Neurobiology of drug action and addiction Richard Palmiter Dept Biochemistry

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

Some dopamine circuit details D1R D2R DA GABA GABA A R NAc VTA

Some dopamine signaling details D1R DA NAc VTA D2R GABA Glu burst 1 sec High affinity Low affinity

Drugs release dopamine D1R D2R DA NAc VTA DA Cocaine, amphetamine Morphine, heroin, nicotine Ethanol ?

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 drug 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 Involuntary drug administration ‘yoked situation’ Voluntary drug administration is more addictive than involuntary administration

Chronic drug exposure changes the brain

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

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

Imagining the brain on drugs Volkow (2004) Nat Rev. Reduced D2R availability & blood flow correlate with addiction

Drug-induced changes produce sensitization locomotion PBS Drug days Sensitization reflects stable changes Cross -sensitization

Presumably, some of the drug- induced changes in neural plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking Which changes are addictive? Are they reversible?

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

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

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 !! Conditioned place preference for morphine can be erased by blocking protein synthesis after recall Alberini (2006) JN

Dopamine receptor agonists are not addictive Some drugs that release dopamine are not addictive Some aspects of reward learning are intact in mice lacking dopamine Mice without dopamine can still learn a conditioned place preference for morphine or cocaine Other neurotransmitters are involved Problems with the VTA-dopamine hypothesis of addiction

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

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 without Norepinephrine (NE) do not learn CPP for morphine Olson (2006) Science Other neuromodulators are also required NE action in pre-frontal cortex may be necessary for drugs to activate dopamine neurons

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

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 persistenceresistance motivation Piazza (2004)

Many days of self administration, 30 days withdrawal, reinstatement with cocaine or cue cue very low doses Piazza (2004) All rats self- administered the same amount of cocaine

56 rats trained for a long time at self administration Three tests: persistence, resistance, motivation Consider rats ranking in top 1/3 rd of group on each test: thus, individual rat could get score of 0, 1, 2 or 3 Piazza (2004) All rats self- administered the same amount of cocaine

Rat addiction as described here: 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??? Conclusions:

Addiction correlates with impulsivity rather than novelty seeking Belin…. Everitt (2008) A. Identify high and low impulsive rats B. Identify high and low reactivity to novelty rats Persistence, Resistance, Motivation

High correlation between impulsivity and transition to compulsive drug taking Impulsivity precedes drug use Independent of initial propensity to acquire cocaine self administration Impulsivity correlates with low D2 receptor abundance in ventral striatum Early vulnerability to take cocaine correlates better with novelty seeking Conclusions from Belin…Everitt paper