Drug addiction – learning gone wild?

Dr Stuart McLaren

MRCPsych. Phase 1 Psychopharmacology module

15.02.13

Structure of session

• Introduction• Dopamine and the mesolimbic reward systems

in the brain• Systems modulating the mesolimbic system

– GABA– Opioids– Glutamate

• Tolerance and withdrawal• Substitution or maintenance treatments

Substance dependence (3+ in last year)

• Strong desire or sense of compulsion to take alcohol

• Difficulties controlling alcohol-taking behaviour• Physiological withdrawal state when alcohol is

stopped or reduced• Evidence of tolerance• Neglect of alternative pleasures or interests (so-

called ‘salience’)• Persisting with alcohol use despite harmful

consequences

Phases of treatment 1

Substitution therapy

Opiates – methadone, buprenorphine, heroin

Stimulants – controversial

Alcohol – not generally used

Benzodiazepines - controversial

Phases of treatment 2

Detoxification

Opiates – dose methadone or buprenorphine, lofexidine

Stimulants – none, symptomatic

Alcohol – benzodiazepines, anticonvulsants, ? acamprosate

Benzodiazepines - dose

Phases of treatment 3

Relapse prevention

Opiates – naltrexone

Stimulants – none

Alcohol – acamprosate, naltrexone, disulfiram, baclofen

Benzodiazepines - none

Molecular targets of drugs of misuse

Cocaine and amphetaminesPrimary target Dopamine transporter

(DAT)

Main acute effects Dopamine

Adaptions DA-ergic activity, glutamatergic activity

Other actions Local anaesthetic, includes 5-HT, ?NA release

Molecular targets of drugs of misuse

Opiates

Primary target Mu () opiate receptors

Main effects ? Dopamine

Adaptions sensitivity of MOR, upregulation of NA activity

Other actions Kappa () and delta () opiate receptors

Molecular targets of drugs of misuse

Alcohol

Primary target GABA/glutamate

Main effects GABA / glutamate

Adaptions GABA sensitivity, upregulated NMDA glutamate

Other actions Many other systems reward, opioid, GABA-B, dopamine

A simplified model of addiction

Model proposing a network of four circuits involved with addiction

Reward (or reinforcements) – objects or events that make us come back for more

Intracranial self-administration of morphine in a rat

Activation of the reward pathway by electrical stimulation

Activation of human striatum by various rewards

Brain images at different times after drug administration

The role of dopamine in reward circuits

Dopamine (D1-like) receptor structure

Dopamine circuits in the brain

Mechanism of drug-related increase in dopamine activity

• Block of dopamine transporter (DAT) in NAcc e.g. Cocaine

• Reuptake blockade plus direct DA release from terminals e.g. Amphetamine

• Increased DA neuronal firing via disinhibition in the VTA e.g. Alcohol, opiates, nicotine

Dopamine binding to receptors and uptake pumps in the nucleus accumbens: the action of cocaine

Key structures and connections involved in addiction

Lingford-Hughes A et al. Br Med Bull 2010;96:93-110

© The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

fMRI during cocaine intoxication vs. saline infusion

Low level of dopamine D2 receptors in methamphetamine abusers

Where substances of abuse interact with the dopaminergic mesolimbic system and its key modulators.67.

Lingford-Hughes A et al. Br Med Bull 2010;96:93-110

© The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

PET study of the effect of chronic drug exposure

PET scan of raclopride binding in the striatum of cocaine and methamphetamine

abusers

Axial sections with PET showing DA D2 receptors in non human primates

The action of bupropion

• Atypical antidepressant • Used in treatment of nicotine dependence,

detoxification and relapse prevention• DA and NA reuptake inhibitor, antagonist at

nicotinic acetylcholinergic receptor• Meta-analysis of 49 trials > effective than

placebo• Action independent of antidepressant effect

Bupropion blocks the DAT

Conventional mechanism of action of disulfiram in relapse prevention

Other action of disulfiram, DA levels

Other neurotransmitter systems that modulate the mesolimbic system

GABA

GABA-A receptor structure

Alcohol’s effect on neurotransmitter systems involved in the brain’s reward pathways

Action of the brain’s GABA system in the presence of alcohol

Action of the brain’s GABA system after chronic alcohol exposure

The action of baclofen

• GABA – B agonist• Licensed for muscle spasm• Increases tonic inhibition of mesolimbic DA

neurons• Reduces DA release in the ventral striatum• Reduces drug seeking and consumption of

alcohol, cocaine and nicotine• Reduces relapse in alcohol dependence, not yet

mainstream

Other neurotransmitter systems that modulate the mesolimbic system

Opioids

The neuroactive peptide beta-endorphin

Structure of diamorphine

Opioid receptor structure

Opioid receptor function

• Mu (MOR) analgesia, respiratory depression, pupillary constriction

• Kappa (KOR) dysphoria, depersonalization, sedation

• MOR + DOR activation of reward

• KOR attenuates reward

MOR receptors are present in the VTA on the GABA inhibitory neurons

Opiates binding to opiate receptors in the nucleus accubens: increased dopamine

release

The action of naltrexone

• Non-selective opiate antagonist• Increases activity in the OfCx (? control)• Blocks reward associated with MOR in the VTA

via preventing increased DA activity• Used both in opiate and alcohol dependence

relapse prevention• May be useful in some impulse-control disorders

such as pathological gambling

Other neurotransmitter systems that modulate the mesolimbic system

glutamate

Receptors modified by alcohol

Glutamate receptor structure

Alcohol’s effect on neurotransmitter systems involved in the brain’s reward pathways

Alcohol’s effect on endogenous opioids and the mesolimbic DA system

Activation of the brain’s glutamate system

Activation of the brain’s glutamate system with alcohol

The action of acamprosate

• Used in alcohol relapse prevention• Said to be ‘anticraving’ in action glutamatergic activity GABA–ergic activity• Partial agonist at the NMDA receptor in Nacc• May be neuroprotective during alcohol

withdrawal

Tolerance and withdrawal

Two sides of the same coin

Neurotransmitters implicated in substance withdrawal

• ↓dopamine ‘dysphoria’• ↓serotonin ‘dysphoria’GABA -A anxiety, panic• ↓neuropeptide Y anti-stress• ↑dynorphin ‘dysphoria’• ↑CRF stress• ↑noradrenaline stress glutamate hyperexcitability

Actions of the brain’s GABA system in chronic alcohol exposure and

withdrawal

Action of the brain’s glutamate system after chronic exposure to alcohol and during

withdrawal

Alcohol withdrawal

• Benzodiazepines GABA-ergic function• Anticonvulsants e.g. Lamotrigine (glutamate

release inhibitor) • Acamprosate NMDA hyperactivity, and may

have neuroprotective effects (i.e. reduced cell death)

Opiate withdrawal

Lofexidine and clonidine

• Alpha-2 receptor agonist• Reduces noradrenergic overactivity associated

with opiate withdrawal (MOR are inhibitory and NA activity upregulated in ascending brain pathways)

• Main site of action the locus coeruleus• May cause hypotension, clonidine>lofexidine

Substitute or maintenance treatment

A very good evidence base but still controversial with some

Opioid maintenance therapy

Methadone• Full MOR agonist• Receptor occupancy ~ 32%• Long acting (half life ~ 24 hours)

Buprenorphine• Partial MOR agonist, KOR antagonist• High affinity

• Long acting (half life > 24 hours)

Novel mechanisms

Stress/antistress systems

Glial cells

The effect of alcohol on reward and stress circuits in the brain

Astrocyte function