Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

Abstract

Rationale Cocaine addiction is a chronic psychiatric disorder characterized by pathological motivation to obtain cocaine and behavioral and neurochemical hypersensitivity to cocaine-associated cues. These features of cocaine addiction are thought to be driven by aberrant phasic dopamine signaling. We previously demonstrated that blockade of the hypocretin receptor 1 (HCRTr1) attenuates cocaine self-administration and reduces cocaine-induced enhancement of dopamine signaling. Despite this evidence, the effects of HCRTr1 blockade on endogenous phasic dopamine release are unknown. Objective In the current studies we assessed whether blockade of HCRTr1 alters spontaneous and cue-evoked dopamine release in the nucleus accumbens core of freely moving rats. Methods We first validated the behavioral and neurochemical effects of the novel, highly selective, HCRTr1 antagonist RTIOX-276 using cocaine self-administration and fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We then used FSCV in freely moving rats to examine whether RTIOX-276 impacts spontaneous and cue-evoked dopamine release. Finally, we used ex vivo slice FSCV to determine whether the effects of RTIOX-276 on dopamine signaling involve dopamine terminal adaptations. Results Doses of RTIOX-276 that attenuate the motivation for cocaine reduce spontaneous dopamine transient amplitude and cue-evoked dopamine release. Further, these doses attenuated cocaine-induced dopamine uptake inhibition at the level of DA terminals. Conclusion Our results provide support for the standing hypothesis that HCRTr1 blockade suppresses endogenous phasic dopamine signals, likely via actions at dopamine cell bodies. These results also elucidate a second process through which HCRTr1 blockade attenuates the effects of cocaine by reducing cocaine sensitivity at dopamine terminals.

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

“…Thus, based on SB studies alone, it is difficult to completely rule out the potential contribution of OxR2 (or 5HT receptors) in results obtained. Several compounds with greater selectivity for OxR1 have been developed, and a small number of studies indicate that these compounds recapitulate the effects of SB on drug‐seeking behavior (Lopez et al ., ; Levy et al ., ). Dual‐orexin receptor antagonists have also been reported to have anti‐drug‐seeking properties (Srinivasan et al ., ; Steiner et al ., ; Anderson et al ., ), including suvorexant, a compound that has the major advantage of being FDA‐approved for the treatment of insomnia (Gentile et al ., ,b; Simmons et al ., ).…”

“…**P < 0.01. ***P < 0.001. on drug-seeking behavior (Lopez et al, 2016;Levy et al, 2017). Dual-orexin receptor antagonists have also been reported to have antidrug-seeking properties (Srinivasan et al, 2012;Steiner et al, 2013;Anderson et al, 2014), including suvorexant, a compound that has the major advantage of being FDA-approved for the treatment of insomnia (Gentile et al, 2017a,b;Simmons et al, 2017).…”

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

“…Self-administration surgeries were performed as previously described (Brodnik et al, 2015; Levy et al, 2017). Rats were anesthetized using ketamine (100 mg/kg) and xylazine (10 mg/kg), and were implanted with an intravenous silastic catheter placed into the right jugular vein.…”

Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability

“…34 In addition, at doses that attenuated the motivation for cocaine, 5 reduced spontaneous dopamine transient amplitude and cue-evoked dopamine release, and also attenuated cocaine-induced dopamine uptake inhibition at the level of dopamine terminals, confirming its in vivo efficacy. 36 …”