Neuroscience of psychoactive substance use and dependence

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Neuroscience of psychoactive substance use and dependence

  The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerningthe legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Introduction 1 Structure of the report 1 Psychoactive substances and their sociolegal status 1 Global use of psychoactive substances 4 Tobacco 4 Alcohol 5 Illicit use of controlled substances 9 Adverse effects of psychoactive substances and their mechanisms of action1 0 Substance dependence in relation to neuroscience 1 2 The burden of harm to health from psychoactive substance use 1 6 Chapter 2 .

I. World Health Organization

  The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerningthe legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Introduction 1 Structure of the report 1 Psychoactive substances and their sociolegal status 1 Global use of psychoactive substances 4 Tobacco 4 Alcohol 5 Illicit use of controlled substances 9 Adverse effects of psychoactive substances and their mechanisms of action1 0 Substance dependence in relation to neuroscience 1 2 The burden of harm to health from psychoactive substance use 1 6 Chapter 2 .

Chapter 5 . Genetic Basis of Substance Dependence 1 2 5 Introduction

1 2 5 Family, twin and adoption studies: estimations of heritability 1 2 7Identifying chromosomal locations of interest: linkage studies 1 2 7 Candidate gene approach 1 2 8Animal studies 1 2 8 Genetics of tobacco dependence 1 3 0Heritability of tobacco dependence 1 3 0 Tobacco dependence and linkage studies 1 3 1Candidate genes for tobacco dependence 1 3 1 Genetics of alcohol dependence 1 3 2Heritability of alcohol dependence 1 3 2 Alcohol dependence and linkage studies 1 3 3Candidate genes for alcohol dependence 1 3 4 Genetics of opioid dependence 1 3 6Heritability of opioid dependence 1 3 6 Opioid dependence and linkage studies 1 3 6Candidate genes for opioid dependence 1 3 6 Genetics of the combined risk of dependence on tobacco, alcohol,opioids and other psychoactive substances 1 3 8 Heritability of substance dependence 1 3 8Linkage studies of substance dependence 1 3 9 Candidate genes involved in substance dependence 1 4 0 Confounding issues in linkage and candidate gene studies 1 4 7 Environment1 4 7 Genetice heterogeneity 1 4 7 Phenotype1 4 8 Comorbidity1 4 8 Methodological issues1 4 8 Future directions1 4 9 Social and cultural aspects 1 5 0 Risk factors and protective factors for dependence: an overview 1 5 0 Summary1 5 1 vii Chapter 6 . Concurrent Disorders 1 6 9 Introduction1 6 9 Hypotheses that may explain the observed comorbidity 1 7 0 Schizophrenia1 7 1 Tobacco smoking and schizophrenia 1 7 1 Psychostimulant (cocaine and amphetamine) dependence and schizophrenia1 7 4 Alcohol use and schizophrenia 1 7 6 Neurobiological interactions between schizophrenia and the effects of psychoactive substances 1 7 6Depression 1 8 0 Tobacco smoking and depression 1 8 1Psychostimulant dependence and depression 1 8 2 Alcohol use and depression 1 8 3Neurobiological interactions between depression and the effects of psychoactive substances 1 8 4 Discussion and conclusions 1 8 8 Chapter 7 . Ethical Issues in Neuroscience Research on Substance Dependence Treatment and Prevention 2 0 9 Introduction2 0 9 Types of research on neuroscience of substance dependence 2 0 9 Animal experiments2 0 9 Epidemiological research on substance dependence 2 0 9 Experimental studies in humans 2 1 0 Clinical trials of pharmacotherapy for substance dependence 2 1 0Trials of pharmacotherapies to prevent substance dependence 2 1 1 Approach to ethical analysis 2 1 1Principles of biomedical ethics 2 1 6 Human rights 2 1 7 Ethics of animal experimentation in neuroscience research 2 1 8Ethical principles in human biomedical research 2 1 9 Independent ethical review of risks and benefits 2 1 9 Informed consent2 2 0 Recruitment of subjects 2 2 0 Privacy and confidentiality 2 2 1 Emerging ethical issues in neuroscience research 2 2 2Research on vulnerable persons 2 2 2 Are substance dependent people vulnerable persons? 2 2 3Provocation studies 2 2 3 Ethical issues in epidemiological research on substance dependence 2 2 4Ethical issues in clinical trials of pharmacological treatments for substance dependence 2 2 5 Trial designCONTENTS 2 2 5 Distributive justice2 2 6 Conflicts of interest2 2 6 Trials of preventive pharmacological interventions for substancedependence 2 2 7 Early intervention studies 2 2 7Preventive use of drug immunotherapies 2 2 9 Implications of neuroscience research for models of substancedependence 2 3 1 Implications of neuroscience research for the treatment of substancedependence 2 3 2 Access to treatment2 3 2 Legally coerced treatment 2 3 2 Summary and conclusions 2 3 5

Chapter 8 . Conclusion and Implications for Public Health Policy 2 4 1 Introduction

  Th is n eu ro scien ce rep o rt is th e first a ttem p t b y WH O to p rovid e a com p reh en sive overview of th e biological factors related to su bstan ce u sean d dep en den ce by su m m arizin g th e vast am ou n t of kn owledge gain ed in th e last 20-30 years. Th e va rio u s h ea lth a n d so cia l p ro b lem s a sso cia ted with u se o f a n d d ep en d en ce on tob a cco, a lcoh ol a n d illicit su b sta n ces req u ire grea teratten tion by th e p u blic h ealth com m u n ity an d ap p rop riate p olicy resp on ses are n eeded to address these problem s in differen t societies.

NEUROSCIENCE OF PSYCHOACTVE SUBSTANCE USE AND DEPENDENCE

  De p a rt m e n t fo r In t e r n a t io n a lDe ve lo p m e n t (DFID), t h e Be lgia n Gove r n m e n t , a n d t h e In st it u t e o fNeuroscien ces, Men tal Health an d Addiction of the Can adian In stitutes of Health Research for their fin an cial con tribution s to the project. Rya b i n i n , Ge n e t ic s a n d n e u ro s c ie n c e o f a lc o h o l a b u s e a n d dep en den ce: con tribu tion s from an im al m odels xv NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE Rachel Tyndale , Gen etics of alcoh ol an d tobacco u se in h u m an s.

CHAPTER 1 Introduction Th is rep ort d escrib es ou r cu rren t u n d erstan d in g of th e n eu roscien ce of

  It draws on the explosive growth in kn owled ge in th is area in recen t d ecad es, wh ich h as tran sform ed ou ru n derstan din g of th e bioch em ical action of p sych oactive su bstan ces, an d con tribu ted n ew in sigh ts in to wh y m an y p eop le u se th em , an d wh y som eu se th em to th e exten t of cau sin g h arm or of becom in g dep en den t on th em . In th is rep ort, ou r em p h asis will be on alcoh ol an d oth er h yp n otics an d sed atives, n icotin e, op ioid s, can n ab is,c o c a in e , a m p h e t a m in e s a n d o t h e r st im u la n t s, h a llu c in o ge n s, a n d p sych oactive in h alan ts.

CHAPTER 2 Brain Mechanism s: Neurobiology

  Th e dop am in ergic p rojection from th e VTA to th e n u cleu s accu m ben s (discu ssed below) is kn own as th em esolim bic dop am in e system , an d is th e n eu rotran sm itter system th at is m o st st ro n gly im p lica t e d in t h e d e p e n d e n ce -p ro d u cin g p o t e n t ia l o fp sych oactive dru gs (Wise, 1998). Rob in son TE, Kolb B (1999) Alteration s in th e m orp h ology of d en d rites an d d en d ritic sp in es in th e n u cleu s accu m b en s an d p refron tal cortex followin gre p e a t e d t re a t m e n t wit h a m p h e t a m in e o r co ca in e.

CHAPTER 3 Biobehavioural Processes Underlying Dependence Introduction Th is ch ap ter focu ses on sp ecific brain p rocesses th at are in volved in th e

  In all cases, in d ivid u al d ifferen ces in b iology an de n viro n m e n t will a ffe ct t h e n e u ro b io lo gica l e ffe ct s o f p sych o a ct ive su b stan ces; h owever, th is ch ap ter p resen ts b asic m ech an ism s th at m ayu n d e r lie t h e d e ve lo p m e n t o f d e p e n d e n c e fr o m a b io b e h a vio u r a l p ersp ective. Psychom otor sensitiza tion Mo st la b o ra to r y stu d ie s sh owin g th a t th e re p e a te d a d m in istra tio n o f p sych oa ctive su b sta n ces ca n p rod u ce sen sitiza tion of th e m esolim b icdop am in e system in volve two m easures: m easures of levels of dop am in e an d its m etabolites in the n ucleus accum ben s, an d m easures of the psychom otor-activatin g effects of dru gs, su ch as th eir ability to en h an ce locom otor activity in laboratory an im als.

CHAPTER 4 Psychopharm acology of Dependence

  For each on e of th ose, a brief review is p rovided of: — b eh aviou ral m an ifestation s of acu te an d ch ron ic u se of a d ru g in h u m an s an d in an im al m odels;— m olecu lar an d bioch em ical m ech an ism of action in th e m ain brain1 areas in volved with acu te effects; Th e term s su bstan ce, dru g, p sych oactive su bstan ce or p sych oactive dru g, are u sed in terch an geably in th is rep ort, an d m ay refer to n icotin e, alcoh ol or oth er dru gs. Pha rm a cologica l trea tm ent of nicotine d ep end ence An im p roved u n d erstan d in g of d ep en d en ce, an d th e id en tification an d a cce p t a n ce o f n ico t in e a s a d e p e n d e n ce -p ro d u cin g d r u g, h a ve b e e nfu n d a m e n t a l t o t h e d e ve lo p m e n t o f m e d ic a t io n s a n d b e h a vio u ra l treatm en ts for n icotin e d ep en d en ce.

8 Cannabinoids CB1 receptor agonists Relaxation, increased Develops rapidly to Rare, perhaps due Cognitive impairments, risk

4 . Y S P Substance Primary mechanism Behavioural effects Tolerance Withdrawal Effects of prolonged use Table 4 .1 Summary of characteristics of selected psychoactive substances (continued) C of actionM R A H O H A C P OVolatile solvents Most likely GABA-A Dizziness, disorientation, Some tolerance Increased susceptibility Changes in dopamine receptor L G O receptor mediated euphoria, light- develops (difficult to seizures binding and function; decreasedY Oheadedness, increased to estimate) cognitive function; psychiatric and F Dmood, hallucinations, neurological sequelae P E delusions, incoordination,E

1 N

  It is im p ortan t to keep in m in d th at su bstan ce dep en den ce is th e resu lt of n ot on ly th e p rim aryp h arm acological p rop erties of th e p sych oactive su b stan ce, b u t also th e com p lex in terp lay of biological an d en viron m en tal factors th at su rrou n d itsu se. Platt DM, Rowlett JK, Sp ealm an RD (2001) Discrim in ative stim u lu s effects of in t ra ve n o u s h e ro in a n d it s m e t a b o lit e s in r h e su s m o n ke ys: o p io id a n dd o p a m in e rgic m e ch a n ism s.

CHAPTER 5 Genetic Basis of Substance Dependence Introduction Th e aim of th is ch ap ter is to critically assess th e evid en ce for a gen etic

  Fa m ily, tw in a nd a d op tion stud ies: estim a tions of herita b ility Fam ily, twin an d adop tion stu dies can be u sed to determ in e wh eth er or n ot t h e re is a ge n e t ic c o n t r ib u t io n t o p syc h o a c t ive su b st a n c e u se a n ddepen den ce, but they do n ot provide eviden ce to determ in e which particular ge n e is in vo lve d . Th e stu d ies exam in e ch rom osom al location s th at are in h erited togeth er in p eop le wh o h ave th e p h en otyp e in qu estion (e.g. wh oh a ve n ico tin e d ep en d en ce) in o rd er to fin d a rea s o f th e ch ro m o so m e im p ortan t for th e con dition .

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