This document discusses the aetiopathology of alcoholism from multiple perspectives. It states that alcohol misuse results from both individual and environmental risk factors, and that causal mechanisms have been proposed in diverse fields like social sciences, psychology, genetics, pharmacology and neurobiology. Two main models are described - the social learning model which views alcoholism as an acquired behavior, and the disease model which contends that heavy drinking can lead to a loss of control over alcohol intake. The document then examines genetic, biological, psychological and sociocultural factors that may predispose individuals to alcoholism.

1. AETIOPATHOLOGY OF
ALCHOLISM
Dr Sushil Kumar S V
MB BS, MD (psychiatry), MHA, FIPS
Consultant Neuropsychiatrist

2.  ALCOHOL MISUSE IS A BIO-PSYCHOSOCIAL PHENOMENON IT RESULTS FROM THE
CONTRIBUTION OF MULTIPLE INDIVIDUAL AND ENVIRONMENTAL RISK FACTORS.
CAUSAL MECHANISMS HAVE BEEN PROPOSED BY RESEARCHERS IN FIELDS AS DIVERSE AS
 SOCIAL SCIENCES,
 BEHAVIORAL PSYCHOLOGY,
 PSYCHOPATHOLOGY, GENETICS,
 PHARMACOLOGY,
 TOXICOLOGY, AND
 NEUROBIOLOGY.

3. TWO VERY DIFFERENT SCHOOLS OF THOUGHT ATTRACT TO THE CURRENT NOTIONS OF
ALCOHOLISM
THE SOCIAL LEARNING MODEL
IT CONTENDS THAT ALCOHOL MISUSE IS AN ACQUIRED BEHAVIOR WHICH THE
INDIVIDUAL IS CAPABLE OF CORRECTING WITH ADEQUATE COGNITIVE–BEHAVIORAL
TRAINING; EVEN TO THE POINT OF RELEARNING TO DRINK IN A ‘CONTROLLED'
MANNER.
THE DRAWABACKS OF THE LEARNING MODEL TENDS TO PLAY DOWN THE
IMPORTANCE OF PREDISPOSING FACTORS, AND TO IGNORE THE VARIANCE IN
INDIVIDUAL BIOLOGICAL RESPONSES TO ALCOHOL, OR THE BRAIN CHANGES CAUSED
BY CHRONIC INTOXICATION.
IT ASSUMES THAT ALL ALCOHOLICS ARE BASICALLY THE SAME AND THAT THEY ARE NOT
DIFFERENT FROM ANY OTHER DRINKER IN THEIR CAPACITY TO EXERT CONTROL OVER
ALCOHOL USE.

4. THE DISEASE MODELS OF ALCOHOLISM
THE INABILITY TO RESTRICT THE QUANTITY OR FREQUENCY OF DRINKING IS A KEY
NOTION IN THE DISEASE OR ‘MEDICAL' MODEL OF ALCOHOLISM. THIS ANOMALY IS
THOUGHT TO RESULT FROM HEAVY ALCOHOL EXPOSURE, OR ELSE TO PRE-EXIST IN
CONSTITUTIONALLY VULNERABLE INDIVIDUALS.
THIS MODEL FURTHER SUGGESTS THAT, ONCE IN PLACE, SUCH LOSS OF CONTROL OVER
DRINKING IS IRREVERSIBLE.
PIONEER MEDICAL AUTHORS SUCH AS T. TROTTER IN THE EARLY 1800S, MAGNUS
HUSS, WHO COINED THE TERM ALCOHOLISM IN 1849-HAD ALREADY MAINTAINED
THAT THE DISORDER INVOLVES THE LOSS OF VOLUNTARY CONTROL OVER DRINKING
AND THIS IS STILL THE OPINION OF THE SCIENTIFIC COMMUNITY TODAY

5. ACCORDING TO IDEOLOGISTS AND MORALISTS WHO OPPOSED THAT NOTION
BECAUSE IT EXEMPTS THE DRINKER FROM PERSONAL BLAME. THEY VIEWED ANY FORM
OF DRINKING AS INTRINSICALLY WRONG, AND ALCOHOL ITSELF AS AN EVIL WHICH
SHOULD BE ELIMINATED THROUGH PROHIBITION.
THEY MAINTAINED ALCOHOLICS ARE ALWAYS CAPABLE OF CHOOSING WHETHER OR NOT
TO DRINK, AND MUST ASSUME FULL RESPONSIBILITY FOR THEIR BEHAVIOR. THUS
DENYING THE EXISTENCE OF A PATHOLOGICAL PROCESS

6.  SOCIOCULTURAL FACTORS
 THE PREVALENCE OF ALCOHOL PROBLEMS VARIES MARKEDLY ACROSS DIFFERENT
CULTURAL AND SOCIAL SETTINGS;
 THAT CERTAIN ENVIRONMENTAL CONDITIONS APPEAR TO FACILITATE THEIR
OCCURRENCE WHILE OTHERS SEEM TO PREVENT THEM
 MACROCULTURAL INFLUENCES SUCH AS VALUES, BELIEFS, AND MORES; SOCIAL ROLE
FUNCTIONS; LOCAL ECONOMY; CUSTOMS AND DIETARY HABITS; RAPID SOCIAL
CHANGE; AND CULTURAL STRESS DO SHAPE AND DICTATE THE WAY ALCOHOL IS USED
IN SOCIETIES.

7. OCCUPATION AND ALCOHOL
THE RISK OF HOSPITAL ADMISSION FOR ALCOHOLIC PSYCHOSIS, ACUTE INTOXICATION,
AND LIVER CIRRHOSIS IS ELEVATED IN UNSKILLED AND BLUE COLLAR WORKERS WHEN
COMPARED WITH HIGHER OCCUPATIONAL CATEGORIES
ALCOHOLICS ARE OVER-REPRESENTED IN OCCUPATIONS WITH FLEXIBLE WORK
SCHEDULES, IN THOSE LESS SUPERVISED, AND IN THE ONES WHICH FACILITATE ACCESS
TO ALCOHOL
FREQUENCY OF HEAVY DRINKING (I.E. EPISODES OF INTOXICATION, 5+ DRINKS AT A
TIME) IS INVERSELY CORRELATED WITH AGE, INCOME, AND LEVEL OF EDUCATION

8. SOCIOCULTURAL RISK FACTORS
 MALE ROLE
 LOWER EDUCATION
 LOWER INCOME
 MARITAL BREAKDOWN
 CERTAIN OCCUPATIONS
 IDLENESS
 CULTURAL AMBIVALENCE TOWARDS DRINKING
 SOCIAL STRESS

9.  INDIVIDUAL VULNERABILITY
GENETIC INFLUENCES
 THE MOST POWERFUL PREDICTOR OF ALCOHOL MISUSE IN ANY INDIVIDUAL IS THE
OCCURRENCE OF ALCOHOLISM IN FIRST-DEGREE RELATIVES.
 MEN AND WOMEN BELONGING TO FAMILIES WITH ALCOHOLIC PARENTS AND/OR
SIBLINGS ARE TWICE AS LIKELY TO DEVELOP THE DISORDER THAN THOSE WITHOUT
SUCH FAMILY HISTORY.
 THE RISK IS THREEFOLD WHEN THE DISORDER IS PRESENT ALSO IN SECOND- OR
THIRD-DEGREE
 THE EXCESS PROBABILITY OBSERVED WITHIN SINGLE FAMILY GROUPS SUGGESTS THAT
ALCOHOL MISUSE COULD BE A GENETICALLY TRANSMITTED BEHAVIOR

10.  TWIN STUDIES
 THE COMPARISON OF CONCORDANCE RATES FOR ALCOHOLISM IN MONOZYGOTIC
AND DIZYGOTIC TWINS PERMITS TO TEST THE GENETIC BASIS OF THE DISORDER.
 USING GENERAL POPULATION PREVALENCE RATES AS REFERENCE, TO HAVE AN
ALCOHOLIC MONOZYGOTIC SIBLING MARKEDLY INCREASES THE CHANCES OF
DEVELOPING ALCOHOLISM
 DIZYGOTIC CO-TWINS OF ALCOHOLICS ALSO PRESENT ELEVATED RISK RATIOS, BUT TO
A LESSER DEGREE.
 IT MUST BE NOTED THAT BETWEEN 40 AND 70 PER CENT OF THE IDENTICAL CO-
TWINS OF ALCOHOLICS DO NOT PRESENT THE DISORDER, AND THAT SUCH VARIANCE
CAN ONLY BE DUE TO NON-GENETIC CAUSES.

11.  ADOPTION STUDIES
 THE STUDY OF ADOPTED-AWAY CHILDREN OF ALCOHOLIC PARENTS IS A POWERFUL
APPROACH TO THE ELUCIDATION OF THE NATURE OF THE FAMILY TRANSMISSION OF
ALCOHOLISM.
 A GENETIC VULNERABILITY, OF COURSE, SHOULD EXPRESS ITSELF EVEN WHEN SUCH
CHILDREN ARE BROUGHT UP BY NON-ALCOHOLIC ADOPTIVE PARENTS.
 ALL ADOPTION STUDIES CONSISTENTLY REPORT AN INCREASED RISK IN THESE
OFFSPRING, REGARDLESS OF THE FAMILY ENVIRONMENT WHERE THEY GROW UP. THE
PROBABILITY OF OCCURRENCE IN THE PROBANDS IS MUCH HIGHER THAN IN THE
CONTROL ADOPTEES.
 THIS WAS DEMONSTRATED WITH DANISH (RISK RATIO 3.6), SWEDISH (RISK RATIO
1.3), AND AMERICAN (RISK RATIOS 3.5 AND 3.6)

12. THE OFFSPRING OF ALCOHOLIC PARENTS ARE EXPOSED TO AN EXCESS RISK. A MORE
DETAILED ANALYSIS OF THE ADOPTION DATA SHOWS THAT THE BIOLOGICAL PARENTS
OF ALCOHOLIC ADOPTEES, WHEN COMPARED TO THE CONTROLS, ARE NOT ONLY
MORE LIKELY TO PRESENT ALCOHOLISM BUT ALSO ANTISOCIAL BEHAVIOUR.
 ANTISOCIAL PERSONALITY IS ALSO SIGNIFICANTLY MORE PREVALENT IN ALCOHOL-
ABUSING ADOPTEES THAN IN CONTROLS.
 THE EVIDENCE INDICATES THAT THE ALCOHOLISM–ANTISOCIAL PERSONALITY TANDEM
IS MUCH MORE ‘INHERITABLE' THAN ALCOHOLISM ALONE.
 IN DECREASING ORDER OF SIGNIFICANCE, ALCOHOL ABUSE IN ADOPTEES IS
PREDICTED BY THEIR OWN ANTISOCIAL PERSONALITY, BIOLOGICAL PARENTS'
ALCOHOLISM, BIOLOGICAL PARENT'S ANTISOCIAL HISTORY, AND, TO A MUCH LESSER
DEGREE, HISTORY OF ALCOHOLISM OR PSYCHOPATHOLOGY IN THE ADOPTIVE
PARENTS.

13.  BIOLOGICAL PREDISPOSITION
ALCOHOL SENSITIVITY
 COMPARED TO CONTROLS, A SIGNIFICANTLY LARGER PERCENTAGE OF MEN WITH
FAMILY HISTORY OF ALCOHOLISM PRESENT A LESSER PHYSIOLOGICAL RESPONSE TO
ALCOHOL; IN TERMS OF BOTH SUBJECTIVE SENSATIONS AND OBJECTIVE
MEASUREMENTS (POSTCONSUMPTION PLASMA CORTISOL LEVELS).
 A LOWER SENSITIVITY IS ASSUMED TO LEAD TO HEAVIER DRINKING AND PREDICTS THE
EVENTUAL DEVELOPMENT OF ALCOHOLISM. THE ‘INNATE' LOW RESPONSE TO
ALCOHOL IS AN INDEPENDENT RISK FACTOR, REGARDLESS OF FAMILY HISTORY.
 MEN WITH MULTIGENERATIONAL FAMILY HISTORY OF ALCOHOLISM TEND TO DERIVE
A GREATER ANXIOLYTIC EFFECT FROM ALCOHOL. SUCH INCREASED EFFECTS CAN BE
EXPECTED TO REINFORCE HEAVY DRINKING.

14.  BIOCHEMICAL MARKERS
 ON AVERAGE, ALCOHOLICS HAVE LOWER THAN NORMAL LEVELS OF PLATELET SEROTONIN
AND OF ITS METABOLITE 5-HYDROXYINDOLE ACETIC ACID IN CEREBROSPINAL FLUID;
 ESPECIALLY THE PROBLEM DRINKERS WHO EXHIBIT IMPULSIVE AND VIOLENT BEHAVIOUR.
THIS SEROTONIN DEFICIENCY PROFILE WAS ALSO FOUND TO BE ABNORMALLY PREVALENT
IN YOUNG ADULTS WITH A FAMILY HISTORY OF ALCOHOLISM.
 THE MONOAMINE OXIDASE ENZYME IS OF INTEREST BECAUSE IT PARTICIPATES IN THE
BREAKDOWN OF NEUROTRANSMITTERS WHICH ARE INVOLVED IN THE BRAIN ACTION OF
ALCOHOL. ABNORMALLY LOW LEVELS OF MONOAMINE OXIDASE PLATELET ACTIVITY WERE
FOUND TO BE LINKED TO A FAMILY HISTORY OF ALCOHOLISM, AS WELL AS TO AN EARLIER
AGE OF ONSET AND A HIGHER SEVERITY OF THE DISORDER.
 BOTH THESE BIOCHEMICAL DEVIATIONS SEEM TO BE MORE SIGNIFICANT AMONG MALE
THAN FEMALE SUBJECTS, AND TO BE STRONGLY ASSOCIATED WITH ANTISOCIAL
BEHAVIOUR.

15.  NEUROPHYSIOLOGY
EVENT-RELATED POTENTIALS
 ALCOHOLICS HAVE BEEN FOUND TO PRESENT A LOWER THAN NORMAL AMPLITUDE OF
THE P300 WAVE, WHEN SUCH BRAIN POTENTIAL IS EVOKED THROUGH COMPLEX
VISUOMOTOR TASKS. THE P300 POTENTIAL IS THOUGHT TO MEASURE ATTENTIONAL
AND MEMORY PROCESSES, AND ITS AMPLITUDE TENDS TO INCREASE WITH AGE AND
NEUROLOGICAL MATURITY.
 LOW P300 AMPLITUDE COULD BE OBSERVED ALSO IN YOUNG OFFSPRING OF
ALCOHOLICS, BOTH MALE AND FEMALE, WHO HAD NOT YET STARTED DRINKING. IT IS
CONSEQUENTLY SUGGESTED THAT SUCH NEUROPHYSIOLOGICAL FINDING MIGHT BE A
BIOLOGICAL MARKER OF BIOLOGICAL VULNERABILITY TO ALCOHOLISM.
 HOWEVER, P300 ANOMALIES ARE NOT SPECIFIC TO ALCOHOLISM AND ARE OBSERVED
ALSO IN OTHER PSYCHIATRIC DISORDERS.

16. MOLECULAR GENETICS
 A VARIANT (TAQL-A1 ALLELE) OF THE HUMAN DOPAMINE RECEPTOR GENE DRD2 WAS MORE PREVALENT IN ALCOHOLICS THAN IN
CONTROLS (LINKAGE DISEQUILIBRIUM), AND THAT THIS ALLELE COULD BE A MARKER FOR HEIGHTENED RESPONSIVENESS TO
PHARMACOLOGICAL STIMULATION (I.E. INCREASED BASELINE POSITIVE REINFORCEMENT). HOWEVER, SUCH GENETIC VARIANCE EXISTS
ACROSS ETHNIC GROUPS, AND THAT IT IS NOT EVEN A CONSISTENT FINDING IN ALL SAMPLES OF ALCOHOLICS.
 THERE IS LITTLE DOUBT THAT ALCOHOL ABUSE WILL BE FOUND TO BE A POLYGENIC DISORDER.
 THE FIRST GENOME-WIDE SCREENS FOR ALCOHOLISM IN HUMANS HAVE PRODUCED EVIDENCE OF SEVERAL CHROMOSOMAL
REGIONS LINKED TO ALCOHOL DEPENDENCE. A CONCLUSIVE FINDING SO FAR IS A ‘PROTECTIVE' LOCUS NEAR THE ALCOHOL
DEHYDROGENASE GENE CLUSTER IN CHROMOSOME 4. “
 Alcohol Dependence” Phenotype (chr 1&4)
 “Low Level of Response” Phenotype(chr 1)
 “Alcoholism or Depression” Phenotype (chr 1)
 “Unaffected” Phenotype (chr 4 near ADH gene)
 “Maximum Number of Drinks” Phenotype (chr 4)
 ETHANOL AND ACETALDEHYDE METABOLIZING ENZYMES, OF COURSE, ARE KNOWN TO VARY ACROSS DIFFERENT ETHNIC
POPULATIONS, AND SUCH HETEROGENEITY IS ASSUMED TO PLAY A ROLE IN THE CROSS-ETHNIC VARIANCE OF ALCOHOLISM
PREVALENCE
 THE LINKAGE ANALYSIS OF SEVERE ALCOHOL DEPENDENCE HAS IDENTIFIED A LOCUS ON CHROMOSOME 16, NEAR THE MARKER
D16S675.

17.  PSYCHOLOGICAL FACTORS
 PERSONALITY
 ALCOHOLICS DO NOT PRESENT A HOMOGENEOUS PREMORBID PERSONALITY PROFILE.
HOWEVER, SOME DISTINCTIVE TRAIT CLUSTERS HAVE BEEN IDENTIFIED WHICH SEEM
TO CHARACTERIZE DIFFERENT TYPES OF ALCOHOLICS.
 ONE SUCH GROUP (TYPE 1) TEND TO SCORE LOW IN NOVELTY SEEKING AND HIGH IN
HARM AVOIDANCE AND REWARD DEPENDENCE.
 ANOTHER GROUP (TYPE 2) IS FORMED BY THE NATURAL THRILL SEEKERS, WHO
APPEAR TO IGNORE HARMFUL CONSEQUENCES AND PUNITIVE RESPONSES. THIS
LATTER CLUSTER, WHICH PREVAILS MOSTLY IN MALES WITH EARLY-ONSET
ALCOHOLISM, IS ALSO TYPICAL OF ANTISOCIAL PERSONALITIES.
 OF ALL PERSONALITY FEATURES, CONDUCT DISORDER AND ANTISOCIAL BEHAVIOUR
ARE THE STRONGEST PREDICTORS OF ALCOHOL MISUSE. HOWEVER, MORE THAN HALF
THE ALCOHOLIC POPULATION DO NOT HAVE SUCH A PERSONALITY BACKGROUND,
PRESENTING RATHER WITH A NON-SPECIFIC MIXTURE OF THE DIFFERENT PERSONALITY
TYPES DESCRIBED IN CLUSTERS A, B, AND C OF THE DSM-IV CLASSIFICATION.

18.  Type II
 For early onset dependence
 Polysubstance abuse.
 Externalizing symptoms
 Family history positive
 Type I
 Late onset dependence.
 Slowly developing
 Family history negative

19.  PSYCHODYNAMIC PROCESSES
 EARLY PSYCHODYNAMIC WRITINGS VIEWED ALCOHOLISM AND OTHER
ADDICTIONS AS REGRESSIVE BEHAVIOURS CAUSED BY UNCONSCIOUS
CONFLICTS ABOUT LIBIDINAL PLEASURES, HOMOSEXUALITY, AND
AGGRESSION.
 MORE RECENT FORMULATIONS EMPHASIZE EGO AND SELF-
DEVELOPMENTAL PROBLEMS, AND CONSIDER PSYCHOACTIVE
SUBSTANCE ABUSE AS A RESPONSE TO PSYCHOLOGICAL SUFFERING; AN
ATTEMPT AT REESTABLISHING HOMEOSTASIS. THIS IS KNOWN AS THE
SELF-MEDICATION HYPOTHESIS OF ADDICTIONS,( ACCORDING TO
WHICH, PERSONS WITH SELF-REGULATORY DEFICIENCIES IN THE AREAS
OF SELF-CARE, SELF-ESTEEM, SELF-OBJECT RELATIONS, AND AFFECT
TOLERANCE, WOULD DRINK TO PALLIATE THEIR DISTRESS.

20. LEARNING
 ALCOHOL ABUSE AS A BEHAVIOURAL PATTERN WHICH HAS BEEN LEARNED THROUGH
MECHANISMS OF CLASSICAL (I.E. PAVLOVIAN) AND OPERANT CONDITIONING
 ACCORDING TO THIS INTERPRETATION, THE PERPETUATION OF HEAVY DRINKING
RESULTS FROM ITS ASSOCIATION WITH CONDITIONED STIMULI (CUES), AND FROM THE
ACTION OF POSITIVE (PLEASANT EFFECTS) OR NEGATIVE (STRESS REDUCTION)
BEHAVIOURAL REINFORCEMENT. ADDITIONAL COMPONENTS OF THIS EQUATION ARE
THE SO-CALLED ALCOHOL ‘EXPECTANCIES'.
 ALCOHOL ABUSERS TEND TO OVEREMPHASIZE THE PLEASANT ASPECTS OF DRINKING
AND TO EXCLUDE THE NEGATIVE ONES;
 THE LEARNING THEORY OF ALCOHOLISM ASSUMES THAT SUCH A COGNITIVE SET IS
ALSO ACQUIRED THROUGH SOCIAL EXPOSURE.

21.  PSYCHIATRIC COMORBIDITY
 THE PRESENCE OF OTHER PSYCHIATRIC DISORDERS AS ONE OF THE MOST SIGNIFICANT
PSYCHOLOGICAL RISK FACTORS IN ALCOHOLISM.
 THE RISK IS PARTICULARLY HIGH IN PERSONS WITH SCHIZOPHRENIA, BIPOLAR
DISORDER, MAJOR DEPRESSION, SOCIAL PHOBIA, PANIC DISORDER, POST-TRAUMATIC
STRESS, ATTENTION-DEFICIT HYPERACTIVITY DISORDER, AND ANTISOCIAL AND
BORDERLINE PERSONALITY DISORDERS.
 A LARGE PROPORTION OF THE DISORDERS DIAGNOSED ARE ALCOHOL INDUCED AND
TEND TO DISSIPATE IN CONDITIONS OF ABSTINENCE.
 MOST OF THE EXCESS PSYCHOPATHOLOGY OBSERVED IN ALCOHOLICS IS SECONDARY
TO ALCOHOLISM RATHER THAN A PRE-EXISTING RISK FACTOR.
 IT HAS ALSO BEEN SUGGESTED THAT THE COEXISTENCE OF ALCOHOLISM WITH OTHER
PSYCHIATRIC ILLNESSES (E.G. AFFECTIVE DISORDERS) DOES NOT NECESSARILY MEAN
THAT ONE IS CAUSING THE OTHER, BUT RATHER THAT THEY BOTH RESULT FROM A
COMMON GENETIC INFLUENCE.

22.  BRAIN DYSFUNCTION
 ALTERED NEUROPSYCHOLOGICAL FUNCTION CAN BE SEEN AS AN ADDITIONAL RISK
FACTOR IN ALCOHOLISM
 MINIMAL BRAIN DAMAGE, ATTENTION DEFICIT, LEARNING DISABILITIES, HEAD
INJURIES, FETAL ALCOHOL EFFECTS, OR THE ACTIONS OF OTHER DRUGS OF ABUSE ARE
EXAMPLES OF BRAIN CONDITIONS LIKELY TO INCREASE INDIVIDUAL VULNERABILITY.
 A TRANSKETOLASE DEFICIENCY (POSSIBLY GENETIC), WHICH AFFECTS CARBOHYDRATE
METABOLISM IN THE BRAIN, IS BELIEVED TO PREDISPOSE TOWARDS THE OCCURRENCE
OF ALCOHOLIC ORGANIC BRAIN COMPLICATIONS

23. NEUROPHARMACOLOGICAL AND NEUROADAPTIVE MECHANISM WITHIN SPECIFIC
CIRCUITS THAT MEDIATE TRANSITION B/W OCCASIONAL USE TO DEPENDENCE
POSITIVE AND NEGATIVE REINFORCEMENT CHARACTERISTICS OF ALCOHOL DEPENDENCE
SUBSTANCE DEPENDENCE HAS ASPECTS OF BOTH IMPULSIVITY AND COMPULSIVITY AT DIFFERENT STAGE OF ADDICTION CYCLE
IMPULSE CONTROL DISORDERS ARE CHARACTERIZED BY AN INCREASING TENSION OR AROUSAL BEFORE COMMITTING AN IMPULSIVE
ACT, FEELINGS OF PLEASURE, GRATIFICATION OR RELIEF AT TIME OF COMMITTING ACT AND POSSIBLE REGRET ,SELF REPROACH OR
GUILT FOLLOWING ACT
AND COMPULSIVE DISORDERS ARE CHARACTERIZED BY ANXIETY AND STRESS BEFORE COMMITTING A COMPULSIVE REPETITIVE
BEHAVIOR AND RELIEF FROM STRESS BY PERFORMING THE ACT
AS AN INDIVIDUAL MOVES FROM AN IMPULSIVE TO A COMPULSIVE DISORDER THERE IS SHIFT FROM POSITIVE TO NEGATIVE
REINFORCEMENT DRIVING THE MOTIVATED BEHAVIOR, DRUG ADDICTION IS A DISORDER THAT PROGRESSES FROM IMPULSIVITY TO
COMPULSIVITY IN A COLLAPSE CYCLE OF ADDICTION

24. PEER PRESSURE!
MISCONCEPTIONS/MYTHS IMITATION/MODELLING
CURIOSITY!

25. ADDICTION CYCLE HAS 3 STAGES
1.BINGE OR INTOXICATION
2.WITHDRAWAL/NEGATIVE AFFECT
3.PREOCCUPATION /ANTICIPATION
(CRAVING)
BINGE /INTOXICATION STAGE HAVE BEEN WELL ESTABLISHED FROM POSITIVE REINFORCING
EFFECTS OF ALCOHOL
 THIS INVOLVES ELEMENTS OF MESOLIMBIC DOPAMINE SYSTEM {VENTRAL TEGMENTAL AREA
(VTA} DOPAMINE PROJECTION TO THE NUCLEUS ACCUMBENS (NAC) AND DOPAMINE –
DEPENDENT INTERACTIONS IN THE EXTENDED AMYGDALA,BED NUCLEUS OF STRIA TERMINALIS
AND SHELL OF NAC .
 THIS SYSTEM LINKS THE PRELIMBIC CORTEX TO THE CLASSICAL REWARD SYSTEMS OF THE
LATERAL HYPOTHALAMUS, POSSIBLY VIA A DESCENDING COMPONENT OF THE MEDIAL
FOREBRAIN BUNDLE.
 EFFECTS OF ALCOHOL INCLUDING ITS REWARDING, ANXIOLYTIC OR TENSION REDUCING EFFECTS
MAY BE MEDIATED BY THIS CIRCUITRY

26.  GABA ALSO PLAYS ROLE IN REINFORCEMENT AND GABA ANTAGONIST IS KNOWN TO
ANTAGONIZE THE EFFECTS OF ALCOHOL
 BOTH GLUTAMATE AND SEROTONIN HAVE BEEN IMPLICATED IN ACUTE REINFORCING
EFFECTS OF ALCOHOL- GLUTAMATE / NMDA RECEPTOR ANTAGONISTS HAVE BEEN
SHOWN TO SUBSTITUTE FOR ALCOHOL , IN ADDITION 5-HT3 RECEPTOR ANTAGONISTS
BLOCK ALCOHOL SELF ADMINISTRATION
IN THE WITHDRAWAL /NEGATIVE AFFECT STAGE OF ADDICTION CYCLE
 THE NEGATIVE REINFORCEMENT LEADING TO DEVELOPMENT OF DEPENDENCE AND THE
VULNERABILITY TO RELAPSE HAS BEEN SAID TO BE DUE TO COUNTERPRODUCTIVE
NEUROCHEMICAL EVENTS NORMALLY USED TO MAINTAIN EMOTIONAL HOMEOSTASIS
 IN ACUTE WITHDRAWAL –THERE IS A COMPROMISED BRAIN REWARD SYSTEM –WITH
INCREASE IN BRAIN REWARD THRESHOLD ACCOMPANIED BY DECREASE
GABAENRGIC,OPIOID PEPTIDERGIC, DOPAMINERGIC, SERTONERGIC AND GLUTAMATERGIC
FUNCTION, AS WELL AS RECRUITMENT OF BRAIN STRESS SYSTEMS SUCH AS
CORTICOTROPHIN-RELEASING FACTOR (CRF)

27.  IT IS SUGGESTED THAT GABAENRGIC SYSTEM IS HYPO FUNCTIONAL DURING
ACUTE WITHDRAWAL
 THE GLUTAMATE SYSTEM ALSO UNDERGOES CHANGES SUGGESTED BY
ACAMPROSATE ,A PARTIAL MODULATOR OF BRAIN GLUTAMATE RECEPTORS
DECREASING EXCESSIVE DRINKING ASSOCIATED WITH DEPENDENCE AND
ABSTINENCE
 THE DOPAMINERGIC FUNCTION IS COMPROMISED IN WITHDRAWAL –THERE IS
DECREASE IN EXTRACELLULAR LEVELS OF DOPAMINE IN NAC AND DECREASE
IN FIRING IN VTA
 THUS GABA,GLUTAMATE AND DOPAMINE SYSTEM SHOW A NEUROPLASTICTY
DURIN G DEVELOPMENT OF DEPENDENCE THAT HAS MOTIVATIONAL
CONSEQUENCES

28.  ANOTHER MAJOR CONTRIBUTION TO THE AVERSIVE STATE ASSOCIATED WITH INCREASES
IN BRAIN REWARD THRESHOLDS DURING ACUTE WITHDRAWAL HAS BEEN HYPOTHESIZED
TO BE DYSREGULATION OF THE BRAIN CRF STRESS SYSTEM.
 CRF PRESENT THROUGHOUT BRAIN, MORE IN CELL BODIES IN PERIVENTRICULAR NUCLEUS
OF THE HYPOTHALAMUS,THE BASAL FOREBRAIN(NOTABLY THE EXTENDED AMYGDALA) AND
BRAIN STEM.
 CRF NOT ONLY CONTROLS HPA AXIS RESPONSE TO STRESS BUT ALSO BEHAVIORAL
RESPONSE TO IT VIA EXTENDED AMYGDALE
 CRF ITSELF HAS ANXIOGENIC –LIKE EFFECTS AND CRF ANTAGONIST REVERSE MANY
BEHAVIORAL RESPONSES TO STRESS
 ALCOHOL IS ALSO POWERFUL MODULATOR OF STRESS SYSTEM- BOTH ACUTE AND
CHRONIC INTAKE OF ALCOHOL ACTIVATE HPA AXIS AND THIS RESULTS IN CRF RELEASE IN
HYPOTHALAMUS WHICH ACTIVATES STRESS RESPONSE AND EXTRACELLULAR LEVELS OF
CRF INCREASE IN AMYGDALE AND BED OF NUCLEUS STRIA TERMINALIS,CRF ANTAGONIST
REVERSE THESE IN EXPERIMENTAL CONDITION.

29. NEUROPEPTIDE Y (NPY)
 NEUROPEPTIDE Y (NPY) WIDELY DISTRIBUTED IN CNS BUT MORE IN EXTENDED
AMYGDALE –MAY HAVE ROLE. IN CONTRAST CRF –IN WITHDRAWAL NPY DECREASES
AND IS PARALLEL TO INCREASE CRF
 THUS NOT ONLY NEUROTRANSMITTERS BUT ALSO RECRUITMENT OF CRF BRAIN
STRESS SYSTEM AND DYSFUNCTION OF NPY BRAIN ANTISTRESS SYSTEM

30.  THE MODELS IN THIS STAGE ARE BASED ON CONDITIONED REINFORCEMENT AND STRESS.
ENVIRONMENTAL CUES REPEATEDLY PAIRED WITH PRIMARY REINFORCES CAN ACQUIRE REINFORCING
PROPERTIES VIA CLASSICAL CONDITIONING PROCESSES
 IN THIS STAGE - 2 FACTORS COMBINE TO PRODUCE STRONG MOTIVATION FOR DRUG SEEKING THAT
LEADS TO RELAPSE
 A REACTIVATION OF THE NEUROTRANSMITTER SYSTEM IMPLICATED IN ACUTE REINFORCING EFFECTS
OF ALCOHOL ( CRAVING TYPE 1)
 AND RESIDUAL DEFICITS IN REWARD FUNCTION ASSOCIATED WITH PROTRACTED ABSTINENCE
(CRAVING TYPE 2)
 DRIVING THESE NEUROCHEMICAL CHANGES STRUCTURING OF FUNCTIONAL ACTIVITY IN PREFRONTAL
CORTEX AND BASOLATERAL AMYGDALA THAT FACILITATES CUE-INDUCED CRAVING VIA
GLUTAMATERGIC,DOPAMINERGIC AND OPIOID PEPTIDE ACTIVATION .IN CONTRAST STRESS-INDUCED
REINSTATEMENT DEPENDS ON CRF IN EXTENDED AMYGDALA . SUPERIMPOSE BASAL HYPO ACTIVITY
IN PREFRONTAL CORTEX AND DYSREGULATION IN EXTENDED AMYGDALE REWARD SYSTEM ON
CRAVING CIRCUIT AND ONE HAS POWERFUL DRIVING FORCE FOR RELAPSE TO EXCESSIVE ALCOHOL
CONSUMPTION.

31. Experience Transmitter/Receptor
euphoria/pleasure Dopamine, Opioids
 anxiolysis/ataxia  GABA
 sedation/amnesia  GABA +  NMDA
 nausea 5HT3
 neuroadaptation NMDA, 5HT
 stress CRF
 withdrawal GABA, NMDA ( Ca, Mg)
 memory NMDA
 Craving and relapse NMDA

32. 3.Mech of
Relapse
1.Cue related OFC, VTA &
N.Acc
Glutamate
DA
2.Stress
related
Lateral &
Ventral TA
N.Adr,
DA,CRF
3.Drug
related
VTA &
N.Acc
DA
Glutamate
Addiction & its neurobiology

33. Reducing Relapse: Future directions.