The neurobiology of substance misuse and its relationship to dual diagnosis. Dr Anne Lingford-Hughes Reader in Biological Psychiatry and Addiction, University of Bristol Hon Consultant Bristol Area Specialist Alcohol Service, AWP PLEASURE Drugs of abuse increase dopamine concentration in the nucleus DA : accumbens of the mesolimbic system cocaine, amphetamine, alcohol, opiates, nicotine, cannabinoids, NAC MDMA DA independent alcohol, opiates, nicotine, ? benzodiazepines The dopamine reinforcement pathway: where substances of misuse interact. • stimulants VTA + PFC GABA DA Nucleus + accumbens glut • opiates (mu) • alcohol (via opiate mu) • stimulants: direct action on • nicotine DA neurons blocking uptake • cannabis (CB1) (cocaine) and/or stimulating All inhibit GABA neuron release (amphetamine) leading to increased DA- • nicotine ergic neuronal firing. • opiates • ?alcohol Increases in brain dopamine are associated with reinforcing effects of psychostimulants in humans. Volkow et al 1999 Dopamine release & ‘pleasure’ from substances of abuse in man. • In healthy volunteers • In dependent subjects – psychostimulants – Cocaine [methylphenidate, • Volkow et al, Schlaepfer amphetamine] et al • Volkow, Laruelle, Brier, – Nicotine Drevets, Leyton • Barrett et al, Brody et al – alcohol – NOT heroin • Boileau et al • Daglish et al • And in other paradigms: • playing a video game, feeding, expecting a DA agonist in Parkinson’s disease, But in dependence … • For substances of abuse – cocaine, methamphetamine, alcohol - reduced DRD2 levels have been found • do not recover with abstinence • Cause or consequence ? Volkow et al Little change with abstinence in dopamine D2 receptors levels: cocaine Control 1 month 4 months alcohol Control < 6 weeks 1-4 months Predictors of vulnerability? Subjects with low DRD2receptors report methylphenidate as pleasant Dopamine D2 receptors levels and those with high receptors as unpleasant Dopamine D2 receptors Unpleasant Pleasant Volkow et al 1999 Dopamine • The dopamine system is therefore key in mediating reward • Dopamine lies at the heart of substance use, abuse and addiction • Psychiatric disorders that dopamine is implicated in include – Schizophrenia – Psychosis – Depression Reward & DA. • Similarities in motivational dysfunction in schizophrenia and in individuals with substance misuse – less sensitive to reward and punishment. • Anhedonia and other negative affective symptoms may be caused by disruption in DA-ergic functioning leading to lower sensitivity. – disruptions of frontostriatal and corticolimbic networks Iowa Gambling Task : decision making process. As the task progresses, controls shift their preference to ‘good’ decks (C,D) away from ‘bad’ decks (A,B) – unlike patients with schizophrenia or substance dependence (alcohol + stimulants) control control SCZ SUD Bechara et al, Shurman et al Dysfunction of ventral striatal reward prediction in schizophrenia During anticipation of monetary gain or loss, activation seen in ventral striatum of healthy controls and is NOT seen in unmedicated SCZ; related to negative symptoms. Gain – neutral Loss - neutral Juckel et al 2006 Is there a common underlying DA-ergic dysfunction in schizophrenia and substance abuse? Substance abuse Schizophrenia • Reduced DA release • DA ‘hyperactivity’ and DRD2 binding may not occur in the levels ventral striatum • DRD2 levels • DRD2 blockade by negatively correlate antipsychotics with alcohol craving reducing function These reductions in DA function may contribute to the deficits in ventral striatal activation during the anticipation of reward and punishment. Self-medication : negative reinforcement Neuropathology of schizophrenia Symptoms of Substance abuse schizophrenia vulnerability Primary Addiction Hypothesis : positive reinforcement Neuropathology of schizophrenia Symptoms of Substance abuse schizophrenia vulnerability ‘extra reward valence’ Prefrontal cortex glutamate Thalamus Ventral striatum dopamine VTA Hippocampal formation Prefrontal cortex glutamate Thalamus Ventral ++++++++ striatum dopamine VTA Hippocampal formation Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia. Animals with neonatal ventral hippocampal lesions press the lever more for cocaine than control animals. Chambers & Self, 2002 Depression Dopamine also plays a key role. Depression and drug withdrawal have a similar neurobiology. Markou, Koob Nicotine & Depression. • ~50% depressed patients smoke • Number of cigarettes smoked /day is associated with lifetime prevalence of major depression. • Antidepressants can reduce smoking • Which comes first? • Nicotine ameliorates symptoms of depression • Nicotine dependence leads to changes in the brain which result in depressive symptoms – particularly emerging in withdrawal. Nicotine’s biology • Increase in DA is important for pleasurable and reinforcing effects • Nicotine modulates dopamine, serotonin, noradrenaline, ACH, GABA, glutamate • Role for opioid and cannabinoid systems since nicotine is not dependence producing or rewarding in mice lacking mu opioid receptors or CB1 receptors – Role for antagonists: naltrexone or rimonabant Brain monoamine oxidase A and B inhibition (~40%) in cigarette smokers Fowler et al 1996 Nicotine & schizophrenia. • Higher rates of smoking (~90%), extract more nicotine during smoking • Nicotine improves cognitive functioning – Attention, working memory, reaction times • Nicotine withdrawal worsens cognitive deficits. Specific drugs of abuse Cannabis Alcohol Cannabis. • Active psychoactive constituent – ∆9tetrahydrocannabinol • Other constituent – cannabidiol - ?antipsychotic • Receptors – CB1 – brain, neuronal – CB2 – immune cells • Endocannabinoids – Anandamide – 2 Arachidonyl-glycerol (2-AG) Endocannabinoids are Retrograde Modulators of Neurotransmitter Release Pre synaptic neurone e.g. GABA, glutamate dopamine, Ca++ 1 CB HO N H HO N H O O ? Transporter HO N H O anandamide HO N H O Arachidonate Ethanolamine Wilson & Nicoll Nature 2001;410:588-592 Kreitzer & Regehr Neuron 2001;29:717-727 Ohno-Shosaku et al Neuron 2001;29:729-738 Cannabis & schizophrenia • Neurobiological links – Higher CSF levels of anandamide in SCZ – DA transporter levels in THC (-) SCZ are lower than controls, but THC (+) are equivalent – CB1 receptor levels higher in some parts of the brain e.g. prefrontal cortex in SCZ – i.v. ∆9-THC in patients leads to increased positive symptoms in SCZ, worsens memory – Genetic • CB1 receptor and hebephrenic SCZ • Val158Met COMT (but with psychosis) Alcohol. Alcohol : modulates GABA- benzodiazepine receptor function. Acutely : alcohol increases GABA-ergic function leading to - reduced anxiety, ataxia, slurred speech, sedation, disinhibition, reduced levels of consciousness. Chronically : GABA-ergic function is reduced: tolerance The GABAA receptor & alcohol GABA GABA+alcohol GABA+alcohol Cl- Cl- Cl- γ α β β α No alcohol Acute alcohol Chronic alcohol α1−6, β1−3, γ1−3 tolerance ? subunit switch Reduced BDZR Give midazolam: levels in alcohol No difference in BDZR dependence occupancy but reduced total sleep time 40.00 35.00 30.00 total sleep time [mins] 25.00 20.00 15.00 * 10.00 5.00 0.00 Control Alcohol dependent 1 We have shown reduced sensitivity to the sleep inducing effects of benzodiazepine in alcoholism Lingford-Hughes et al 2005 Does this underpin the comorbidity between alcohol misuse and anxiety? Healthy control Panic disorder Malizia et al 1998 Alcohol and the excitatory glutamatergic system. Alcohol acts as an NMDA receptor antagonist Ca2+ flux excitation The NMDA receptor & alcohol • to overcome alcohol antagonising NMDA receptor function • NMDA receptors are upregulated • effects : •long term potentiation (process involved in memory) in the hippocampus is attenuated by alcohol • hyper-excitable state in withdrawal • seizures, DTs Alcohol withdrawal • increased activity in – NMDA receptor Ca2+ flux – L-subtype of Ca2+ channel – noradrenergic activity hyper-excitability cell death • decreased – GABA-ergic activity – Mg2+ inhibitory system (NMDA receptor) – DAergic activity Hippocampal damage during alcohol withdrawal Role of the NMDA receptor system Dead Control Alcohol Withdrawal Alive courtesy of Prendergast & Littleton Hippocampal damage during alcohol withdrawal Role of the NMDA receptor system Dead Alcohol Withdrawal Control Alcohol Withdrawal + Acamprosate (200 mM) Alive cell death also reduced with other NMDA antagonists, but courtesy of Prendergast & Littleton not diazepam Alcohol withdrawal • Multiple cycles of ethanol withdrawal significantly increased sensitivity to seizures – Diazepam suppressed withdrawal symptoms but did not alter seizure susceptibility Mhatre et al 2001 • Ethanol withdrawal is associated with increases in glutamate in the brain – Acamprosate blocks this • Repeated ethanol withdrawal leads to greater levels of glutamate & increased mortality – Acamprosate blocks this Dahchour & De Witte 2003 Treatment. What is being treated? Psychiatric disorder Substance misuse disorder www.bap.org.uk Treatment of comorbid depression • Overall, antidepressants may improve mood but not necessarily alcohol /drug behaviour in depressed dependent patients. • Alcohol – SSRIs appear effective in improving drinking behaviour and depression only in severely depressed patients. – SSRIs should be avoided in type 2 alcoholism • Cocaine – Desipramine and fluoxetine show no significant advantage over placebo in cocaine dependence alone or in cocaine misusing methadone maintained opioids addicts • Nicotine – Limited studies but should offer NRT and/or bupropion • TCAs are not recommended due to potentially serious interactions between TCAs and substance; overdose Schizophrenia with substance misuse and dependence: • Given the dearth of information, it is difficult to draw up recommendations • Typical antipsychotics do not seem to improve substance misuse and may even contribute to it, so we recommend that their use be avoided where possible • Atypical antipsychotics appear to have a more favourable outcome though there are no controlled data to support this supposition (except nicotine) • Clozapine has been reported to reduce substance misuse and improve psychosis but this data is still preliminary Summary. The neurobiology of substance misuse and its relationship to dual diagnosis. • Knowledge about neurobiology of substance misuse is increasing – able to compare with psychiatric disorders and predict the potential consequences of substance misuse • Dopamine is a key neurotransmitter involved in substance misuse and many psychiatric disorders – Too much and too little – Modifiers: opioid, cannabinoid, glutamate – all potential therapeutic targets.