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: [email protected]
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: [email protected]
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