Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep

Abstract

Recent evidence suggests that blockade of the hypocretin receptor 1 may act as a useful pharmacotherapy for cocaine abuse. Here we investigated the extent to which various doses of a hypocretin receptor 1 antagonist, SB-334867, affect cocaine self-administration at varying doses of cocaine and across a range of effort requirements, and tested if these SB-334867 doses produce sedative effects. First, we trained animals to self-administer one of three doses of cocaine on a progressive ratio schedule, and then tested the effects of three doses of SB-334867. Responding for cocaine was then analyzed to segregate features of relatively high and low effort requirements across the progressive ratio session. In another set of experiments we tested the sleep-promoting effects of the same doses of SB-334867. Our data indicate that blockade of hypocretin receptor 1 preferentially reduces high effort responding for cocaine at levels that do not promote sedation.

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

“…A series of prior research reports demonstrated that hcrt/ox functionally contributes to motivational effects of psychostimulant drugs. Hcrt/ox antagonists reduce drug-taking predominantly in tasks requiring more effort to receive intravenous drug infusions (e.g., Bentzley and Aston-Jones 2015; Brodnik et al 2015). In the present report, suvorexant failed to significantly suppress drug-taking (Figure 2A).…”

“…Results from España et al (2010) revealed that SB-334867 reduced cocaine infusions earned on 6-h discrete-trials as well as progressive-ratio but not fixed-ratio 1 schedules of reinforcement. One mechanism found to underlie the ability of hcrt/ox receptor antagonists to reduce reinforcing and motivational efficacy of drugs of abuse is by attenuating stimulant-evoked elevations in ventral striatal DA efflux (e.g., Brodnik et al 2015; Prince et al 2015). In a prior study, we observed that suvorexant reduces cocaine-evoked elevations in ventral striatal DA (Gentile et al 2017), and others have bridged functional contribution of mesolimbic DA transmission in the context of psychostimulant-evoked 50-kHz USVs.…”

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.…”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…Specifically, the breakpoint for cocaine is reduced by peripheral injection of SB-334867 but not the OX2R antagonist 4PT (Borgland et al, 2009; Brodnik et al, 2015; Prince, Rau, Yorgason, & Espana, 2015). This effect of the OX1R appears to specifically involve the ventral tegmental area where injection of SB-334867 recapitulates the lowering of the breakpoint (Espana et al, 2010) and OX-A injection increases breakpoint (Espana, Melchior, Roberts, & Jones, 2011).…”

“…Zhou et al, 2012), there is other evidence suggesting that OX becomes involved when animals must work to attain their preferred blood levels of cocaine. Thus, SB-334867 significantly reduces fixed ratio 1 operant responding for very low doses of cocaine (Brodnik, Bernstein, Prince, & Espana, 2015) and also operant responding in a discrete trials paradigm involving highly restricted periods of access (Espana et al, 2010). Further, both SB-334867 and genetic knockout of the OX1R lead animals to consume less cocaine under a high work, fixed ratio 5 paradigm (Hollander, Pham, Fowler, & Kenny, 2012).…”