Alcohol: Its effects on the brain and implications for future treatment. Dr Mark Daglish

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1 Alcohol: Its effects on the brain and implications for future treatment Senior Lecturer in Addiction Psychiatry University of Queensland Dr Mark Daglish Director of Addiction Psychiatry Royal Brisbane & Women s Hospital

2 Overview Alcohol s effects in the brain Dependence Damage Where might treatments work? What s on the horizon?

3 Alcohol Causes Brain Atrophy

4 Alcohol Causes Brain Atrophy Normal Alcoholic

5 NMDA glutamate receptor Alcohol is an NMDA receptor antagonist Ca 2+ flux excitation

6 NMDA glutamate receptor Alcohol is an NMDA receptor antagonist Ca 2+ flux excitation ethanol block

7 Chronic alcohol use and glutamate receptors NMDA receptors increase in number with chronic alcohol use hyperexcitable state = withdrawal seizures excitotoxic brain damage Acamprosate may reduce these

8 Glutamate : excitatory system Acutely, alcohol inhibits this system : NMDA Chronic alcohol compensatory up-regulation? loss of magnesium also contributes

9 Glutamate : excitatory system During withdrawal compensatory receptor up-regulation + loss of magnesium leads to excess brain stimulation

10 Dead Alcohol withdrawal in the hippocampus leads to cell death : how best to prevent this probably not with benzodiazepines, but anti-glutamate drugs. Alive Hippocampus bathed in alcohol : cells are alive. When the alcohol is removed, cells in the hippocampus die due to influx of Ca 2+

11 Association between brain size and abstinence from alcohol. pre post differences Increase in hippocampal, cerebral and cerebellar volumes. 52 yr old woman, 60 units to 2 units/week 3.5 yr interval Liu et al Lancet, 2000, 355:

12 Alcohol & Brain Shrinkage Neurogenesis Adult brains grow new brain cells! Alcohol may block this Abstinence produces some regrowth BDNF is one possible mechanism Excitatory neurotoxicity During detox?every morning

13 The GABAA receptor: alcohol is an agonist greater inhibitory activity by increasing Cl - flux GABA-ergic hypofunction: vulnerability to alcoholism? subunit (6 types) confer alcohol sensitivity alcoholism associated with polymorphism of 6 subunit Chronic ethanol exposure is associated with reduced GABA receptor function and reduced levels of specific subunits: tolerance

14 Reduced BDZR levels in alcohol dependence Give midazolam: No difference in BDZR occupancy but reduced total sleep time total sleep time [mins] * Control 1 Alcohol dependent We have shown reduced sensitivity to the sleep inducing effects of benzodiazepine in alcoholism Lingford-Hughes et al 2005

15 Localisation of brain function Different areas of the brain subserve different functions

16 The Reward Pathway

raclopride binding DA neuron dopamine Lots of dopamine

17 Imaging synaptic dopaminergic neurotransmission in vivo with [11C]raclopride DA neuron Little dopamine High raclopride binding DA neuron dopamine Lots of dopamine Little raclopride binding raclopride labels D2/3 receptors

18 Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2 receptors. Volkow et al 1999 Change in BP (Placebo MP)

19 Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Volkow et al 1999

20 Dopamine Down Regulation Chronic exposure and dependence lead to decreased dopamine D2 receptor availability Volkow et al

Cocaine Low levels of cocaine selfadministration : NOT reinforcing.

21 Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Cocaine Low levels of cocaine selfadministration : NOT reinforcing. Cocaine is reinforcing i.e. consumed larger quantities than dominant monkeys. Morgan, et al 2002 Nature Neuroscience, 5 ( 2),

22 Heinz et al 2005

23 Increase in global opiate receptor availability in the brain in early abstinence from alcohol and opiates * Receptor Availability (Vd) * : significantly different to control p< Subject Type Control alcohol dependent opiate dependent n = 28 n = 11 n = 10

24 Opioid Blockers Is this why naltrexone works in alcohol dependence? Are there other opioid modulators out there that would work better?

25 Implications for Treatment Pharmacogenomics Who do acamprosate & naltrexone work for? Other targets D cycloserine & CBT? Better GABA drugs? Glutamate, dopamine Neuroprotective agents

The future of pharmacological treatment.

The future of pharmacological treatment. Anne Lingford-Hughes Professor of Addiction Biology, Imperial College. Hon Consultant CNWL NHS Foundation Trust. What substances and when? What Nicotine Alcohol