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

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

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

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

5. Animals like drugs that release dopamine
self administration

6. Animals like dopamine
self stimulation
Glu

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

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

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

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

11. Chronic drug exposure changes the brain

12. Imagining the brain on drugs
Is reduced D2R availability due to less receptor or more DA?
Volkow (2004) Nat Rev.

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

14. 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

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

16. 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?

17. 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

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

19. 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)??

20. Conditioned place preference for morphine
removed by blocking protein synthesis after recall
Alberini (2006) JN

21. 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

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

23. 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

24. 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

25. 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

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
very low doses
Piazza (2004)

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
Piazza (2004)

30. 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???