Abstract

Studies with both rats and nonhuman primates demonstrate that sex can be an important vulnerability factor for cocaine abuse. Females are more sensitive than males to the reinforcing effects of drugs. Estrogen, in particular, may play an important role in modulating the reinforcing and locomotor activating effects of psychomotor stimulants. An additional factor in the vulnerability to initiate drug self-administration is stress. We hypothesize that estrogen, stress and cocaine converge to activate the dopamine-regulated molecule DARPP32, and that this underlies the enhanced vulnerability to behavioral effects of cocaine seen in female animals. This may also increase the risk of female animals to stress-induced relapse to cocaine self-administration. In Specific Aim 1 we will identify interactions between sex, stress, and ovarian hormones on acquisition of cocaine self-administration. The effect of maternal separation stress on acquisition of cocaine self-administration will be compared in male and female rats and in ovariectomized females with and without estrogen replacement. An additional goal of this study is to explore the molecular neuroadaptations that underlie the effects of sex, estrogen, and stress on cocaine self-administration. Cocaine increases synaptic dopamine, which acts at D1 receptors, leading to phosphorlyation and activation of DARPP-32, an inhibitor of protein phosphatase 1, by PKA. This signaling pathway is critical for modulating both the reinforcing properties of drugs of abuse and the persistent neuroadaptations associated with cocaine exposure, stress and estrogen treatment. In Aim 3, genetic manipulation of DARPP-32 will be used to examine the ability of this molecule to knockout mice that lack either DARPP-32 or its homologue I-1. It is hypothesized that female mice lacking DARPP-32 or I-1 may show a greater attenuation in the behavioral properties of cocaine, estrogen and stress and thus lead to novel treatment strategies for cocaine abuse in women.

Recent Findings

Sex differences in ‘binge’ cocaine self-administration:
Our results support the hypothesis that females show more compulsive and binge patterns of use with females self-administering more cocaine than males over the seven days, showing a longer initial ‘binge’ length compared males, and a greater disruption in diurnal patterns of use. Preliminary data from OVX female rats have revealed that compared to vehicle treated rats, estrogen treated rats ‘binge’ for longer initial periods of time and take more cocaine suggesting that estrogen may underlie sex differences in ‘binge’ cocaine self-administration.

Sex differences in motivation to obtain cocaine following ‘binge’ self-administration:
Results showed that motivation to self-administer cocaine was decreased immediately following ‘binge’ cocaine self-administration, but only in females. Abstinence increases breakpoints in both males and females. Preliminary results have revealed that levels of phosphoralated DARPP-32 in the striatum correlate with these behavioral data. Specifically, following ‘binge’ cocaine self-administration, phosphoralated levels of DARPP-32 are decreased relative to drug naïve control animals, particularly in females and in the 0-day groups.

Sex differences during withdrawal from ‘binge’ cocaine administration:
At 12 hours post cocaine, both males and females showed high levels of behavioral signs of withdrawal. At 24 hours post cocaine, these levels were decreasing in males, but they were still elevated in females. Sex differences were also observed in locomotor activity during cocaine withdrawal. Female control rats showed high levels of locomotion throughout a 15 minute testing phase; whereas, locomotor behavior progressively decreased over the 15 minute testing phase in male control rats suggesting that they habituated to the locomotor testing apparatus. Following chronic cocaine, both male and female cocaine withdrawn rats showed decreased locomotor responses at 24 hrs. post cocaine compared to drug naïve control rats, and as observed in both groups of males, cocaine treated females showed a progressive decrease in locomotor responding.

Mouse Model for Cocaine Self-Administration:
Data from mouse self-administration paradigm in which 9 male mice self-administered cocaine and 9 control animals self-administered saline. Both groups were tested on a progressive ratio schedule for their breakpoints for saline or cocaine. Proteomic analysis was used to find sex-differences in responses to cocaine in different mouse models with altered stress response or changes in signaling pathways.

View New and Forthcoming Publications