Abstract
Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats’ sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse.
Highlights
Drug dependence—or addiction—is often described as a chronic mental disorder characterized by compulsive drug intake and loss of control over intake despite adverse consequences [1,2,3,4]
We first show that intermittent episodes of opiate injections rather than constant exposure with morphine pellets lead to longer lasting hyperactivity to heroin challenges
We show for the first time that protracted abstinence to opiate may induce a long-lasting dysregulation of the circadian activity in rats
Summary
Drug dependence—or addiction—is often described as a chronic mental disorder characterized by compulsive drug intake and loss of control over intake despite adverse consequences [1,2,3,4]. A primary problem for the treatment of drug abuse remains to be the understanding of the brain neuroadaptations following repeated drug use that might be responsible for the persistent vulnerability to drug craving and seeking after abstinence [5,6]. The average period of time to relapse to opiate use is 25 days, while the rate of relapse is. A correlate of arousal and sleep periods in humans, has been studied in animal models of opiate dependence. It has been shown that similar to humans [8,10], abrupt drug cessation can alter the circadian biphasic activity for several days during abstinence in animal models of opiate dependence [11,12,13]
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