Effects of quetiapine treatment on cocaine self-administration and behavioral indices of sleep in adult rhesus monkeys

Abstract

Rationale Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. Objective The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. Methods Seven adult male rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003–0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25–75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14–16 days) quetiapine treatment (25–250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (≥ 80% cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. Results Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night, nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. Conclusions These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant abuse.

Use of Preclinical Drug Vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction

“…In agreement with these clinical results, subchronic treatment with the DA D2 antagonists flupenthixol, haloperidol, chlorpromazine, and quetiapine did not decrease and sometimes increased cocaine choice [22, 58, 59]. Consistent with these published results, subchronic treatment with DA antagonist risperidone also failed to attenuate cocaine vs. food choice (Hutsell, Negus, and Banks, unpublished observations).…”

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys

“…The reason a receptor antagonist would increase low-dose cocaine choice over food is not known. The present findings replicate earlier results using cocainefood choice (Brutcher and Nader, 2015), where oral quetiapine did not affect cocaine choice when preferred (i.e., .80% choice) cocaine doses were available for self-administration. These data appear in contrast to the findings in psychiatric patients in which quetiapine treatment decreased cocaine/amphetamine craving (Brown et al, 2003), although the latter findings required up to 5 weeks of treatment, and dollars spent on drugs (i.e., actual self-administration) were not affected by quetiapine treatment.…”

“…The first treatment occurred at approximately 0730 (90 minutes prior to the experimental session) and the second treatment at approximately 1700. This quetiapine dose was chosen as the minimally disruptive dose in male monkeys (Brutcher and Nader, 2015). During the first 4 weeks of treatment, only food-maintained responding was examined, after which saline and the quetiapine dose-response curve was redetermined as described earlier; oral quetiapine treatment continued throughout the redetermination of the self-administration dose-response curve.…”

Cocaine choice procedures in animals, humans, and treatment-seekers: Can we bridge the divide?

“…Non-human animal studies, conducted primarily in rhesus monkeys but also in rats, have tested the following medications while specifically using drug-choice procedures: aripiprazole (Thomsen et al, 2008), buspirone (John et al, 2015), d-amphetamine (Negus, 2003; Thomsen et al, 2013; Banks et al, 2015b), fenfluramine (Banks et al, 2011), fluoroamphetamine (Banks et al, 2011), flupenthixol (Negus, 2003), lisdexamfetamine (Banks et al, 2015b), methadone (Negus and Mello, 2004), methamphetamine (Banks et al, 2011), napthylisopropylamine (Banks et al, 2011), phendimetrazine (Banks et al, 2013c; Banks et al, 2013a), phenmetrazine (Banks et al, 2011, 2013b), quetiapine (Brutcher and Nader, 2015), and xanomeline (Thomsen et al, 2014). In general, drugs that could be considered “agonist replacement” medications like d-amphetamine, lisdexamfetamine, phendimetrazine, and phenmetrazine reduced cocaine choice (Negus, 2003; Banks et al, 2013c; Banks et al, 2013b, a; Thomsen et al, 2013; Banks et al, 2015b).…”

“…In general, drugs that could be considered “agonist replacement” medications like d-amphetamine, lisdexamfetamine, phendimetrazine, and phenmetrazine reduced cocaine choice (Negus, 2003; Banks et al, 2013c; Banks et al, 2013b, a; Thomsen et al, 2013; Banks et al, 2015b). Antagonist-type pharmacotherapies, conversely, either failed to decrease cocaine choice [e.g., buspirone, flupenthixol or methadone (Negus, 2003; Negus and Mello, 2004; John et al, 2015)] or produced only transient decreases in cocaine choice [e.g., quetiapine or aripiprazole (Thomsen et al, 2008; Brutcher and Nader, 2015)]. Xanomeline, a muscarinic M1/M4 receptor agonist, decreased cocaine choice and was not associated with tolerance in rats (Thomsen et al, 2014).…”