Neurocircuitry of Relapse Circuitry Mediating Motivated Behavior Opioids
Neurocircuitry of Relapse
Circuitry Mediating Motivated Behavior Opioids Cocaine Amphetamines Anterior Cingulate Basal Ganglia Glutamate Ventral Orbital Amygdala Hippocampus Opioids Ethanol THC Nicotine VTA dopamine Drug Reward
PET/f. MRI of Cocaine Craving Childress et al. , 1999; Am. J. Psychiat
Self-administration of Cocaine
Rats Taking Cocaine
Mc. Farland Kalivas, JNeurosci, 2001; Mc. Farland et al. , JNeurosci, 2003, 2004 MOTOR MEMORY Nuc Accum Prefrontal Cortex COKE Drug Seeking Dopamine GABA Glutamate Dopamine Cells LIMBIC PRIME GABA Peptides CUE STRESS Basolateral Amygdala Extended Amygdala CRF; Norepinephrine
Role of Cortical Glutamate in Regulating Drug-Seeking Behavior Inhibit Here d. PFC Krista Mc. Farland Record Glutamate Here NA core Drug Seeking
Inhibition of the Dorsal PFC Blocks Cocaine-induced Glutamate Release in the Accumbens and Reinstatement * 300 Saline 250 200 * * 220 Bac/Mus * * 150 100 50 0 Cocaine -120 -90 -60 -30 0 30 60 90 120 Time (min) 200 * Active Lever Presses Glutamate (% change) Mc. Farland et al. , J. Neuroscience, 2003 180 160 140 120 100 80 60 40 20 0
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
Change in Gene Expression Leap Between Behavior and Proteins 3 Weeks
Cortico-accumbens Pathology Dysregulated Glutamatergic Response to Motivational Stimuli x. CT N. Acc pfc AGS 3
AGS 3 Structure/ Function N C Scott Bowers And Steve Lanier, LSU Med Ctr, New Orleans Bowers et al. , Neuron (2004)
AGS 3 and Receptor - G Protein Coupling Second Messenger Metabotropic Receptor Gbg Gia Withdrawal from Cocaine Increases AGS 3 in PFC and NAcore Accumbens core Transmitter S AGS 3 C S C Repeated Saline Repeated Cocaine GTP GDP AGS-3 200 150 100 50 0 *
Active Lever Presses Reversing Cocaine-induced Rise in AGS-3 in the PFC Prevents Reinstatement Reinstate Self-admin Pump in Rn 8 Extinction Pump Out AS Rn AS 2 weeks 8 * No effect on food reinstatement; 2 nd antisense oligo also works
Conclusions Ø Cocaine withdrawal increases AGS 3 and decreases Gi signaling in the PFC. Ø Increased AGS 3 partly underlies cocaineprimed reinstatement. Hypothesis AGS 3 contributes to the dysregulation of prefrontal cortex in addiction.
Basal Extracellular Glutamate is Reduced in the Accumbens after Withdrawal From Cocaine [Glu]i - [Glu]o Pierce et al. , J. Neuroscience, 1996 10 5 0 Saline (5. 7 µM) -5 Cocaine (2. 5 µM) -10 0 2 4 6 [Glu]i 8 10
What Regulates Extracellular Glutamate Levels? Baker et al. , J. Neuroscience, 2002 Dave Baker
N-acetylcysteine Blocks Reinstatement-induced Rise in Glutamate Baker et al. , Nature Neuroscience, 2003 Active Lever Presses Glutamate (pmol/sample) Cocaine NAC or Saline 120 100 80 60 40 * 20 0 Time (min) Extinction Test Saline NAC Ø Effect of N-acetylcysteine is dose-related Ø N-acetylcysteine does not alter food reinstatement or cocaine self-administration
Glu PKA Glu Glu m. Glu. R 2/3 Glu NAC GSH Cys N-acetylcysteine (NAC): 1) 2) 3) 4) Cys/Glu exchanger Cys Increases Cys/Glu exchange Restores extracellular glutamate Stimulates m. Glu. R 2/3 autoreceptors Inhibits synaptic glutamate release
Relapse Cortico-accumbens Pathology Drug Associated Stimulus Altered Accumbens Function Relapse to Drug-Seeking Reduced x. CT (Baker et al. , Nat. Neuro, 2003) Reduced Homer (Swanson et al. , JNeurosci, 2001; Szumlinski et al. , Neuron, 2004) Decreased Glutamate (Pierce et al. , JNeurosci, 1996)) N. Acc pfc Reduced PFC Function Increased AGS 3 (Bowers et al, Neuron, 2004)
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