The molecular basis of drug addiction

266 Pages·2016·5.13 MB·English

by  Rahman

VOLU MEONEHUNDREDANDTHIRTYSEVEN
P
ROGRESS IN
MOLECULAR BIOLOGY
AND TRANSLATIONAL
SCIENCE
The Molecular Basis of Drug
Addiction
VOLU MEONEHUNDREDANDTHIRTYSEVEN
P
ROGRESS IN
MOLECULAR BIOLOGY
AND TRANSLATIONAL
SCIENCE
The Molecular Basis of Drug
Addiction
Editedby
SHAFIQUR RAHMAN
DepartmentofPharmaceuticalSciences,
SouthDakotaStateUniversity,
Brookings,SouthDakota,USA
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CONTRIBUTORS
RichardL.Bell
DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
ThomasP.Beresford
DepartmentofVeteransAffairsMedicalCenter,LaboratoryforClinicalandTranslational
ResearchinPsychiatry,Denver,Colorado,USA
DepartmentofPsychiatry,SchoolofMedicine,UniversityofColorado,Denver,
Colorado,USA
PatrickChan
DepartmentofPharmacyandPharmacyAdministration,WesternUniversityofHealth
Sciences,CollegeofPharmacy,Pomona,California,USA
HowardJ.Edenberg
DepartmentsofBiochemistryandMolecularBiologyandMedicalandMolecularGenetics,
IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
EricA.Engleman
DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
ShekethaR.Hauser
DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
SimonN.Katner
DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
KabirullahLutfy
DepartmentofPharmaceuticalSciences,CollegeofPharmacy,WesternUniversityofHealth
Sciences,Pomona,California,USA
WilliamJ.McBride
DepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
JeanetteMcClintick
DepartmentsofBiochemistryandMolecularBiologyandMedicalandMolecularGenetics,
IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,USA
BethanyS.Neal-Beliveau
DepartmentofPsychology,PurdueSchoolofScience,IndianaUniversity-PurdueUniversity
Indianapolis,Indianapolis,Indiana,USA
PamelaM.Quizon
DepartmentofDrugDiscoveryandBiomedicalSciences,SouthCarolinaCollege
ofPharmacy,UniversityofSouthCarolina,Columbia,SouthCarolina,USA
ix
x Contributors
ShafiqurRahman
DepartmentofPharmaceuticalSciences,SouthDakotaStateUniversity,Brookings,
SouthDakota,USA
PatrickJ.Ronan
DepartmentofVeteransAffairsMedicalCenter,LaboratoryforClinicalandTranslational
ResearchinPsychiatry,Denver,Colorado,USA
ResearchService,SiouxFallsVAHealthCareSystem,SiouxFalls,SouthDakota,USA
DepartmentofPsychiatryandDivisionofBasicBiomedicalSciences,SanfordSchool
ofMedicineattheUniversityofSouthDakota,SiouxFalls,SouthDakota,USA
Wei-LunSun
DepartmentofDrugDiscoveryandBiomedicalSciences,SouthCarolinaCollegeof
Pharmacy,UniversityofSouthCarolina,Columbia,SouthCarolina,USA
KarenK.Szumlinski
DepartmentofPsychologicalandBrainSciences,UniversityofCaliforniaSantaBarbara,
SantaBarbara,California,USA
JoachimD.Uys
DepartmentofCellularandMolecularPharmacologyandExperimentalTherapeutics,
MedicalUniversityofSouthCarolina,Charleston,SouthCarolina,USA
JacquelineS.Womersley
DepartmentofCellularandMolecularPharmacologyandExperimentalTherapeutics,
MedicalUniversityofSouthCarolina,Charleston,SouthCarolina,USA
NarinWongngamnit
DepartmentofVeteransAffairsMedicalCenter,LaboratoryforClinicalandTranslational
ResearchinPsychiatry,Denver,Colorado,USA
DepartmentofPsychiatry,SchoolofMedicine,UniversityofColorado,Denver,
Colorado,USA
SubstanceAbuseTreatmentProgram,DepartmentofVeteransAffairs,Denver,Colorado,USA
NurulainT.Zaveri
AstraeaTherapeutics,LLC,MountainView,California,USA
JunZhu
DepartmentofDrugDiscoveryandBiomedicalSciences,SouthCarolinaCollege
ofPharmacy,UniversityofSouthCarolina,Columbia,SouthCarolina,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%oftheglobalpopulation. Acuteandchronicexposuretodrugsofabuse
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,thereisaneedtotranslatethecurrentknowledgeregardingmolecular
mechanisms of drug addiction derived from neurobiological research into
thediscoveryofnewtherapeutics.
Thisvolume,TheMolecularBasisofDrugAddiction,consistsofeightchapters
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 etal.). The second
chapter reviews the role of glutamate neurotransmitter receptor system in
mediatingthedevelopmentofalcoholdependence.Thechapterdiscussesthe
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
glutamatereceptors,transporters,enzymes,andscaffoldingproteinsinvolving
alcoholdependence(Belletal.).Thethirdchapterpresentsandhighlightsthe
evidenceforS-glutathionylationasaredox-sensingmechanismandhowthis
may be involved in the response to drug-induced oxidative stress. The
function of S-glutathionylated proteins involved in neurotransmission,
dendriticspinestructure,anddrug-inducedbehavioraloutputsarereviewed
withspecificreferencetoalcohol,cocaine,andheroin(UysandReissner).The
fourth chapter provides a comprehensive account of the state of knowledge
regardingmechanismsofCannabissignaling inthebrainandthemodulation
of key brain neurotransmitter systems involved in addiction and psychiatric
disorders (Ronan etal.). 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
pertaintodifferentbrainnicotinicreceptorsubtypesandassociatedsignaling
pathwaysthatcontributetothemolecular mechanismsofalcoholismand/or
comorbidbraindisorders(Rahmanetal.).Theseventhchapterfocusesonand
reviews the adenylyl cyclase and cyclic adenosine 3,5-monophosphate/
proteinkinaseAsystemasacentralplayerinmediatingtheacuteandchronic
effects of opioids in opiate abusers (Chan and Lutfy). The eighth chapter
concentrates on Caenorhabditis elegans, a nonvertebrate model, to study the
molecularandgeneticmechanismsofdrugaddictionandtoidentifypotential
targets for medication development (Engleman etal.).
Together, this body of work not only provides a deeper understanding
of our current knowledge on specific neurotransmitter systems, functional
proteins,signalingmolecules,genes,andadditionaltargetsfordrugaddiction,
butalsoindicatescomplexinteractionsbetweendrugsof abuse,endogenous
neuromodulators, signaling molecules, and the mechanisms underlying the
structuralandfunctionalplasticityinthebrain.Ihopethatthemolecularbasis
ofdrugaddictionresearchsummarizedinthisvolumewillgeneratenewideas
ondiversetargetsandstimulatetranslationalresearchforfurther mechanistic
understanding and insight into effective strategies for novel therapeutics in
the management of drug addiction.
Iwouldliketothankalltheauthorsfortheiroutstandingcontributionsto
thisvolume.IamverythankfultoDr.P.MichaelConn,theEditor-in-Chief
of the Book Series, for his guidance. Finally, I also thank Ms. Mary Ann
Preface xiii
Zimmerman,theSeniorAcquisitionsEditorandMs.HeleneKabes,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 understandingandlove.
SHAFIQURRAHMAN
Editor
CHAPTERONE

Molecular Mechanism: ERK

Signaling, Drug Addiction,

and Behavioral Effects

Wei-LunSun,PamelaM.Quizon,JunZhu1

DepartmentofDrugDiscoveryandBiomedicalSciences,SouthCarolinaCollegeofPharmacy,University
ofSouthCa rol ina,C olumbia,S outh Carolina,U SA
1C orres pondinga uthor:e-m ailad dress:zhu [email protected].

Contents
1. Introduction 3

2. ERKSignalingPathway 4

3. ERKSignalingandDrugAddiction 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. ConclusionsandFutureDirections 23

Acknowledgment 25

References 25

Abstract
Addictiontopsychostimulantshasbeenconsideredasachronicpsychiatricdisorder

characterized by craving and compulsive drug seeking and use. Over the past two

decades, accumulating evidence has demonstrated that repeated drug exposure

causeslong-lastingneurochemicalandcellularchangesthatresultinenduringneu-

roadaptation in brain circuitry and underlie compulsive drug consumption and

relapse.Throughintercellularsignalingcascades,drugsofabuse induceremodeling

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

propertiesandrelapseofdrugseekingbehaviors.Wealsodiscusstheneurobiological

ProgressinMolecularBiologyandTranslationalScience,Volume137
ISSN187 7-1173 ©2016ElsevierInc.
http:/ /dx.doi.org /10.1016/bs.pmbts.2015.10.017 A llrig htsreser ved. 1
2 Wei-LunSunetal.

andbehavioraleffectsofpharmacologicalandgeneticinterferenceswithERK-associ-

ated molecular cascades in response to abused substances. Understanding the

dynamicmodulationofERKsignalinginresponsetodrugsmayprovidenovelmolec-

ulartargetsfortherapeuticstrategiestodrugaddiction.

ABBREVIATIONS
AC Adenylylcyclase

AMPH Amphetamine

Amy Amygdala

BDNF Brain-derivedneurotrophicfactor

BNST Bednucleusofthestriatalterminals
Ca2+ Calc ium
CaM Calcium/calmodulin

CaMK CaMkinase

CB1-R Cannabinoidreceptor1

CB2-R Cannabinoidreceptor2

CPP Conditionedplacepreference

CPu Caudateputamen

CREB cAMPresponseelement-bindingprotein

DA Dopamine-regulatedphosphoprotein-32

D1-R DopamineD1receptor

D2-R DopamineD2-Receptor

ERK Extracellularsignal-regulatedkinase

Glu Glutamate

HIPP Hippocampus

IEG Immediateearlygene

MAPK Mitogen-activatedproteinkinase

MEK MAPKkinase

METH Methamphetamine

mGluR1/5 Metabotropicglutamatereceptor-1/5

MKP-1/3 MAPKphosphatases1and3

MSK Mitogen-andstress-activatedproteinkinase

NAc Nucleusaccumbens

nAChRs Nicotinicacetylcholinereceptors

pCREB PhosphorylatedCREB

pERK PhosphorylatedERK

PFC Prefrontalcortex

pGluN2B Phosphorylationofglutamatereceptor,ionotropic,N-methyl

D-aspartate2B

PKA ProteinKinaseA

PKC ProteinKinaseC

pMEK PhosphorylationofMEK

PP2A Proteinphosphatase2A