Oxytocin as a potential therapeutic for endocrine dysfunction in cocaine use disorder - Project Summary Compared with men, women progress more rapidly from casual cocaine use to misuse, have greater difficulty quitting, and have shorter periods of cocaine abstinence. Hormonal milieu both impacts, and is impacted by, the progress of cocaine use disorder (CUD) in women, leading to lasting endocrine dysfunction that may contribute to a worsened phenotype. Progesterone (P4) is a key hormone in regulation of cocaine use in women and in cocaine self-administration in nonhuman animals. Furthermore, chronic cocaine substantially disrupts cyclicity of endogenous P4 in animals. Unfortunately, P4 administration is not a viable treatment for endocrine dysfunction as it does not restore the estrous or menstrual cycle. Conversely, the hypothalamic paraventricular nucleus (PVN) neuropeptide oxytocin (OXT) shows promise as a pharmacotherapy for both endocrine dysfunction and CUD. Circulating and central OXT levels fluctuate with hormone cycles and co-vary with P4. Notably, rostral PVN- OXT neurons, which express P4 receptors, have strong projections to the nucleus accumbens (NAc), a crucial target for cocaine reinforcement. Systemic OXT administration reduces cocaine taking and restores normal estrous cycles during cocaine exposure. However, the neural mechanisms by which OXT exerts its effects in rats, its interactions with P4, and its therapeutic efficacy in monkeys remains unknown. Our working hypothesis is that OXT's therapeutic effects on endocrine dysfunction and cocaine misuse are mediated through reciprocal interactions with P4, an effect consistent across estrous (rat) and menstrual (monkey) cycles. In Aim 1 we will evaluate the neural mechanisms driving OXT’s therapeutic effects in female rats. We hypothesize that as cocaine use increases, the suppression of P4 reduces PVN-OXT signaling to the NAc, leading to greater motivation to earn cocaine (i.e., demand) in female rats. To investigate P4 and OXT interactions, we will use retrogradely transported OXT-promoter-driven DREADDs combined with a daily behavioral-economic demand procedure, which will allow us to manipulate PVN-OXT signaling to the NAc and measure its effects on estrous cyclicity and cocaine demand. In Aim 2 we will evaluate the therapeutic potential of OXT to treat endocrine dysfunction and decrease cocaine demand in the highly translational, female rhesus monkey with a menstrual cycle that is like humans. We will characterize menstrual cycles with awake daily blood sampling prior to, during, and after active cocaine taking using a daily behavioral-economic demand procedure as in Aim 1. We will administer OXT during cocaine demand and in abstinence to evaluate its therapeutic potential to restore the menstrual cycle and reduce demand. Our complementary approach will leverage the strengths of each model, as rats provide the opportunity to evaluate neural mechanisms responsible for OXT’s therapeutic effects and monkeys provide the opportunity to evaluate the translatability of OXT’s therapeutic effects on the estrous cycle to the menstrual cycle. Endocrine dysfunction is a neglected contributor to addiction, and the current application will address key knowledge gaps in this area that will contribute to our understanding and treatment of women’s health and addiction.
