Relapse to drug abuse following abstinence is a significant impediment in the treatment of cocainedependence. Although various factors (stress, conditioned cues, drugs) that contribute to relapse have beenstudied in males, the impact in females has been less explored. We have recently shown sex differences forconditioned cue-induced and drug-primed reinstatement of cocaine-seeking in an animal model of relapse.Moreover, the differences seen in females are closely linked to the estrus phase of the estrous cycle.Building on these previous studies, this SCOR project will provide a comprehensive approach to examinesex and estrous cycle dependent differences in reinstatement of cocaine-seeking produced by varioustrigger factors. Using direct pharmacological activation of the neural pathways that mediate stress responses(e.g., ascending noradrenergic pathways and corticotropin-releasing factor receptors) we predict that femalerats (particularly during the estrus phase) will show greater reinstatement of cocaine-seeking than male ratsexposed to the same stressor. The use of the exact same stressors and cue reactivity approaches in boththe animal model and the human clinical laboratory (SCOR Project #2),will provide a high degree ofhomology and integration. Following characterization of stress and stress+cue induced reinstatement inmales and females, we will examine sex and estrous cycle dependent pharmacotherapy interventions thatwill attenuate relapse, specifically: a) clonidine, a noradrenergic receptor agonist that may selectively blockstress-induced reinstatement; b) progesterone, an ovarian hormone that we have recently found to beinversely related to cocaine-seeking in females; and c) aripiprazole, a novel dopamine receptor partialagonist that blocks cue and drug-primed reinstatement in males, but has never been tested in females. Theinformation gained from these studies will integrate with the clinical SCOR projects that will focus on genderdifferences and relapse in cocaine (Project #2) and nicotine (Project #4) dependent women andmen,including the relationship of ovarian hormones to drug-seeking. In addition, this project will parallel thepreclinical animal model of sex and estrous cycle dependent differences in nicotine-seeking andreinstatement in Project #3.This preclinical animal model of relapse will characterize fundamental sex and estrous cycle dependentdifferences in cocaine-seeking behavior produced by known risk factors for relapse in humans (i.e., stress,cues, drugs). Furthermore, we will assess pharmacotherapies that may be generalized across males andfemales, as well as interventions that may be gender-specific. The results from these studies will helpidentify promising pharmacotherapeutic agents for future testing in the human laboratory setting.
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| Moran-Santa Maria, Megan M; Vanderweyen, Davy C; Camp, Christopher C et al. (2018) Network Analysis of Intrinsic Functional Brain Connectivity in Male and Female Adult Smokers: A Preliminary Study. Nicotine Tob Res 20:810-818 |
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| Moreland, Angela D; McRae-Clark, Aimee (2018) Parenting outcomes of parenting interventions in integrated substance-use treatment programs: A systematic review. J Subst Abuse Treat 89:52-59 |
| Spencer, Sade; Neuhofer, Daniela; Chioma, Vivian C et al. (2018) A Model of ?9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens. Biol Psychiatry 84:601-610 |
| Cox, Brittney M; Bentzley, Brandon S; Regen-Tuero, Helaina et al. (2017) Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand. Biol Psychiatry 81:949-958 |
| Melis, Miriam; Frau, Roberto; Kalivas, Peter W et al. (2017) New vistas on cannabis use disorder. Neuropharmacology 124:62-72 |
| Leong, Kah-Chung; Freeman, Linnea R; Berini, Carole R et al. (2017) Oxytocin Reduces Cocaine Cued Fos Activation in a Regionally Specific Manner. Int J Neuropsychopharmacol 20:844-854 |
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