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-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.

• Authors: Steven J Simmons, Rose Martorana, Helene Philogene-Khalid, Fionya H Tran, Taylor A Gentile, Xinyan Xu, Shu Su, Scott M Rawls, John W Muschamp
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 234 Issue 21 Pg. 3207-3215 (Nov 2017) ISSN: 1432-2072 [Electronic] Germany
• PMID: 28786030 (Publication Type: Journal Article)

Chemical References

• Azepines
• Benzodioxoles
• Hcrtr1 protein, rat
• Orexin Receptors
• Pyrrolidines
• Triazoles
• suvorexant
• Synthetic Cathinone

Topics

• Animals
• Azepines (pharmacology)
• Benzodioxoles (administration & dosage)
• Craving (drug effects)
• Dopaminergic Neurons (drug effects)
• Dose-Response Relationship, Drug
• Infusions, Intravenous
• Male
• Mesencephalon (drug effects)
• Orexin Receptors (drug effects)
• Pyrrolidines (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Self Administration
• Triazoles (pharmacology)
• Vocalization, Animal (drug effects)
• Synthetic Cathinone