Abstract
Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats (“high-responders”) that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D3 receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D2/D3/sigma receptor antagonist (haloperidol), and a 5-HT2C receptor agonist (CP-809,101) to reduce MDPV (0.0032–0.1 mg/kg/infusion) self-administration in high- and low-responding rats as well as rats self-administering cocaine (0.032–1 mg/kg/infusion). VK4-40, VK4-116, haloperidol, and CP-809,101 were equipotent and effective at reducing drug-taking in all three groups of rats, including the high-responders; however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared with male rats. Together, these studies suggest that drugs targeting dopamine D3 or 5-HT2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders.
SIGNIFICANCE STATEMENT There are no United States Food and Drug Administration-approved treatments for stimulant use disorder, perhaps in part because candidate medications are most often evaluated in preclinical models using male subjects with well-regulated drug-taking. In an attempt to better model aberrant drug taking, this study found compounds acting at dopamine D3 or 5-HT2C receptors can attenuate drug-taking in male and female rats that self-administered two different stimulants and exhibited either a high or low substance use disorder-like phenotype.
Footnotes
- Received August 17, 2022.
- Accepted December 13, 2022.
This work was supported by the National Institutes of Health: National Institute of Drug Abuse [Grants R01-DA039146 and R36-DA050955], the jointly-sponsored National Institutes of Health Predoctoral Training Program in the Neurosciences [Grant T32-NS082145], and the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism NIDA Intramural Research Program [Grants Z1A-DA000424 and Z1A-DA000527].
No author has an actual or perceived conflict of interest with the contents of this article.
↵1Current affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA and The Scripps Research Institute, La Jolla, CA, USA.
Part of this work was presented as a poster presentation at the 2021 Experimental Biology/ASPET Annual Meeting as Doyle MR, Bhattacharya A, Rice KC, Collins GT (2021) MDPV high-responder phenotype as a tool to evaluate candidate medications for stimulant use disorder.
↵
This article has supplemental material available at jpet.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
