Neurocircuitry of Relapse

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Neurocircuitry of Relapse. Opioids Cocaine Amphetamines. Anterior Cingulate. Drug Reward. Basal Ganglia. Opioids Ethanol THC Nicotine. Ventral Orbital. VTA dopamine. Glutamate. Amygdala Hippocampus. Circuitry Mediating Motivated Behavior. - PowerPoint PPT Presentation

Text of Neurocircuitry of Relapse

  • Neurocircuitry of Relapse

  • Circuitry Mediating Motivated Behavior

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

  • Self-administration of Cocaine

  • Rats Taking Cocaine

  • COKE CUE McFarland and Kalivas, JNeurosci, 2001; McFarland et al., JNeurosci, 2003, 2004

  • Role of Cortical Glutamate in Regulating Drug-Seeking Behavior

  • Inhibition of the Dorsal PFC Blocks Cocaine-induced Glutamate Release in the Accumbens and ReinstatementMcFarland et al., J. Neuroscience, 2003050150200250300-120-90-60-300306090120Time (min)******CocaineGlutamate (% change)100

  • 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

  • Leap BetweenBehaviorand Proteins

  • Cortico-accumbens PathologyDysregulated Glutamatergic Response to Motivational Stimuli

  • AGS3 Structure/ Function

  • AGS3 and Receptor - G Protein CouplingTransmitterMetabotropicReceptor

  • Reversing Cocaine-induced Rise in AGS-3 in the PFC Prevents Reinstatement* No effect on food reinstatement; 2nd antisense oligo also works

  • 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.

  • Basal Extracellular Glutamate is Reduced in the Accumbens after Withdrawal From Cocaine Pierce et al., J. Neuroscience, 1996

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

  • N-acetylcysteine Blocks Reinstatement-induced Rise in GlutamateBaker et al., Nature Neuroscience, 2003 Effect of N-acetylcysteine is dose-related N-acetylcysteine does not alter food reinstatement or cocaine self-administration

  • Cys/Glu exchangerN-acetylcysteine (NAC):Increases Cys/Glu exchange3) Stimulates mGluR2/3 autoreceptors4) Inhibits synaptic glutamate release2) Restores extracellular glutamate

  • RelapseCortico-accumbens PathologyReduced PFC FunctionIncreased AGS3 (Bowers et al, Neuron, 2004)Altered Accumbens FunctionReduced 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))