3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

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, 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.

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

“…Consistent with previous studies reporting unusually high levels of drug-taking in male and female rats that self-administer MDPV, rats that self-administered MDPV had a more severe SUD-like phenotype score than rats that self-administered cocaine, regardless of access condition or duration of self-administration. This was primarily due to the increase in infusions earned, responses made during the pre-session time out, and responses made when drug was signaled to be unavailable, replicating and extending our previous studies with high-responder rats [25][26][27][28][29]. Given that sensitivity to punishment frequently contributes to severe SUD-like phenotype [3,4,[6][7][8] and considering some rats that selfadministered MDPV had very high punishment scores, it was somewhat unexpected that rats that self-administered cocaine or MDPV did not differ with regard to the punishment endpoint.…”

“…Studying rats with more extreme phenotypes may provide a more translational framework to understand factors that underlie the transition from regular to disordered patterns of substance use. Though a relatively small subset of rats (17-22%) develop the most severe SUD-like phenotype when they are allowed to self-administer cocaine [3,8], a much larger proportion of rats (~30-40%) engage in aberrantly high levels of drug-taking when MDPV is available for self-administration [25][26][27][28][29]. Thus, the primary goals of the current studies were to directly compare the SUD-like phenotype in male and female rats self-administering MDPV or cocaine, and to determine how manipulating access condition (short-, long-, and intermittent-access) impacted these SUD-like phenotypes.…”

“…Rats were anesthetized using 2% isoflurane and surgically prepared with a chronic indwelling catheter in the left femoral vein, which was attached to a vascular access button secured in the mid-scapular region, as previously described [26][27][28]63,64]. Penicillin G (60,000 U/rat) or Excede (20 mg/kg) was administered subcutaneously following surgery, and catheters were flushed daily with 0.5 ml heparinized saline (100 U/ml) to maintain catheter patency.…”

“…3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone that functions as a cocaine-like monoamine uptake inhibitor, but unlike cocaine which is roughly equipotent at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively) MDPV is ~800-fold selective for DAT and NET over SERT [22][23][24]. We have previously reported that 30-40% of male and female rats that are allowed to selfadminister MDPV during daily 90-min sessions rapidly develop a high-responder phenotype, characterized by levels of MDPV intake ~2-5 times greater than lowresponders across a range of doses, greater breakpoints under progressive ratio schedules of reinforcement, and higher rates of responding during periods of signaled drug unavailability [25][26][27][28][29]. Though consistent with MDPV high-responder rats engaging in SUD-like behaviors, it is unclear if the phenotype observed in these rats would extend to other core SUD-related behaviors, such as resistance to punishment by footshock, (i.e., "continued use despite adverse consequences"), or if the "severity" of the SUD-like phenotype is sensitive to access condition manipulations, as has been reported for cocaine.…”