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

Abstract

GABAA receptor positive allosteric modulators (GABAA 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 GABAA 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 GABAA 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 GABAA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABAA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABAA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.

Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) and R(-) MDMA on actigraphy-based daytime activity and sleep parameters in rhesus monkeys.

“…Both in the studies with rodents (Balogh et al, 2004) and in the present study, racemic MDMA-induced delayed sleep onset was associated with increased general daytime activity, suggesting that the effects of racemic MDMA on sleep latency are associated with its daytime stimulant effects. Similar effects have been previously reported for other psychostimulant drugs, such as amphetamine (Murnane et al, 2013) and methamphetamine (Andersen et al, 2013; Berro et al, 2016, 2017a b…”

“…Although racemic MDMA and other amphetamine-type drugs exert similar effects on sleep latency, those drugs seem to exert distinct effects on other sleep parameters. In our previous studies, amphetamine and methamphetamine administration also impaired sleep by decreasing sleep efficiency and increasing sleep fragmentation (Murnane et al, 2013; Andersen et al, 2013, Berro et al, 2016, 2017a,b). While MDMA had no significant effects on sleep fragmentation (data not shown), it significantly decreased WASO, also increasing sleep efficiency in animals with low baseline sleep efficiency.…”

Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

“…The data were analyzed by comparison with standard concentration curves using Chromeleon 6.8 Chromatography Data System (Thermo Fisher Scientific, Waltham, MA, USA). The doses of cocaine and methamphetamine used in the microdialysis experiments were based on previous studies from our group (Kirkland Henry et al 2009; Murnane et al 2013; Berro et al 2017). In vivo microdialysis sessions were performed no more frequently than every two weeks for each subject.…”

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits

“…Exposure to psychostimulants like cocaine, nicotine, and methamphetamine alters GABAergic neurotransmission (174–176). GABA also plays a role in both impulsivity and learning/memory (177–179).…”