Yohimbine reinstates extinguished 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats with prior exposure to chronic yohimbine

Abstract

Although exposure to acute stress has been shown to reinstate extinguished responding for a wide variety of drugs, no studies have investigated stress-induced reinstatement in animals with a history of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) self-administration. Thus, rats were trained to press a lever for MDMA (0.50 mg/kg/infusion) in daily sessions, and lever pressing was subsequently extinguished in the absence of MDMA and conditioned cues (light and tone). We then tested the ability of acute yohimbine (2.0 mg/kg), a pharmacological stressor, to reinstate lever-pressing under extinction conditions. Additionally, to model chronic stress, some rats were injected daily with yohimbine (5.0 mg/kg × 10 days) prior to reinstatement tests. To assess dopaminergic involvement, chronic yohimbine injections were combined with injections of SCH-23390 (0.0 or 10.0 μg/kg), a dopamine D1-like receptor antagonist. In a separate experiment, rats with a history of food self-administration were treated and tested in the same way. Results showed that acute yohimbine injections reinstated extinguished MDMA and food seeking, but only in rats with a history of chronic yohimbine exposure. Co-administration of SCH-23390 with chronic yohimbine injections prevented the potentiation of subsequent food seeking, but not MDMA seeking. These results suggest that abstinent MDMA users who also are exposed to chronic stress may be at increased risk for future relapse, and also that the effects of chronic stress on relapse may be mediated by different mechanisms depending on one’s drug use history.

Chronic restraint stress causes a delayed increase in responding for palatable food cues during forced abstinence via a dopamine D1-like receptor-mediated mechanism

“…These results support and extend our previous findings with the pharmacological stressor yohimbine [9, 10] by showing that a non-pharmacological stressor, restraint, also produces lasting increases in palatable food-seeking behavior. We hypothesize that this is due to engagement of a common pathway involved in food seeking.…”

“…The release of dopamine in PFC and the activation of D 1 Rs in general appear to be critical mechanisms underlying food-seeking behavior [16, 17, 19]. Results showing that SCH-23390 combined with yohimbine [9, 10] and restraint stress (present study) blocked the effects of both stressors on food seeking provide further support for a shared mechanism.…”

“…In our previous studies with yohimbine, we found that the effects of chronic yohimbine on palatable food seeking were evident at least 1 week later [9, 10]; however, the time-course of chronic stress effects on food seeking has not been systematically studied. In the present study we found that increased food seeking was observed 7 days, but not 1 day, following the cessation of chronic stress.…”

“…), a D 1 R antagonist, immediately prior to placement in restrainers. SCH-23390 was dissolved in physiological saline at a concentration of 10.0 μg/ml, and the dose is based on previous research [9, 10, 16, 18]. Unstressed rats were injected daily with SCH-23390 or vehicle and then returned to their home cages.…”

“…The prototype α-2 adrenoceptor antagonist yohimbine has been the stressor of choice in contemporary reinstatement studies because of its robust and reliable effects on reinstatement of food seeking when administered acutely [8]. Moreover, we recently showed that rats with a history of chronic yohimbine exposure showed greater acute yohimbine- and food-priming-induced reinstatement of food seeking several days after the cessation of chronic yohimbine treatment [9, 10]. …”