Rationale: Stress interacts with cocaine to produce enhanced neurochemical and behavioral responding to cocaine; however, few studies have examined unconditioned behavioral responses to aversive stimuli after repeated cocaine. OBJECTIVES. Studies were conducted to measure the approach/avoidance response to an aversive stimulus after repeated cocaine treatment in male and female rats.
Methods: An unconditioned approach/avoidance task was used in which rats were placed into a box with a novel, aversive stimulus (formaldehyde; Form), and place aversion was assessed.
Results: Initial studies established a dose-response curve using different concentrations of Form, and also determined that avoidance of Form was abolished by pretreatment with an anxiolytic dose of chlordiazepoxide. To examine the effects of prior cocaine treatment, intact or gonadectomized male and female rats were pretreated with daily saline or cocaine (15 mg/kg, IPx5 days), and their approach/avoidance response to Form was tested 4-7 days later. In intact males, cocaine decreased the avoidance of Form, and previous gonadectomy completely abolished this response. Decreased avoidance behavior did not appear to be linked to behavioral sensitization to cocaine, since gonadectomized males demonstrated locomotor sensitization when given subsequent cocaine challenge. In females, avoidance of Form was not altered by either cocaine or gonadectomy. Three experiments further characterized the approach/avoidance response to Form in males. In the first experiment, daily footshock stress did not significantly alter the avoidance of Form. In a second study, rats that displayed high and low locomotor responses to a novel cage showed no differences between groups in their avoidance of Form. In the third experiment, intra-nucleus accumbens microinjection of fluphenazine (5 micro g/side) attenuated the daily cocaine-induced decrease in avoidance of Form.
Conclusions: These studies demonstrate that gonadal hormones may mediate cocaine-induced alterations in approach/avoidance to an aversive stimulus in males, and suggest that testosterone may act centrally to modulate dopamine responsiveness in the nucleus accumbens.