The document discusses the neurobiology of addiction and rationale for pharmacological interventions. It describes the common reward pathway in the brain activated by drugs like dopamine, opioids, nicotine, and cannabinoids. It outlines three stages in the addiction process - initiation due to reward, development of dependence and motivation, and mechanisms of relapse. It then provides rationale for decreasing reward, motivation/craving, and preventing relapse by targeting specific neurotransmitter systems. Several pharmacological agents are proposed to work through these mechanisms, such as decreasing dopamine, modulating glutamate and GABA, and regulating serotonin. Combination therapies and targeting specific subtypes of alcoholics are also suggested.

1. Common reward pathway.
DA
n
N
A
D
o
p
a
m
i
n
e
Opioi
ds
Nico
tine
Canna
b
Glutamat
e
GABA
5HT

2. Reward pathway :VTA to NucAc
VTA
Nuc
Ac
PFC
A
m
yg
Explosive
release of DA

3. Motivation pathway:PFC to N.Ac
VTA
Nuc
Ac
PFC
A
m
yg
Glutamate
release

4. Craving:Amygdala to PFC/N.Ac
DA n
NA
PFC
A
m
yg
Glutamate release
(Weiss et al,2000)

5. Salience.
DA n
NA
PFC
A
m
yg

6. Addiction & its neurobiology
1.Initiation of
abuse
Reward
pathway
VTA→
NAc
Dopamine,
(Opioids,
Cannabds)
.
2.From abuse
to dependence
1.Motivation
& drive
Orbitofr.
cortex
Glutamate
2.Memory
& Learning
Amygdala
& Hippcm
Glutamate
3.Control Prefrontal
cortex
Glutamate
■Neural plasticity-reinforces drug seeking behavior.

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

8. Rationale of interventions.
1. Decreasing the rewarding effects of
drugs:
■ Decreasing the positive
reinforcement.
■ Making drug taking unpleasant.
2. Decreasing the motivation or craving.
3. Preventing relapse.
4. Applying the genetic understanding.
5. No medication for specific indication of

9. Rationale of interventions.
■ Decreasing DA release.
■ Inhibiting the excitatory glutamate.
■ Enhancing the inhibitory GABA.
■ Balancing Glutamate v/s GABA
■ Regulating the 5HT neurotransmission.
(Koob, 2000)

10. 1. Decreasing the reward
■ Through the opioid system.
■ Naltrexone- Depot Intramuscular.
■ Through the cannabinoid system.
■ Rimonabant.

11. Decreasing the reward.
Rimonabant
DA
n
N
A
Opioid
s
Nico
tine
Canna
b
Glutamat
e
GABA
Decreased DA
release
Naltrexone

12. Decreasing the
reward-Rimonabant.
■ Cannabinoids modulate the reinforcing
effects of alcohol.
■ Endogenous cannabinoid agonists also
promote alcohol craving.
■ CB1 receptor, antagonist, Rimonabant,
decreases alcohol consumption in
rodents.
■ Under phase II human trial.

13. Decreasing the motiv/craving.
DA
n
N
A
Opioi
ds
Nico
tine
Canna
b
Glutamat
e
GABA

14. GABA & Glutamate.
■ Alcohol enhances GABA and inhibits
glutamate.
■ GABA-A, major receptor-most of alcohol’s
effects.
■ Rx for withdrawal involves drugs acting on
it.eg: Gabapentin.
■ GABA-B agonist, Baclofen also shown to
reduce craving and alcohol intake.
(Addolorato et al, 2002; Bonnet et al,2003)

15. Glutamate
■ Alcohol reduces glutamate activity by
interacting with NMDA receptors.
■ NMDA antagonist in treating alcohol
dependence.Eg: Memantine.
■ AMPA-kainate receptors activity
reduction
■ Increasing GABA.Eg:Topiramate.
(Bisaga et al, 2004, Johnson et al,
2003)

16. Serotonin
■ Serotonin dysregulation asstd –disorders
of attention, motivation & emotion.
■ Co-occuring mood disorders.
■ Alcohol alters serotonin
neurotransmission.
■ Medications to regulate the
dysequilibrium.
■ 5HT receptor antagonism, reuptake
inhibition.

17. 2.Decreasing motiv/craving.
1. Acamprosate
2. Topiramate.
3. Gabapentin.
4. Ondansetron
5. Baclofen
6. Memantine
7. SSRIs.

18. 1.Acamprosate
■ Blockade of Glutamate NMDA receptors .
■ Activation of GABA receptors.
■ Normalizes the ethanol altered GABA-A
recep.
■ Calcium channel blockade-in withdrawal.
■ It also modulates NMDA receptor subunit
expression.
■ Acamprosate restores the imbalance in the
excitatory & inhibitory NTs, caused by alcohol.
(Littleton, 1995; Rammes et al, 2001)

19. Acamprosate-Efficacy.
■ Reduces alcohol intake on various outcome
measures, and ameliorates withdrawal
symptoms
■ Reduces the intensity of post cessation alcohol
craving on exposure to cues.
■ Meta-anlayses show a significant but modest
effect on outcome.
■ Better tolerated.
■ Dose: 333 mg tabs Wt<60kg:1-1-2
>60 kg:1-2-2 or 2-2-2
(Kiefer et al,2003)

20. 2.Topiramate.
■ Topiramate has actions both in the
GABAergic and glutaminergic systems.
■ Decreases DA level both in the VTA & Nac,
modulates DA release in the reward pathway.
■ Decreases drinks/day, no. of heavy drinking
days, percentage of days abstinent, and
interference due to drinking.
■ Dose: 25 mg with wkly increase by 25-50 mg in
twice daily dosing, upto 100-150 mg.
(Johnson et al,2003)

21. Topiramate-efficacy
■ Good for combination with other Rx that
demonstrate effect in a subset of
patients.
■ Topiramate+Ondansetron/Naltrexone in
early onset alcoholics.
■ Topiramate+SSRI for later onset Type A
alcoholics.
■ Topiramate+mood stabilisers for pts
with comorbid affective disorders.

22. 3.Baclofen.
■ GABA(B) receptor agonist-approved as
an antispasmodic medication.
■ Blocks effect of alcohol on GABA
synapses.
■ GABAmimetic action-decreasing
hyperexcitability during withdrawal.
■ In pts with glutamate-GABA imbalance.
(Colombo et al,2004)

23. Baclofen- Efficacy.
■ Reduced voluntary alcohol intake in
alcohol-preferring rats.
■ Reduced alcohol craving and intake in
alcoholics.
■ Rapid suppression of withdrawal symptoms.
■ Outpatient detoxification.
■ Reduces compulsion to drink in Early onset
but not in Late onset alcoholism.
■ Dose: 10 mg tabs, titrated upto 50 mg/day in
thrice daily dosing.
(Flannery et al,2004; Addolorato et al,2002)

24. 4.Ondansetron
■ Serotonin-3 (5-HT3) antagonist
approved for treatment of nausea.
■ 5-HT3 antagonists attenuated effects of
alcohol and other addictive drugs
through indirect regulation of DA
release in mesocorticolimbic areas.
■ 5-HT deficiency in the early-onset
subtype.
(Johnson et al,2000)

25. Ondansetron-Efficacy.
■ Efficacious in early onset(<25 yrs), but
not in late onset alcoholics.
■ Reduced drinking and an increased
number of abstinent days.
■ Improvements in symptoms of
depression, anxiety and hostility.
■ Dose: 4 mg/day in twice daily dosing.
(Johnson et al,2000)

26. 5.SSRIs ??
■ Preclinical studies- reduced levels of
serotonin asstd with alcoholism,
indicating a biological predisposition.
■ Chronically, SSRIs reduce 5-HT levels,
thereby reciprocally enhancing DA
function and substituting for alcohol’s
rewarding effects.
■ Animal studies- SSRIs reduced alcohol
consumption in a dose dependent
fashion.

27. SSRIs- Efficacy??
■ Was hypothesized to be helpful in Type
B alcoholics.
■ Pts with early onset and sociopathic
profiles indicative of 5-HT
abnormalities.
■ Studies disproved this, contrarily Type A
alcoholics fared better, and Type B had a
poorer outcome.
(Kranzler et al,:Pettinati et al,2001& 2003)

28. Sertraline
■ Differential effect with Type II & I
alcoholics.
■ With Type II- an increased alcohol
intake vs those on placebo.
■ With Type I- significant increase in
abstinence rates, with benefit observed
even 6m after treatment.
■ Dose: 200mg/day
(Pettinati et al, 2000)

29. 6.Gabapentin
■ Influences the synthesis of GABA and
glutamate.
■ For insomnia associated with alcohol
dependence, in protracted withdrawals.
■ Ongoing trial of Naltrexone+Gabapentin
during initial period of abstinence.
■ Efficacy in withdrawal state??
(Karam-Hage et al,2000)

30. 7.Bupropion
■ Through the DA & NA-ergic systems
■ In comorbid nicotine dependent pts, as a
smoking cessation aid.
■ Unpublished case reports of decreased
pleasure & alcohol intake.
■ No controlled trials.

31. 8.Memantine.
■ NMDA antagonist- decreases
glutamatergic neurotransmission.
■ Shown to decrease alcohol craving
before the administration of alcohol but
not after it in moderate drinkers.
■ Open label pilot study- dosage of 20
mg/day- reduces drinking.
(Farmington et al,2005; Bisaga et al, 2004)

32. Combination pharmacotherapy
■ Addiction is not a homogenous disease.
■ Multiple brain sites & circuits are involved.
■ Thus,treatment must target multiple sites.
■ Or, be an optimal combination of medications.
■ Eg:
■ Acamprosate+Disulfiram
■ Acamprosate+Naltrexone.
■ Acamprosate+SSRIs.
■ Naltrexone+Disulfiram
■ Naltrexone+Ondansetron.

33. In specific subgroups.
1. Pts actively drinking:
1. Naltrexone,
2. Acamprosate,
3. Topiramate,
4. Gabapentin,
5. SSRIs,
2. For amelioration of withdrawal symptoms:
1. Acamprosate
2. Baclofen,
3. Gabapentin,
4. Memantine

34. In Type II & I.
■ Type II
■ For early onset dependence
■ Polysubstance abuse.
■ Externalizing symptoms
■ Family history positive
■ Type I
■ Late onset dependence.
■ Slowly developing
■ Family history negative
Ondansetron,
Naltrexone
Baclofen
Sertraline,
Acamprosate

35. Current status.
■ FDA approved for long term treatment in
alcoholism
■ Oral and depot injectable Naltrexone.
■ Acamprosate Disulfiram.
■ FDA approved for other indications, but not
for alcoholism. In phase II trials for
alcoholism.
■ Topiramate SSRIs
■ Ondansetron Bupropion
■ Baclofen Gabapentin
■ In phase I trials
■ Memantine Rimonabant
■ Kudzu Dopamine 3 antagonists