GABA(A) receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine, in rhesus monkeys

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Berro, Lais F. [UNIFESP]
Andersen, Monica L. [UNIFESP]
Tufik, Sergio [UNIFESP]
Howell, Leonard L.
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GABA(A) receptor positive allosteric modulators (GABA(A) receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA(A) receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA(A) receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA(A) receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA(A) receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA(A) receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine. (C) 2017 Elsevier Ltd. All rights reserved.
Neuropharmacology. Oxford, v. 123, p. 299-309, 2017.