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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

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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-min pre-lever period as well as during 2-h 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 the following: (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.

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Acknowledgements

The authors acknowledge generous grant monies provided by the National Institute on Drug Abuse (R00 DA031767 awarded to JWM, R01 DA039139 awarded to SMR, Animal Core of P30 DA013429 awarded to Ellen M. Unterwald) for completion of this report.

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Authors and Affiliations

  1. Center for Substance Abuse Research (CSAR), Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA

    Steven J. Simmons, Rose Martorana, Helene Philogene-Khalid, Fionya H. Tran, Taylor A. Gentile, Xinyan Xu, Shu Su, Scott M. Rawls & John W. Muschamp

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  1. Steven J. Simmons
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  2. Rose Martorana
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  3. Helene Philogene-Khalid
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  4. Fionya H. Tran
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  5. Taylor A. Gentile
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  7. Shu Su
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  8. Scott M. Rawls
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  9. John W. Muschamp
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Correspondence to Steven J. Simmons.

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Simmons, S.J., Martorana, R., Philogene-Khalid, H. et al. 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. Psychopharmacology 234, 3207–3215 (2017). https://doi.org/10.1007/s00213-017-4709-3

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