Antecedents and Consequences of Cocaine Taking: Impact of Oxytocin

灵长类动物的支配行为和社会地位影响着生理、神经结构、行为和反应

Dominance behaviors and social status in primates affects physiology, neural structure, behavior and response to drugs of abuse. Oxytocin (OXT), a peptide hormone associated with dominance behavior modulates cocaine self-administration and is associated with hippocampal (HC) volume. Male dominance commonly relies on aggression while female dominance commonly relies on grooming. We hypothesize that the different behaviors associated with male and female social structure account for the sex differences in cocaine self-administration observed in socially-housed cynomolgus monkeys. Thus, both dominance behavior and sex moderate drug response, yet studies on the interaction of these two variables are sorely missing. We hypothesize that dominance behavior is a significant factor accounting for biologically relevant variability in research with non- human primates. Therefore, we propose a prospective study on the effects of sex, menstrual cycle, dominance behavior and cocaine self-administration on OXT levels and HC volume in rhesus monkeys and the effects of manipulating OXT on cocaine self-administration. We will use standardized, same-sex dyad-interaction tests to obtain a dominance-index for each monkey. Our preliminary data show that the dominance-index, even in singly-housed non-human primates, is related to striatal dopamine release, the reinforcing effects of cocaine, the appetitive effects of amphetamine, and HC volume. Thus the dominance-index is a relevant measure of a behavioral trait related to both social and non-social reinforcers. Aim 1. Determine the effect of dominance- index on HC volume and OXT levels in male (n = 10) and female (n = 10) rhesus monkeys. Aim 2a. Determine the reinforcing effects of self-administered i.v. cocaine and palatable food as a function of dominance-index. Aim 2b. Determine the effects of menstrual cycle and dominance-index on the reinforcing effects of self- administered i.v. cocaine and palatable food. Aim 3. Determine the effects of (9 mo) cocaine self- administration on HC volume and OXT levels as a function of the dominance-index. Aim 4. Determine the effects of a) increasing OXT levels by acute administration of SOC1, developed by Iain MacGregor, b) decreasing OXT effects by acute administration of the OXT antagonist 2,5- diketopiperazine (DTP) and c) SOC1 + DTP on cocaine self-administration as a function of the dominance-index. Impact. We will dynamically and prospectively track HC volume and OXT levels in male and female rhesus monkeys in order to assess the extent to which these measures are risk factors for drug use, consequences of drug use, or both. By using naturally varying dominance-indexes, we will be able to tease out the effects of environmental conditions from cocaine taking. This proposal will provide an empirical basis for the development of biologically-informed manipulations of the oxytocin system, and behaviorally-informed treatments based on social behavior for both males and females.