaddiction,isalso
animportantriskfactorformanydiseasessuchascancer,atrialfibrillation,andhyper-
tension[11–17].IntheUnitedStatesalone,about17millionpeopleofdifferentage
groups suffer from alcohol-related disorders [18]. This suggests that alcohol abuse
mayexerttremendouseconomicconsequencesnotonlyforthedrinkingindividuals
but also onthe society at large [19].
Although most people, under normal circumstances, drink alcohol responsibly
(limitingtoone’soncelimit,notgettingdrunk,notlettingalcoholcontrolone’slife
orrelationships,etc.),certainsocioeconomiccuessuchasstress,dysfunctionalfamily
environment,qualityofemotionalandsocialsupport,riskyhabits,andlearnedbehav-
iormayaugmentalcoholdrinking,resultinginpersistenthigherbloodalcoholconcen-
trations (BACs) [20–22]. Continued alcohol drinking results in the development of
Journeyfromresponsiblealcoholdrinkingtoalcoholism 3
Fig.1.3 Alcoholismriskfactorsandcomorbidity.
tolerance after which the consumption of a constant amount of alcohol produces a
lesser effect and therefore increasing amounts of alcohol are required to produce
thesameeffect[23,24].Tolerancemayencouragealcoholconsumption,contributing
to alcohol dependence (alcoholism) in genetically predisposed people and systemic
damageinallheavydrinkers.Inalcoholics,abstinenceinducesthewithdrawalsymp-
tomswithvaryingseverity.Theresumptionofalcoholconsumptionrapidlyreduces
thewithdrawalsymptoms.Therefore,alcoholicsdrinkalcoholnotforitspositiverein-
forcementsbutforavoidingitsnegativereinforcements.Ingeneral,thepathwayfrom
responsible use tosubstance abuse includesthe following:
l TheRewardStage:Thissteprepresentsasubject’sinitialintroductiontoalcoholordrugsuse
either due to peer pressure or due to the familial circumstances. If the initial exposure is
pleasant,thenalcoholordrugusemayexpandinasocialcontextwithahigherfrequency.
l DevelopmentofTolerance:Consistentuseresultsinthedevelopmentoftolerance,charac-
terizedbyaperpetualincreaseinsubstanceuseforthedesiredoutcome.Itiswellestablished
thatthealcohol-oropioid-inducedpleasureeffectsalsoinitiateanegativeaffectivestatethat
isamotivationalimpetusforcompulsivesubstanceabusebehavior[25–27].
l Development of Addiction: Development of structural and physiological tolerance occurs
when alcohol withdrawal may cause severe adverse effects including seizures and death
and craving. The resumption of substance consumption suppresses the withdrawal symp-
toms.Atthisstage,theresumptionofalcoholconsumptionensuressurvivalandnotreward.
Table1.1listssomeofthecharacteristicsofdifferentstagesofalcoholdrinking.BAC,cen-
tralneurons,neurotransmitters,andreceptorsplayakeyroleintheprocesses[24,28,29].
1.1 Alcohol responsive brain regions and networks
Reward, tolerance, and addiction are the phenomena of the central nervous system
(CNS) because alcohol and other drugs of abuse act on specific brain regions and
changetheirstructureandfunctioneithertransientlyorlongsomely30–32.Theproceed-
ing sections describe possible roles of different brain regions in the development of
addiction.
4 NeurobiologyofAlcoholandtheBrain
Table1.1 Journeyfromresponsiblealcoholdrinkingtoalcoholism.
Stagesofalcohol
addiction Possiblemechanismsdiscussedinthereview
Acutephase:positive RisingBAC,DA ,OP ,GABA ,and5-HT
ergic ergic ergic ergic
reinforcementa neuronsandrespectivereceptors
Acutephase:negative FallingBAC,NMDARandGABAR,andreceptor/voltage-
reinforcementb gatedNa+channels
Hangover/tolerance/ Alcoholmetabolism,acetaldehydeaccumulation,excitatory
craving NTsignaling,and5HTRs
Alcoholaddiction Adenosine,DAR,5HTR,GABAR,andgluR
Withdrawalsymptoms NMDA/GluRs,GABA,hyperexcitation,andseizures
Abbreviation:BAC,bloodalcoholconcentrations;DA,dopamine;OP,opioid;5-HT,5-hydroxytryptophanor
serotonin;DAR,dopaminereceptor;NT,neurotransmitter.
aPositivereinforcement:Aneventthatincreasestheprobabilityofaresponseonwhichitiscontingent.
bNegativereinforcement:Aneventthatwhenomittedorterminatedincreasestheprobabilityoftheresponseonwhichit
iscontingent.
1.1.1 Alcohol-responsive brain regions
Thebrainregionsassociatedwithalcoholeffectsareanteriorfrontalcortex(AFC),dor-
solateralprefrontalcortex(dlPFC),medialolfactorycortex(mOLc),ventraltegmental
area(VTA),prefrontalcortex(PFC),amygdala(AMG),nucleusaccumbens(NAc),hip-
pocampus (HPC), anterior cingulate cortex (ACC), insula, and habenula [30–32].
Fig.1.4showsneuronalnetworksconnectingdifferentbrainregionsandtheeffectsthey
modulate.Abriefdescriptionoftheselectedbrainregionsisdescribedbelow:
l Theorbitofrontalcortex(OFC):OFCoccupiestheentireventralsurfaceofthefrontallobes
containingdiversesubstructures(Fig.1.5A[33],Fig.1.5B[34]).Anatomically,OFCcon-
sistsoftwosubregions,medialOFC(mOFC)andlateralOFC(lOFC)thataredistinctivein
PFC
(ACC, inferior PFC,
PFC (medial OFC)
DlPFC, lateral PFC)
Salience attribution Inhibitory control
Conditioning Decision making
Planning
Insula AFC NAc VTC Amygdala
Hippocampus
introspection Reward
Stress reactivity
Mood
Conditioning
Dorsal Striatum Habenula
Habits, drive, action anti-reward
Fig.1.4 Interactingneuronalnetworkandcircuitsassociatedwithreward,tolerance,and
addiction.NAcandVTA:rewardandaversiveresponses.AMGandmedialOFC:emotional
responseandsalienceattribution.HPCanddorsalstriatum:memoriesandhabits.ACC,inferior
PFC,dlPFC,andlateralOFC:conditioning/memoryandexecutivecontrol.VentralACC,VTA:
motivation/drive.Insula,ACC:interoception.Habenula:aversion/avoidance.