Rapid Induction of Conditioned Opiate Withdrawal in the Rat

Abstract

Previous studies of conditioned op iate withdrawal in ani mals either have suffered from a lack of readily quantifiable data (e.g., measurement of diarrhea and vocalization in rodents) or were very long and costly (e.g., disruption of operant responding in monkeys). In this study, an attempt was made to produce a rapid and quantifiable measure of conditioned opiate withdrawal in the rat. Rats were trained to lever-press for food reinforcement on a fixed-ratio-15 schedule. All rats were then implanted with two subcutaneous 75-mg morphine pellets and allocated into three groups. The paired group received four naloxone injections (0.025 mg lkg SC) in the operant chambers paired with a distinctive tone and smell. The unpaired group was also exposed to the tone and smell in the chambers on four occasions, but received the naloxone injections in the home cage. The saline control animals were never exposed to naloxone or the tone and smell. On the test day, all rats were exposed to the tone and smell and injected with saline. The paired group showed a significant reduction in operant responding in response to the tone and smell when compared either with the other two groups, or to their own response rates on the previous day. In a second experiment, the paired and unpaired groups were ag ain challenged with the tone and smell and a saline injection 1 month after removal of the morphine pellets. Ag ain, the paired group showed a significant disruption of response. These results suggest that the conditioned stimulus acquired significant behavior-disruptive properties manifest even in the absence of opiate receptor occupancy. A rapidly acquired, quantifiable measure of conditioned withdrawal in the rat will allow systematic evaluation of the neurobiological basis for this phenomenon. INeuropsychopharmacology 8:15-21, 1993J tioned withdrawal" may have motivational signifIcance in drug dependence (O'Brien 1975;O'Brien et al. 1988).Several animal models of conditioned withdrawal have been demonstrated in rats and monkeys. In early studies, rats injected with morphine for 6 weeks showed signifrcant signs of physical withdrawal in a morphine paired environment even up to 155 days after the last morphine injection (Wikler and Pescor 1967). In operant conditioning studies in monkeys, signifIcant condi tioned withdrawal was observed in morphine-depen dent animals (2-month history of morphine injections): the monkeys showed an immediate suppression of food-maintained responding on a nxed-ratio-l0 sched ule in response to stimuli associated with injection of nalorphine (Goldberg and Schuster 1967). These con ditioned stimuli acted as negative reinforcers since the monkeys lever-pressed to turn off the conditioned

Conditioned Opioid Withdrawal Decreases Nociceptin/Orphanin FQ Levels in the Frontal Cortex and Olfactory Tubercle

“…Similar results were produced when the number of responses rather than the percentage baseline responding was expressed, i.e., the elevated baseline in the paired group had no effect on the degree of suppression of responding (data not shown). Naloxone injections also produced diarrhea in some rats, but not vocalization and weight loss as previously reported (Baldwin and Koob 1993). Physical signs were not systematically quantified at any time in this study.…”

“…The method to produce conditioned opioid withdrawal was from a previous study from this laboratory with minor modifications (Baldwin and Koob 1993). Briefly, rats were trained to respond for food in an operant chamber while they were food-restricted (10 g food per day in the home cage).…”

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…The doses of naloxone required to precipitate a place aversion are below those that produce overt physical or somatic signs of opiate withdrawal (Schulteis et al, 1994). The place aversion response does not require maintenance of opiate dependence because its manifestation continues to be present weeks after animals are 'detoxified' (eg up to 16 weeks after the morphine pellets are removed; see Baldwin and Koob, 1993;Hand et al, 1988;Stinus et al, 1990Stinus et al, , 2000, which clearly indicates that the memory of withdrawal can have long-lasting effects on behavioral responses.…”

Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

“…Among the factors that may contribute to loss of control over drug intake and relapse after periods of abstinence are conditioned associations that are formed over a course of repeated drug experience. Within the domain of opiate withdrawal symptomatology, it is now recognized that somatic/autonomic signs and affective or emotional signs (e.g., anxiety, depression, dysphoria), each with their own unique underlying neurophysiological substrates (reviewed by Maldonado et al 1996;Schulteis and Koob 1996), may differentially motivate continued drug use, with the affective signs hypothesized to be of greater motivational significance than the somatic signs.A considerable body of both clinical and preclinical literature suggests that positive (drug reward) and negative (drug withdrawal) affective states can become associated with stimuli in the drug-taking environment and that these conditioned stimuli themselves acquire motivational significance in maintaining compulsive use and in precipitating relapse after periods of abstention (Baldwin and Koob 1993;Childress et al 1994; …”

“…A considerable body of both clinical and preclinical literature suggests that positive (drug reward) and negative (drug withdrawal) affective states can become associated with stimuli in the drug-taking environment and that these conditioned stimuli themselves acquire motivational significance in maintaining compulsive use and in precipitating relapse after periods of abstention (Baldwin and Koob 1993;Childress et al 1994;O'Brien et al 1976O'Brien et al , 1993Ramsay and Woods 1997;Schulteis and Koob 1996;Schulteis et al 1997a;Wikler 1973).…”