Exposure to a cocaine-associated environment elicits craving and/or an increase in propensity for relapse in cocaine users. Persistent and reoccurring environmentally triggered motivation for cocaine is likely elicited by plasticity in associative learning, memory, motivation, and executive cognitive function, implicating the involvement of the hippocampal formation, amygdala, nucleus accumbens, and frontal cortex in this phenomenon. However, the neural bases of context-induced drug relapse have been largely uncharacterized in part due to the scarcity of animal models that can be used to assess the motivational effects of environmental stimuli predictive of drug availability, as opposed to the motivational effects of conditioned stimuli paired explicitly with cocaine infusions. Using a new animal model in which cocaine seeking is elicited by exposure to a context predictive of drug availability, we have recently demonstrated that the functional integrity of the dorsal hippocampus (DH), basolateral amygdala (BLA), dorsomedial prefrontal cortex (dmPFC) and nucleus accumbens core (NACc) is necessary for contextual reinstatement of cocaine seeking. Taking a systems neurobiological approach, the proposed project expands the mapping of this critical pathway by further examining the role of the hippocampal formation, specifically the involvement of the ventral hippocampus (VH), subiculum, and entorhinal cortex, in contextual reinstatement of cocaine and food seeking using the tetrodotoxin-induced reversible neural inactivation method. Using similar techniques, the project will also further investigate the involvement of the NACc and nucleus accumbens shell in contextual reinstatement of cocaine and food seeking, as the former structure is postulated to be the input structure of the relapse circuitry toward the basal ganglia (Aim 1). Reversible asymmetrical inactivation (i.e., disconnection) will then be used to test the hypothesis that, within the contextual relapse circuitry, sequential information processing occurs between the DH and dmPFC as well as between the BLA and dmPFC via parallel loops, and information is then sequentially processed by the dmPFC and NACc (Aim 2). Lastly, the project will test the hypotheses that AMPA and metabotropic glutamate (mGLU) receptors within the relapse circuitry play a critical role in contextual reinstatement and that cocaine-induced adaptations in these receptor systems facilitate cocaine seeking. To this end, the project will examine dose-dependent effects of locally infused selective AMPA, group 1 mGLU, and group 2 mGLU receptor antagonists and/or agonists on contextual reinstatement of cocaine and food seeking (Aim 3). In summary, the objective of the proposed project is to elucidate the neurobiological and neuropharmacological mechanisms of contextual cocaine seeking. The resulting data have the potential to provide a rationale for the development of novel treatments for cue-induced drug relapse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Arguello, Amy A; Wang, Rong; Lyons, Carey M et al. (2017) Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats. Psychopharmacology (Berl) 234:2431-2441
Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A et al. (2014) Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 39:660-9
Xie, Xiaohu; Wells, Audrey M; Fuchs, Rita A (2014) Cocaine seeking and taking: role of hippocampal dopamine D1-like receptors. Int J Neuropsychopharmacol 17:1533-8
Wells, Audrey M; Arguello, Amy A; Xie, Xiaohu et al. (2013) Extracellular signal-regulated kinase in the basolateral amygdala, but not the nucleus accumbens core, is critical for context-response-cocaine memory reconsolidation in rats. Neuropsychopharmacology 38:753-62
Xie, Xiaohu; Arguello, Amy A; Wells, Audrey M et al. (2013) Role of a hippocampal SRC-family kinase-mediated glutamatergic mechanism in drug context-induced cocaine seeking. Neuropsychopharmacology 38:2657-65
Xie, Xiaohu; Lasseter, Heather C; Ramirez, Donna R et al. (2012) Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats. Addict Biol 17:287-99
Xie, Xiaohu; Arguello, Amy A; Reittinger, Andrew M et al. (2012) Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats. Psychopharmacology (Berl) 223:271-9
Lasseter, Heather C; Wells, Audrey M; Xie, Xiaohu et al. (2011) Interaction of the basolateral amygdala and orbitofrontal cortex is critical for drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 36:711-20
Wells, Audrey M; Lasseter, Heather C; Xie, Xiaohu et al. (2011) Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats. Learn Mem 18:693-702
Lasseter, H C; Xie, X; Ramirez, D R et al. (2010) Sub-region specific contribution of the ventral hippocampus to drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuroscience 171:830-9

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