Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats

Orexins are hypothalamic neuropeptides which bind to two G-protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor. While a role for OX1R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX2R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX2R in ethanol-taking and ethanol-seeking behaviour. Indiana ethanol-preferring rats were trained to self-administer ethanol (10% w/v) or sucrose (0.7–1% w/v) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. The selective OX2R antagonist TCS-OX2-29 was administered i.c.v. to assess its effect on operant self-administration and cue-induced reinstatement following extinction. Following i.c.v. injection TCS-OX2-29 reduced self-administration of ethanol, but not sucrose. Despite reducing ethanol self-administration, TCS-OX2-29 had no impact on cue-induced reinstatement of ethanol seeking. To determine where in the brain OX2R were acting to modulate ethanol self-administration, TCS-OX2-29 was microinjected into either the shell or core of the nucleus accumbens (NAc). Intra-NAc core, but not shell, infusions of TCS-OX2-29 decreased responding for ethanol. Importantly, the doses of TCS-OX2-029 used were non-sedating. Collectively, these findings implicate OX2R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX2R had no impact on sucrose self-administration. Thus, OX2R in addition to OX1R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX1R, no impact of OX2R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX2R in ethanol self-administration compared to cue-conditioned ethanol-seeking.

GABAergic Regulation of REM Sleep in Reticularis Pontis Oralis and Caudalis in Rats

The nucleus reticularis pontis oralis (RPO) and nucleus reticularis pontis caudalis (RPC) are implicated in the generation of rapid eye movement sleep (REM). Work in cats has indicated that GABA in RPO plays a role in the regulation of REM. We assessed REM after local microinjections into RPO and RPC of the γ-aminobutyric acid-A (GABAA) agonist, muscimol (MUS), and the GABAA antagonist, bicuculline (BIC). Rats (90-day-old male Sprague-Dawley) were implanted with electrodes for recording electroencephalographs (EEG) and electromyographs (EMG). Guide cannulae were aimed into RPO ( n = 9) and RPC ( n = 8) for microinjecting MUS (200, 1,000.0 μM) and BIC (0.056, 0.333, 1.0, 1,000.0, and 10,000.0 μM). Animals received bilateral microinjections of saline, MUS, and BIC (0.2 μl microinjected at 0.1 μl/min) into each region followed by 6-h sleep recordings. In RPO, MUS (1,000.0 μM) suppressed REM and BIC (1,000.0 μM) enhanced REM. In RPC, MUS (200, 1,000.0 μM) suppressed REM, but BIC (1,000.0 μM and less) did not significantly affect REM. Higher concentrations of BIC (10,000.0 μM) injected into RPO ( n = 9) and RPC ( n = 4) produced wakefulness and escape behavior. The results indicate that GABA in RPO/RPC is involved in the regulation of REM and suggest site-specific differences in this regulation.