The Role of Ventromedial PFC 5-HT2C Receptors in Cocaine-Seeking Behavior

Project: Research project

Project Details


The Role of Ventromedial PFC 5-HT2C Receptors in Cocaine-Seeking Behavior The Role of Ventromedial PFC 5-HT2C Receptors in Cocaine-Seeking Behavior Cocaine dependence is a significant health and societal problem for which there is currently no medical treatment. One difficulty in developing treatments is that cocaine dependence is associated with a high incidence of relapse, which may occur even after prolonged periods of abstinence. Factors contributing to relapse include incentive motivational effects produced by sampling cocaine and exposure to drug related cues. Measuring extinction and reinstatement of cocaine-seeking behavior elicited by cocaine-priming injections or exposure to cocaine-associated cues provides an animal model to study the neural mechanisms involved in the incentive motivational effects of these stimuli. Research suggests that different neural circuits that overlap in the prefrontal cortex (PFC) underlie incentive motivational effects produced by cocaine priming and cocaine-associated cues. Furthermore, studies have shown that both dopamine (DA) and serotonin (5-HT) play critical roles in mediating these effects. Although numerous studies have investigated the neural substrates underlying DA-mediated effects, few studies have attempted to localize the neurobiological substrates controlled by 5-HT. Yet recent research suggests that 5-HT2C receptor (R) agonists administered peripherally reduce incentive motivation for cocaine, and microinjections into the ventromedial PFC (vmPFC) decrease cocaine induced hyperactivity, outcomes that may result from inhibition of mesolimbic DA systems. This research will test the hypothesis that stimulation of vmPFC 5- HT2CRs inhibits incentive motivation for cocaine by examining whether intra-vmPFC 5-HT2CR agonist microinfusions reduce cocaine-primed and cue-elicited reinstatement of cocaine-seeking behavior. Follow up experiments will determine whether the intra-vmPFC agonist effects are region specific, reversed by a 5- HT2CR antagonist, and specific to motivation for cocaine by comparing the agonist effects on cocaine seeking to sucrose seeking. Finally, the hypothesis that intra-vmPFC agonist infusions decrease neural activation within the mesolimbic system via GABA inhibition of mPFC excitatory outputs will be examined using Fos and glutamic acid decarboxylase (GAD) expression as markers for neural activation and GABA neurons, respectively. We predict that intra-vmPFC agonist infusions will increase Fos in the PFC via local stimulation of 5-HT2CRs and that the Fos-labeled neurons in this region will co-express GAD. Furthermore, we predict that Fos expression will be decreased in mesolimbic regions, consistent with a reduction in PFC excitatory output. The findings will elucidate the role of mPFC 5-HT2CRs in incentive motivation for cocaine and may have implications for developing new treatments for cocaine dependence.
Effective start/end date5/1/094/30/12


  • HHS: National Institutes of Health (NIH): $150,726.00


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