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Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.

ABSTRACT: In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (-)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (-)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (-)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.

SUBMITTER: Fredriksson I

PROVIDER: S-EPMC7075949 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.

Fredriksson Ida I Applebey Sarah V SV Minier-Toribio Angelica A Shekara Aniruddha A Bossert Jennifer M JM Shaham Yavin Y

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200106 5

In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-adm ...[more]

PMID: 31905372

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Project description:We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation.Significance statementIn human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving.

Dataset Information

Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.

Publications

Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence.

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