Drug addiction – learning gone wild? Dr Stuart McLaren MRCPsych. Phase 1 Psychopharmacology module

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 amphetamines Primary targetDopamine transporter (DAT) Main acute effects  Dopamine Adaptions  DA-ergic activity,  glutamatergic activity Other actionsLocal anaesthetic, includes 5-HT, ?NA release

Molecular targets of drugs of misuse Opiates Primary targetMu (  ) opiate receptors Main effects?  Dopamine Adaptions  sensitivity of MOR, upregulation of NA activity Other actionsKappa (  ) and delta (  ) opiate receptors

Molecular targets of drugs of misuse Alcohol Primary targetGABA/glutamate Main effects  GABA /  glutamate Adaptions  GABA sensitivity, upregulated NMDA glutamate Other actionsMany 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: © The Author Published by Oxford University Press. All rights reserved. For permissions, please

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: © The Author Published by Oxford University Press. All rights reserved. For permissions, please

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 -Aanxiety, panic ↓neuropeptide Yanti-stress ↑dynorphin‘dysphoria’ ↑CRFstress ↑noradrenalinestress  glutamatehyperexcitability

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