Role of hypocretin/orexin receptor blockade on drug-taking and ultrasonic vocalizations (USVs) associated with low-effort self-administration of cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV) in rats

Abstract

Rationale Synthetic psychostimulant abuse, including cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV), continues to increase in many countries. Similar to cocaine but with greater potency, MDPV elicits a transient sympathomimetic response by blocking cellular uptake of dopamine (DA) and norepinephrine (NE)—administration in some users is reported as euphoria-inducing much like cocaine and amphetamine. Pharmacological agents that disrupt excitatory transmission onto midbrain DA-producing neurons, including hypothalamic hypocretin/orexin (hcrt/ox) receptor antagonists, present attractive targets to aide abstinence maintenance by reducing psychostimulant-associated reward and reinforcement. Objective The present study sought to assess the degree to which suvorexant, a dual hcrt/ox receptor antagonist, influences drug-taking as well as ultrasonic vocalizations (USVs) associated with MDPV self-administration. Methods Rats were trained to self-administer MDPV (~0.03 mg/kg/inf, 3-s) for 14 days under a fixed-ratio 1 schedule of reinforcement, and effects of suvorexant (0, 3, 10, 30 mg/kg, i.p.) on drug-taking was assessed. USVs were recorded during a 30-minute pre-lever period as well as during 2-hours of MDPV self-administration. Results We observed that suvorexant modestly suppressed the number of MDPV infusions earned. Notably, we observed that suvorexant reduced 50-kHz USVs associated with pre- and post-lever time-points but did not noticeably alter call type profiles. Upon comparison of the two measures, we observed trending positive associations between suvorexant-induced changes in drug-taking and 50-kHz USVs. Conclusions Results from this exploratory study provide support for: (1) studying how suvorexant may provide benefit to humans with stimulant use disorders, (2) identifying a potential role for orexin transmission in cathinone abuse, and (3) further interrogating the potential utility of rat USVs to predict drug consumption in preclinical models of substance use disorders.

Chemokines and ‘bath salts’: CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats

“…((±)-MDPV; synthesized by Dr. Allen Reitz) and AMD3100 (AstaTech) were dissolved in sterile water and injected intraperitoneally (ip). Doses were based on AMD3100 (1-10 mg/kg) reducing cocaine's rewarding effects (Kim et al, 2017) and MDPV (2 mg/kg) causing CPP, locomotor activation, and 50-kHz USV calls (Gregg et al, 2016; Simmons et al, 2017). Each rat was used once for an experiment (either locomotor, CPP or USV) and then euthanized immediately following behavioral experimentation.…”

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

“…Fentanyl HCl powder (National Institute of Drug Abuse [NIDA] Drug Supply Program) was dissolved in 0.9% sterile saline to a concentration of 8 μg/ml. Suvorexant (NIDA Drug Supply Program) was dissolved in dimethyl sulfoxide (DMSO; 100%) through vortexing; 0, 10 or 30 mg/kg was injected at a fixed volume of 100 μl (ip) 30min prior to testing, as described in previous publications [27].…”

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

“…***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). Thus, further work is required to fully understand the utility of single vs. dualorexin receptor antagonists for the treatment of addiction (Khoo & Brown, 2014;Yeoh et al, 2014).…”