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Neurobiology of drug action and addiction Richard Palmiter Dept Biochemistry The dopamine reward system Prefrontal cortex Hippocampus Striatum Nucleus accumbens Substantia nigra Ventral tegmental area Wise (2002) Neuron Some dopamine circuit details D1R GABAAR D2R DA GABAAR NAc GABA VTA Drugs release dopamine DA Cocaine, amphetamine Morphine, heroin, nicotine D1R D2R NAc Ethanol ? DA VTA Animals like drugs that release dopamine self administration Animals like dopamine self stimulation DA Glu D1R D2R NAc Medial forebrain bundle (MFB) passes through lateral hypothalamus DA VTA Dopamine help animals learn where important (salient) things happen Animals like the effects of drugs Conditioned place preference drug Animals learn to like the place where they experience the effects of drugs Drugs usurp to dopamine system Drugs have greatest effect when given in a novel environment Voluntary drug administration is more addictive than involuntary administration Voluntary drug administration Involuntary drug administration ‘yoked situation’ Chronic drug exposure changes the brain Imagining the brain on drugs Is reduced D2R availability due to less receptor or more DA? Volkow (2004) Nat Rev. Distal spines Medium spiny neuron morphology in NAc changes Robinson, TE (2004) amphetamine Drugs produce stable changes in the brain cortex What are these changes and do they explain addiction? Glu Glu D1R Glu glial cells DA D2R NAc Glu R •Morphological •Receptors •Signaling pathways •[Glutamate] DA VTA locomotion Drug-induced changes produce sensitization days PBS 1 2 3 4 25 Drug Sensitization reflects stable changes Cross -sensitization Presumably, when some of those drug-induced changes become large enough or persistent enough the associations between state and place become habitual Which changes are addictive?? Are they reversible? Bodily state influences drug-taking activity self administration Lever presses Hungry (stressed) animals will lever press more for drugs or electrical stimulation than fed animals How does stress enhance responding? fed fasted Lever presses Reinstatement of drug taking activity extinction training drug self administration reinstatment saline self administration •Cue •Stress •Drug (i.v) cue What happens during reinstatement? Memories (associations) are recalled •Long-term memories require protein synthesis •Memories become labile when recalled •Restoring memories requires protein synthesis again !! Could bad associations be removed by blocking protein synthesis during recall (reinstatement)?? Conditioned place preference for morphine removed by blocking protein synthesis after recall Alberini (2006) JN Problems with the VTA-dopamine hypothesis of addiction • Dopamine agonists are not addictive • Some drugs that release dopamine are not addictive • Some aspects of reward learning are intact in mice lacking dopamine • Mice with dopamine signaling restored to dorsal striatum (not NAc) show normal appetitive behaviors • Other neurotransmitters are involved Drugs release dopamine, but… DA D1R D2R NAc Cocaine, amphetamine Morphine, heroin, nicotine DA VTA Dopamine receptor agonists are not drugs Is dopamine action in nucleus accumbens critical for the pleasurable effects of drugs and drug/place association ? Conditioned place preference drug Animals learn to like the place where they experience the effects of drugs Mice without DA can learn CPP for morphine & cocaine Mice without the cocaine receptor (DAT) can learn CPP for cocaine Hnasko (2005,2007) Nature, JN; Jones (2005) PNAS Serotonin Other neuromodulators are also required Conditioned place preference drug Mice without norepinephrine do not learn CPP for morphine Animals learn to like the place where they experience the effects of drugs Olson (2006) Science Mice lacking mGlu5 do not show cocaine CPP Lever presses Drug taking does not necessarily lead to addiction extinction training 3 months drug reinstatment self administration saline self administration •Cue •Stress •Drug (i.v) cue Deroche-Gamonet..Piazza, 2004 Science Hallmarks of Addiction i. Subject has difficulty limiting drug intake persistence ii. Subject has high motivation to take drug motivation i. Subject continues to take drug despite adverse consequences resistance Many days of self administration, 5 days withdrawal, reinstatement with cocaine, then divide into groups based on response 40% lowest persistence 40% highest resistance motivation Piazza (2004) Many days of self administration, 30 days withdrawal, reinstatement with cocaine or cue 40% lowest very low doses 40% highest cue Piazza (2004) 56 rats trained for a long time at self administration Three tests: persistence, resistance, motivation Consider rats ranking in top 1/3rd of group on each test: thus, individual rat could get score of 0, 1, 2 or 3 Piazza (2004) Conclusions: Rat addiction as described here is: •Requires long self-administration paradigm •Independent of amount of cocaine delivered during training •Independent of motor activity •Vulnerability is function of individual What are those individual differences???