Influence of Contingent and Noncontingent Drug Histories on the Development of High Levels of MDPV Self-Administration

Doyle, Michelle R.; Sulima, Agnieszka; Rice, Kenner C.; Collins, Gregory T.

doi:10.1124/jpet.121.000655

Cited by 3 publications

(9 citation statements)

References 47 publications

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“…When allowed to self-administer the stimulant drug MDPV, a subset rats rapidly develop patterns of responding that result in significantly greater levels of drug-intake (high-responders) than low-responder rats self-administering MDPV, or rats that self-administer cocaine. These high-responder rats exhibit behaviors thought to be consistent with stimulant use disorder in humans, including high levels of drug-taking and -seeking, and reach higher final ratios under progressive ratio schedules of reinforcement (Gannon et al, 2017;Doyle et al, 2021a;Abbott et al, 2022). The primary goal of this study was to evaluate the effects of several drugs that interact with receptors that have been targeted for the development of medications for stimulant use disorder to determine if their potency and effectiveness to reduce drug-taking differed as a function of: (1) the self-administered drug (MDPV versus cocaine), ( 2) the behavioral phenotype (high-responder versus low-responder), or (3) sex (male versus female).…”

Section: Discussionmentioning

confidence: 99%

“…The temperature-and humidity-controlled vivarium operated on a 14/10 hour light cycle (lights on at 6am) and experiments were conducted while lights were on. A subset of male rats (n=9) also participated in another self-administration experiment before beginning this study, where they self-administered MDPV and either cocaine, ketamine, nicotine, or fentanyl for ~6 weeks (Doyle et al, 2021a). The self-administration behavior of these rats did not differ from the rats with no prior experimental history.…”

Section: Subjectsmentioning

confidence: 99%

“…Rats were subsequently classified as being a high-or low-responder based upon previously established criteria (Gannon et al, 2017(Gannon et al, , 2018aDoyle et al, 2021a;Abbott et al, 2022). Briefly, the percentage of responses that were made during the 5-sec post-infusion timeout out of total responses on the active lever in drug components was calculated for the 3 sessions preceding the final saline substitution.…”

Section: Trainingmentioning

confidence: 99%

“…Recently we identified a reliable and persistent high-responder phenotype that emerges in ~30% of male and female rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) and structurally-related synthetic cathinones, characterized by high levels of dysregulated drugtaking and -seeking that might be related to stimulant use disorder (Gannon et al, 2017(Gannon et al, , 2018a(Gannon et al, , 2021Doyle et al, 2021a;Abbott et al, 2022). These high-responder rats earn more infusions across a range of self-administration doses (i.e., upward shift in the dose-response curve), make more responses during signaled periods of drug unavailability, and reach greater breakpoints under progressive ratio schedules of reinforcement (Gannon et al, 2017;Doyle et al, 2021a;Abbott et al, 2022). Since high-responder rats exhibit a robust stimulant use disorder-like phenotype, they may provide a translationally-relevant framework for evaluating candidate medications for stimulant use disorder.…”

Section: Introductionmentioning

confidence: 99%

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

Doyle

Peng

Cao

et al. 2023

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Section: Trainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Doyle

Peng

Cao

et al. 2023

J Pharmacol Exp Ther

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Doyle,

Beltran,

Bushnell

et al. 2024

Preprint

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Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT 2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

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Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone

Manke,

Nunn,

Sulima

et al. 2023

Brain Sciences

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Background: As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone whose affective properties (and abuse potential) are largely unknown. The following experiments begin to characterize these effects and how they may be impacted by drug history (a factor affecting reward/aversion for other drugs of abuse). Methods: Eutylone was assessed for its ability to induce conditioned taste avoidance (CTA; aversive effect) and conditioned place preference (CPP; rewarding effect) and their relationship (Experiment 1). Following this, the effects of exposure to cocaine or 3,4-methylenedioxymethamphetamine [MDMA] on eutylone’s affective properties were investigated (Experiment 2). Results: Eutylone produced dose-dependent CTA and CPP (Experiment 1), and these endpoints were unrelated. Pre-exposure to cocaine and MDMA differentially impacted taste avoidance induced by eutylone (MDMA > cocaine) and did not impact eutylone-induced place preference. Conclusions: These data indicate that eutylone, like other synthetic cathinones, has co-occurring, independent rewarding and aversive effects that may contribute to its abuse potential and that these effects are differentially impacted by drug history. Although these studies begin the characterization of eutylone, future studies should examine the impact of other factors on eutylone’s affective properties and its eventual reinforcing effects (i.e., intravenous self-administration [IVSA]) to predict its use and abuse liability.

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Influence of Contingent and Noncontingent Drug Histories on the Development of High Levels of MDPV Self-Administration

Cited by 3 publications

References 47 publications

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

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

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

Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone

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