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, though 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 wellregulated 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 D 3 receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D 2 /D 3 /sigma receptor antagonist (haloperidol), and a 5-HT 2C receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in highand low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). haloperidol,101 were equipotent and effective at reducing drugtaking 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 to male rats. Together, these studies suggest that drugs targeting dopamine D 3 or 5-HT 2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders.
A subset of rats that self‐administer synthetic cathinones, such as 3,4‐methylenedioxypyrovalerone (MDPV), develop high levels of drug intake and patterns of responding similar to the compulsive, binge‐like patterns of cathinone (e.g., “bath salts”) use reported in humans. Though high‐responder rats exhibit some behaviors thought to be related to substance use disorder, the effects of punished responding in these rats were unknown. These studies evaluated whether (1) high‐responder rats were less sensitive to footshock‐punished responding than low‐responder rats using both unsignaled and signaled footshock procedures; (2) whether sensitivity to footshock was dependent on the self‐administered dose of MDPV. Inhibition curves for unsignaled footshock (0.05‐0.9 mA, increasing across sessions) were evaluated in forty adult Sprague Dawley rats self‐administering 0.01, 0.032, and 0.1 mg/kg/infusion MDPV under a FR5 schedule of reinforcement; footshocks were paired with ~50% of drug infusions. Rats were then trained on a signaled footshock procedure, in which a change in stimulus conditions signaled that the next infusion would be paired with a footshock (intensities individualized to each rat’s IC50). Rats could avoid this footshock by withholding responding for 30‐sec. After rats learned the signaled shock procedure, inhibition curves were generated using a range of footshock intensities (0.05‐0.9 mA). High‐ and low‐responder rats were similarly sensitive to unsignaled punishment by footshock (mean IC50s‐ high‐responders: 0.30mA; low‐responders: 0.36mA). However, high‐responder rats (mean: 45mA) received significantly more total current than low‐responder rats (mean: 18mA). Compared to low‐responder rats, high‐responder rats respond more in the presence of the signal indicating impending shock and avoid a smaller proportion of shocks. This suggests high‐responder rats may be less able to adapt their behavior in response to a stimulus associated with punishment. These studies suggest that the high levels of drug‐taking observed in the high‐responder rats reflects a compulsive‐like pattern of responding, which may be related to continued use despite adverse consequence, a DSM symptom of substance use disorder.
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