Neurobiology of drug action and addiction Richard Palmiter Dept Biochemistry

The dopamine reward system Substantia nigra Ventral tegmental area Nucleus accumbens Prefrontal cortex Hippocampus Striatum Wise (2002) Neuron

Some dopamine circuit details D1R GABAAR DA D2R GABAAR GABA NAc VTA

NAc DA VTA Drugs release dopamine Cocaine, amphetamine Morphine, heroin, nicotine DA D2R Ethanol ? NAc VTA

Animals like drugs that release dopamine self administration

Animals like dopamine self stimulation Glu

Dopamine help animals learn where important (salient) things happen

Animals like the effects of drugs Conditioned place preference 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 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.

Medium spiny neuron morphology in NAc changes Distal spines Robinson, TE (2004) amphetamine

What are these changes and do they explain addiction? Drugs produce stable changes in the brain cortex What are these changes and do they explain addiction? Glu Glu D1R Glu R Glu DA DA D2R Morphological Receptors Signaling pathways [Glutamate] glial cells NAc VTA

Drug-induced changes produce sensitization locomotion days 1 2 3 4 25 PBS 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?

How does stress enhance responding? Bodily state influences drug-taking activity self administration self administration self administration self administration Hungry (stressed) animals will lever press more for drugs or electrical stimulation than fed animals How does stress enhance responding? Lever presses fed fasted

Reinstatement of drug taking activity extinction Lever presses reinstatment Cue Stress Drug (i.v) training drug saline 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

NAc Drugs release dopamine, but… DA VTA Cocaine, amphetamine D1R Morphine, heroin, nicotine DA D2R NAc VTA Dopamine receptor agonists are not drugs

Hnasko (2005,2007) Nature, JN; Jones (2005) PNAS Is dopamine action in nucleus accumbens critical for the pleasurable effects of drugs and drug/place association ? Mice without DA can learn CPP for morphine & cocaine Mice without the cocaine receptor (DAT) can learn CPP for cocaine Serotonin Hnasko (2005,2007) Nature, JN; Jones (2005) PNAS

Mice lacking mGlu5 do not show cocaine CPP Other neuromodulators are also required Mice without norepinephrine do not learn CPP for morphine Olson (2006) Science Mice lacking mGlu5 do not show cocaine CPP

Drug taking does not necessarily lead to addiction saline drug Lever presses training extinction reinstatment cue Cue Stress Drug (i.v) 3 months Deroche-Gamonet..Piazza, 2004 Science

Hallmarks of Addiction Subject has difficulty limiting drug intake persistence Subject has high motivation to take drug motivation 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 motivation persistence resistance Piazza (2004)

Many days of self administration, 30 days withdrawal, reinstatement with cocaine or cue very low doses 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)

What are those individual differences??? 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???