Neurocircuitry of Relapse

1. Neurocircuitry of Relapse

2. Opioids Cocaine Amphetamines Anterior Cingulate Drug Reward Basal Ganglia Opioids Ethanol THC Nicotine Ventral Orbital VTA dopamine Glutamate Amygdala Hippocampus Circuitry Mediating Motivated Behavior

3. PET/fMRI of Cocaine CravingChildress et al., 1999; Am.J.Psychiat

4. Self-administration of Cocaine

5. Rats Taking Cocaine

6. McFarland and Kalivas, JNeurosci, 2001; McFarland et al., JNeurosci, 2003, 2004 Drug Seeking Nuc Accum Prefrontal Cortex MOTOR MEMORY Dopamine GABA Glutamate Dopamine Cells Dopamine Cells GABA Peptides LIMBIC PRIME Basolateral Extended Amygdala Amygdala STRESS CRF; Norepinephrine COKE CUE

7. Record Glutamate Here Inhibit Here NA core Drug Seeking dPFC Krista McFarland Role of Cortical Glutamate in Regulating Drug-Seeking Behavior

8. 220 Saline 200 180 Bac/Mus 160 140 120 Active Lever Presses 100 80 60 40 20 0 Inhibition of the Dorsal PFC Blocks Cocaine-induced Glutamate Release in the Accumbens and ReinstatementMcFarland et al., J. Neuroscience, 2003 * * 300 * * 250 * 200 * Glutamate (% change) 150 100 50 Cocaine 0 -120 -90 -60 -30 0 30 60 90 120 Time (min)

9. Conclusion The circuit mediating reinstatement of drug-seeking includes the glutamatergic projection from the prefrontal cortex to the nucleus accumbens. • Hypothesis Changes in protein function in the projection from the prefrontal cortex to the nucleus accumbens are targets for developing drugs to treat addiction

10. 3 Weeks Change in Gene Expression Leap Between Behavior and Proteins

11. xCT N. Acc pfc AGS3 Cortico-accumbens PathologyDysregulated Glutamatergic Response to Motivational Stimuli

12. AGS3 Structure/ Function N C Scott Bowers And Steve Lanier, LSU Med Ctr, New Orleans Bowers et al., Neuron (2004)

13. AGS3 and Receptor - G Protein Coupling Withdrawal from Cocaine Increases AGS3 in PFC and NAcore Accumbens core Gbg Second Messenger AGS3 S C S C S C Gia Repeated Saline Repeated Cocaine GTP 200 * 150 GDP AGS-3 100 50 0 Metabotropic Receptor Transmitter

14. Rn AS Rn AS Extinction Extinction Reinstate Reinstate Self-admin Pump in Pump Out 8 Active Lever Presses 2 weeks 8 Reversing Cocaine-induced Rise in AGS-3 in the PFC Prevents Reinstatement * No effect on food reinstatement; 2nd antisense oligo also works

15. Conclusions • Cocaine withdrawal increases AGS3 and decreases Gi signaling in the PFC. • Increased AGS3 partly underlies cocaine-primed reinstatement. Hypothesis AGS3 contributes to the dysregulation of prefrontal cortex in addiction.

16. 10 5 [Glu]i - [Glu]o 0 Saline (5.7 µM) -5 Cocaine (2.5 µM) -10 0 2 4 6 8 10 [Glu]i Basal Extracellular Glutamate is Reduced in the Accumbens after Withdrawal From CocainePierce et al., J. Neuroscience, 1996

17. Dave Baker What Regulates Extracellular Glutamate Levels?Baker et al., J. Neuroscience, 2002

18. Cocaine E x t i n c t i o n 1 2 0 T e s t NAC or Saline 1 0 0 8 0 Glutamate (pmol/sample) Active Lever Presses 6 0 4 0 * 2 0 0 S a l i n e N A C Time (min) N-acetylcysteine Blocks Reinstatement-induced Rise in Glutamate Baker et al., Nature Neuroscience, 2003 • Effect of N-acetylcysteine is dose-related • N-acetylcysteine does not alter food reinstatement or cocaine self-administration

19. PKA Glu Glu Glu Glu mGluR2/3 Glu Glu GSH NAC Cys Cys Cys/Glu exchanger N-acetylcysteine (NAC): Increases Cys/Glu exchange 2) Restores extracellular glutamate 3) Stimulates mGluR2/3 autoreceptors 4) Inhibits synaptic glutamate release

20. Drug Associated Stimulus Relapse to Drug-Seeking N. Acc N. Acc pfc pfc RelapseCortico-accumbens Pathology Altered Accumbens Function Reduced xCT (Baker et al., NatNeuro, 2003) Reduced Homer (Swanson et al., JNeurosci, 2001;Szumlinski et al., Neuron, 2004) Decreased Glutamate (Pierce et al., JNeurosci, 1996)) Reduced PFC Function Increased AGS3 (Bowers et al, Neuron, 2004)