Stress resilience-associated behaviors following predator scent stress are accompanied by upregulated nucleus accumbens mGlu5 transcription in female Sprague Dawley rats.

Despite the higher prevalence of post-traumatic stress disorder (PTSD) in women, the majority of preclinical research has been conducted utilizing male subjects. We have found that male rats exposed to the predator scent 2,4,5-trimethyl-3-thiazoline (TMT) show heterogenous long-term anxiety-like behavior and conditioned fear to the TMT environment. Stress-Resilient males exhibit increased mGlu5 mRNA expression in the basolateral amygdala (BLA) and prefrontal cortex (PFC). Here we sought to determine whether the same behavioral and genetic responses would be observed in female rats exposed to TMT. Female Sprague-Dawley rats were exposed to TMT for ten minutes, while Controls were exposed to an unscented environment. Anxiety and anhedonia were assessed 7-14 days later with elevated plus maze (EPM), acoustic startle response, light-dark box, and sucrose preference test (SPT). TMT-exposed females spent less time in the EPM open arms, exhibited greater startle amplitude, and reduced sucrose intake compared to Controls. Median split analyses conducted on EPM and SPT data yielded stress-Susceptible and -Resilient phenotypes that displayed behavior in the light-dark box consistent with EPM and SPT behavior. Susceptible females displayed greater BLA mGlu5 mRNA expression than Resilient and Control rats and did not show conditioned fear, in contrast to previous results in males. Resilient females displayed greater mGlu5 mRNA expression in the nucleus accumbens. These data indicate that the predator scent stress model of PTSD produces distinct stress-Susceptible and Resilient phenotypes in female rats that are associated with changes in mGlu5 mRNA expression in several brain regions.

Systemic oxytocin increases glutamate efflux in the nucleus accumbens core of cocaine-experienced male and female rats but only increases dopamine efflux in males.

Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nucleus accumbens core. This effect is blocked by intra-accumbens antagonism of mGlu2/3 and, together with our finding that intra-accumbens oxytocin increases glutamate concentrations in this brain region, indicates that pre-synaptic regulation of glutamate release by oxytocin influences cocaine relapse. However, mGlu2/3 receptors also regulate dopamine release in the nucleus accumbens. Here we aimed to determine whether systemic oxytocin increases glutamate and dopamine concentrations in the nucleus accumbens core of cocaine-experienced and cocaine-naïve male and female rats. A subset of rats self-administered cocaine (0.5 mg/kg/infusion) and then underwent extinction training for 2-3 weeks. Rats were implanted with microdialysis probes in the accumbens core and samples were collected for a baseline period, and following saline (1 mL/kg), and oxytocin (1 mg/kg, IP) injections. Locomotion was assessed during microdialysis. In cocaine-experienced rats, oxytocin increased glutamate concentrations in the accumbens core to the same extent in males and females but only increased dopamine concentrations in male rats. Oxytocin did not alter glutamate levels in cocaine-naïve rats. Oxytocin did not produce sedation. These results extend previous findings that systemic oxytocin increases nucleus accumbens dopamine in a sex-specific manner in cocaine-experienced rats. These data are the first to find that systemic oxytocin increases nucleus accumbens glutamate after cocaine experience, providing a mechanism of action by which oxytocin attenuates the reinstatement of cocaine seeking in both male and female rats.

Alcohol consumption is preferred to water in rats pretreated with intravenous cocaine.

Clinical and anecdotal reports suggest a high incidence of alcohol administration during cocaine use, potentially as a means to diminish the aversive effects of cocaine that follow the initial positive drug effects. We have previously shown that in the operant runway, oral ethanol significantly reduces the approach-avoidance retreats that develop in response to IV cocaine. The current study was intended to test whether rats given the same dose of IV cocaine administered in our previous study would choose to consume ethanol rather than water in a two bottle choice paradigm. We also examined whether significant serum levels of the psychoactive cocaine metabolite, cocaethylene, were found in our animals that may account for the preference for ethanol. Animals pretreated with cocaine drank significantly more ethanol than did animals pretreated with saline. There were no measurable levels of cocaethylene at 10 or 40 min post-cocaine and extremely low values at the 20-min time point, indicating that cocaethylene formation does not reinforce the co-administration of cocaine and alcohol in rats. These data demonstrate that the presence of cocaine serves as a primary factor in the preference for alcohol in thirsty rats, potentially to reduce the well-documented negative/anxiogenic properties of cocaine.

Ethanol consumption reduces the adverse consequences of self-administered intravenous cocaine in rats.

RATIONALE: Human drug users report that the initial positive effects of cocaine are followed by a dysphoric state characterized by anxiety and drug-craving. As a means of presumably attenuating these negative aftereffects, 50-90% of cocaine users choose to co-administer ethanol during cocaine binges. This co-administration reportedly prolongs the "high" and diminishes the "low" associated with cocaine use. OBJECTIVE: The current study was intended to assess whether this phenomenon could be modeled in the animal laboratory. We have previously shown that animals running a straight alley for an intravenous cocaine reward develop a unique approach-avoidance "conflict" behavior that is characterized by stop and retreat behaviors as the subjects approach the goal box. The retreats are thought to reflect the concurrent positive (reward) and negative (anxiety) associations with the goal box and can be dose-dependently reduced by pretreatment with diazepam, which presumably attenuates the anxiety stemming from the conflict. METHODS: To test the role of ethanol in reducing cocaine-induced anxiety, rats were trained to run a straight-arm alley for a single daily injection of cocaine (1.0 mg/kg IV). RESULTS: Rats that had the opportunity to then drink either an 8% or a 4% sucrose-ethanol solution immediately following their daily runway trial came to exhibit fewer retreats than rats that did not drink ethanol following their cocaine injection. CONCLUSIONS: These results suggest that ethanol effectively reduces the development of approach-avoidance conflict in animals running an alley for IV cocaine, a result that may account for the prevalence of cocaine-ethanol co-administration in humans.