Neurobiology of drug action and addiction

1. Neurobiology of drug action and addiction Richard Palmiter Dept Biochemistry

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

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

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

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

6. Animals like drugs that release dopamine self administration

7. Glu Animals like dopamine self stimulation

8. Dopamine help animals learn where important (salient) things happen

9. Animals like the effects of drugs drug Conditioned place preference Animals learn to like the place where they experience the effects of drugs

10. Drugs usurp to dopamine system Drugs have greatest effect when given in a novel environment

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

12. Chronic drug exposure changes the brain

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

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

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

16. Drug-induced changes produce sensitization locomotion days 1 2 3 4 25 PBS Drug Sensitization reflects stable changes Cross -sensitization

17. 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?

18. self administration self administration Bodily state influences drug-taking activity 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 fedfasted

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

20. 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

21. Problems with the VTA-dopamine hypothesis of addiction • 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

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

23. 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

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

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

26. 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

27. Many days of self administration, 5 days withdrawal, reinstatement with cocaine, then divide into groups based on response motivation persistence resistance Piazza (2004)

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

29. 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 All rats self-administered the same amount of cocaine Piazza (2004)

30. Conclusions: • 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???

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

32. Conclusions from Belin…Everitt paper • 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