Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague Dawley Rats: Comparisons with Methamphetamine and Cocaine.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

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

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-HT2A, 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.

Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague-Dawley Rats: Comparisons with Methamphetamine and Cocaine.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV, or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague-Dawley rats were provided 90-min or 12-h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12-h access to methamphetamine and those that had 90-min or 12-h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal mono-amine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits and lethality, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

Cardiovascular and Locomotor Effects of Binary Mixtures of Common "Bath Salts" Constituents: Studies with Methylone, MDPV, and Caffeine in Rats.

Background and Purpose: The use of "Bath Salts" drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among "Bath Salts" constituents contribute to the adverse effects often reported in users. Experimental Approach: This study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures. Dose-addition analyses were used to determine the effect levels predicted for a strictly additive interaction for each dose pair. Key Results: Methylone, MDPV, and caffeine increased heart rate and locomotion, with methylone producing the largest increase in heart rate, MDPV producing the largest increase in locomotor activity, and caffeine being the least effective in stimulating heart rate and locomotor activity. MDPV and caffeine increased mean arterial pressure, with caffeine being more effective than MDPV. The nature of the interactions between methylone and MDPV tended toward sub-additivity for all endpoints, whereas interactions between MDPV or methylone and caffeine tended to be additive or sub-additive for cardiovascular endpoints, and additive or supra-additive for increases in locomotion. No pharmacokinetic interactions were observed between individual constituents, but methylone displayed non-linear pharmacokinetics at the largest dose evaluated. Conclusion and Implications: These findings demonstrate that the composition of "Bath Salts" preparations can impact both cardiovascular and locomotor effects and suggest that such interactions among constituent drugs could contribute to the "Bath Salts" toxidrome reported by human users.

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

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.

Interactions between impulsivity and MDPV self-administration in rats.

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are recreational drugs of abuse often identified in 'bath salts' preparations. Humans report compulsive patterns of bath salts use, and previous work suggests that a subset of rats develop unusually high levels of MDPV self-administration. This study aims to test the hypothesis that high levels of impulsivity (e.g., inability to withhold responding for a sucrose reward) will predispose rats to high levels of MDPV self-administration relative to rats with lower levels of impulsivity. The 1-choice serial reaction time task (1-CSRTT) was used to assess impulsivity (i.e., premature responding) in 10 female and 10 male Sprague Dawley rats. Rats were then allowed to self-administer 0.032 mg/kg/inf MDPV or 0.32 mg/kg/inf cocaine, after which full dose-response curves for MDPV (0.001-0.1 mg/kg/inf) or cocaine (0.01-1 mg/kg/inf) were generated under a FR5 schedule of reinforcement. After a history of self-administering MDPV or cocaine, impulsivity was reassessed under the 1-CSRTT, prior to evaluating the acute effects of MDPV (0.032-0.32 mg/kg) or cocaine (0.1-1 mg/kg) on impulsivity. Level of impulsivity was not correlated with subsequent levels of either MDPV or cocaine self-administration, and level of drug self-administration was also not correlated with subsequent levels of impulsivity, although acute administration of MDPV and cocaine did increase premature responding. In failing to find direct relationships between either impulsivity and subsequent drug-taking behaviour, or drug-taking behaviour and subsequent assessments of impulsivity, these findings highlight the complexity inherent in the associations between impulsive behaviour and drug-taking behaviour in both animal models and humans.

Modeling Stimulant and Opioid Co-use in Rats Provided Concurrent Access to Methamphetamine and Fentanyl.

Concurrent use of stimulants (e.g., methamphetamine) and opioids (e.g., fentanyl) has become increasingly common in recent years and continues to pose an enormous health burden, worldwide. Despite the prevalence, relatively little is known about interactions between the reinforcing effects of stimulants and opioids in this pattern of polysubstance use. The goals of the current study were to evaluate the relative reinforcing and relapse-related effects of methamphetamine and fentanyl using a concurrent access, drug-vs.-drug choice procedure. Male Sprague-Dawley rats were first allowed to acquire self-administration for either 0.1 mg/kg/infusion methamphetamine or 0.0032 mg/kg/infusion fentanyl, independently, after which concurrent access to both drugs was provided. When training doses of methamphetamine and fentanyl were concurrently available, a subset of rats self-administered both drugs, either within a session or alternating across sessions, whereas the remaining rats responded exclusively for one drug. When the cost of the preferred drug was increased (i.e., unit dose reduced), or the cost of the non-preferred drug was decreased (i.e., unit dose increased), choice was largely allocated toward the cheaper alternative. Following extinction of responding, methamphetamine- and fentanyl-paired cues reinstated responding on both levers. Responding reinstated by a priming injection of methamphetamine or fentanyl allocated more responding to the lever previously reinforced by the priming drug. The current studies suggest that choice of methamphetamine and fentanyl is largely allocated to the cheaper alternative, although more co-use was observed than would be expected for economic substitutes. Moreover, they lay the groundwork for more fully evaluating interactions between commonly co-abused drugs (e.g., stimulants and opioids) in order to better understand the determinants of polysubstance use and develop effective treatment strategies for individuals suffering from a polysubstance use disorder.

Application of dose-addition analyses to characterize the abuse-related effects of drug mixtures.

Polysubstance use makes up a majority of drug use, yet relatively few studies investigate the abuse-related effects of drug mixtures. Dose-addition analyses provide a rigorous and quantitative method to determine the nature of the interaction (i.e., supraadditive, additive, or subadditive) between two or more drugs. As briefly reviewed here, studies in rhesus monkeys have applied dose-addition analyses to group level data to characterize the nature of the interaction between the reinforcing effects of stimulants and opioids (e.g., mixtures of cocaine + heroin). Building upon these foundational studies, more recent work has applied dose-addition analyses to better understand the nature of the interaction between caffeine and illicit stimulants such as MDPV and methamphetamine in rats. In addition to utilizing a variety of operant procedures, including drug discrimination, drug self-administration, and drug-primed reinstatement, these studies have incorporated potency and effectiveness ratios as a method for both statistical analysis and visualization of departures from additivity at both the group and individual subject level. As such, dose-addition analyses represent a powerful and underutilized approach to quantify the nature of drug-drug interactions that can be applied to a variety of abuse-related endpoints in order to better understand the behavioral pharmacology of polysubstance use.

Relative reinforcing effects of cocaine and 3,4-methylenedioxypyrovalerone (MDPV) under a concurrent access self-administration procedure in rats.

BACKGROUND: Recent evidence suggesting that polysubstance use is the norm rather than the exception highlights the need for a better understanding of interactions amongst the abuse-related effects of commonly co-abused drugs. Synthetic cathinones remain one of the most popular families of novel psychoactive substances and are typically used in preparations containing multiple stimulants. Evaluating the reinforcing effects of drugs under both single-operant procedures and procedures in which alternatives are available can provide a more complete characterization of their reinforcing effects and economic interactions. METHODS: These studies utilized a drug-versus-drug choice procedure in 18 male Sprague-Dawley rats to evaluate economic interactions between the synthetic cathinone, MDPV, and cocaine in addition to how a history of concurrent access impacts reinstatement behavior. RESULTS: When equi-effective doses of MDPV and cocaine were made concurrently available, approximately half of the subjects responded exclusively on the MDPV-reinforced lever whereas the other half responded exclusively on the cocaine-reinforced lever. Allocation of responding was reversed when the cost of the preferred drug increased, or the cost of the non-preferred drug decreased. Drug-paired cues and MDPV, cocaine, and methamphetamine pretreatments reinstated responding on both drug levers, regardless of preference. CONCLUSION: These data demonstrate that MDPV and cocaine act as economic substitutes and suggest that measures of reinforcing effectiveness determined under a progressive ratio schedule of reinforcement can predict drug choice. These data also suggest that environmental stimuli associated with a particular drug might stimulate class-specific drug-seeking, however, further studies are needed to test the generality of this claim.

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

A subset of rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) develop unusually high levels of drug taking. A history of responding maintained by cocaine, but not food, prevents the development of this high-responder phenotype; however, it is unclear how histories of noncontingent cocaine exposure or self-administering drugs from other pharmacological classes would affect its development. In the current studies, 5 groups of male Sprague-Dawley rats were used to determine whether histories of responding maintained by drugs from different pharmacological classes (e.g., MDPV, cocaine, fentanyl, nicotine, or ketamine) would differentially impact the development of the high-responder phenotype when MDPV was available for self-administration. Two additional groups were used to determine whether noncontingent exposure to cocaine would prevent the development of the high-responder phenotype when MDPV was available for self-administration, and whether noncontingent exposure to MDPV would facilitate the development of the high-responder phenotype when cocaine was available for self-administration. Consistent with previous reports, a history of response-contingent cocaine, and to a lesser extent noncontingent cocaine, prevented the MDPV high-responder phenotype; however, when responding was initially maintained by fentanyl, nicotine, or ketamine, the MDPV high-responder phenotype developed in ∼45% of rats. By manipulating behavioral and pharmacological histories prior to evaluating MDPV self-administration, the current studies provide additional evidence that a history of response-contingent (or noncontingent) cocaine can prevent the transition from well regulated to aberrant drug-taking when responding is maintained by MDPV. Although the mechanism(s) that underlies this novel high-responder phenotype are unknown, elucidation may provide insight into individual differences relating to substance use disorder. SIGNIFICANCE STATEMENT: A subset of outbred Sprague-Dawley rats self-administer high levels of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Understanding the behavioral and/or pharmacological factors that can prevent the development of dysregulated MDPV self-administration may provide insight into individual differences in vulnerability to develop a substance use disorder.

Impact of Morphine Dependence and Withdrawal on the Reinforcing Effectiveness of Fentanyl, Cocaine, and Methamphetamine in Rats.

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10-40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.

Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.

The 3,4-methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.

Interactions between reinforcement history and drug-primed reinstatement: Studies with MDPV and mixtures of MDPV and caffeine.

Many drugs of abuse are mixed with other psychoactive substances (e.g., caffeine) prior to their sale or use. Synthetic cathinones (e.g., 3,4-methylenedioxypyrovalerone [MDPV]) are commonly mixed with caffeine or other cathinones (e.g., 3,4-methylenedioxy-N-methylcathinone [methylone]), and these "bath salts" mixtures (e.g., MDPV + caffeine) can exhibit supra-additive interactions with regard to their reinforcing and discriminative stimulus properties. However, little is known about relapse-related effects of drug mixtures. In these studies, male Sprague-Dawley rats self-administered 0.032 mg/kg/inf MDPV or a mixture of MDPV + caffeine (0.029 + 0.66 mg/kg/inf, respectively) and then underwent multiple rounds of extinction and reinstatement testing to evaluate the influence of reinforcement history and drug-associated stimuli on the effectiveness of saline (drug-paired stimuli alone), MDPV (0.032-1.0 mg/kg), caffeine (1.0-32 mg/kg), and mixtures of MDPV:caffeine (in 3:1, 1:1, and 1:3 ratios, relative to each drug's ED50 ) to reinstate responding. Dose-addition analyses were used to determine the nature of the drug-drug interaction for each mixture. MDPV and caffeine dose-dependently reinstated responding and were equally effective, regardless of reinforcement history. Most fixed ratio mixtures of MDPV + caffeine exhibited supra-additive interactions, reinstating responding to levels greater than was observed with caffeine and/or MDPV alone. Drug-associated stimuli also played a key role in reinstating responding, especially for caffeine. Together, these results demonstrate that the composition of drug mixtures can impact relapse-related effects of drug mixtures, and "bath salts" mixtures (MDPV + caffeine) may be more effective at promoting relapse-related behaviors than the constituents alone. Further research is needed to determine how other polysubstance reinforcement histories can impact relapse-related behaviors.

MDPV self-administration in female rats: influence of reinforcement history.

RATIONALE: A subset of male rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) have unusually high levels of drug intake; however, factor(s) that influence this behavior (e.g., reinforcement history and sex) are unknown. OBJECTIVES: Characterize the reinforcing potency and effectiveness of MDPV in female rats to determine whether (1) a subset of females also develop high levels of MDPV self-administration (i.e., a high-responder phenotype) and (2) the degree to which the high-responder phenotype is influenced by various reinforcement histories (i.e., responding for cocaine or food). METHODS: Female Sprague Dawley rats initially responded for MDPV (0.032 mg/kg/infusion), cocaine (0.32 mg/kg/infusion), or food (45-mg grain pellet) under fixed ratio (FR) 1 and FR5 schedules of reinforcement. After 20 sessions, the cocaine- and food-history rats responded for MDPV for 20 additional sessions. Dose-response curves for MDPV were generated under FR5 and progressive ratio (PR) schedules of reinforcement. RESULTS: A subset of rats responding for MDPV developed high levels of MDPV intake. A history of responding for cocaine, but not food, inhibited the development of high levels of MDPV intake. Large individual differences were observed in the level of self-administration when MDPV was available under an FR5, but not PR, schedule of reinforcement. CONCLUSIONS: MDPV functions as a powerful reinforcer in female rats, as has been previously reported in male rats. The substantial variability in MDPV self-administration between subjects may be related to individual differences in human drug-taking behavior.

Self-administration of the synthetic cathinones 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopentiophenone (α-PVP) in rhesus monkeys.

RATIONALE: The availability and abuse of synthetic analogues of cathinone have increased dramatically around the world. Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone [MDPV] and α-pyrrolidinopentiophenone [α-PVP], are cocaine-like inhibitors of monoamine transporters and common constituents of "bath salts" or "flakka" preparations. Studies in rats suggest that MDPV and α-PVP are 3 to 4-fold more effective reinforcers than cocaine; however, comparisons of the relative reinforcing effectiveness of MDPV and α-PVP have not been reported in other species. OBJECTIVES: Accordingly, in the present study, 4 adult male rhesus monkeys responding under a progressive ratio schedule of reinforcement were used to characterize the reinforcing effects of MDPV and α-PVP and to compare directly these effects with those of cocaine and methamphetamine. RESULTS: MDPV was the most potent reinforcer, followed by α-PVP, methamphetamine, and cocaine. α-PVP was the most effective reinforcer, followed by MDPV, cocaine, and methamphetamine. In addition to making more responses to obtain MDPV and α-PVP, monkeys also responded for longer periods of time when MDPV or α-PVP was available compared with when either cocaine or methamphetamine was available for infusion. CONCLUSIONS: These studies confirm recent reports from rodents and provide strong evidence that the synthetic cathinones MDPV and α-PVP are capable of maintaining high levels of responding for prolonged periods of time, and that they function as more effective reinforcers than either cocaine or methamphetamine. The relative strength of these reinforcing effects may account for the high rates of "bath salts" use reported in humans.

Behavioral economic analysis of the reinforcing effects of "bath salts" mixtures: studies with MDPV, methylone, and caffeine in male Sprague-Dawley rats.

RATIONALE: "Bath salts" preparations often contain combinations of synthetic cathinones (e.g., 3,4-methylenedioxymethcathinone [methylone], 3,4-methylenedioxypyrovalerone [MDPV]), and caffeine, and evidence suggests that mixtures of synthetic cathinones and caffeine (e.g., MDPV + caffeine or methylone + caffeine) can be more potent and/or effective reinforcers than predicted for an additive interaction. OBJECTIVE: To use demand curve analyses to compare the reinforcing effectiveness of MDPV and methylone to mixtures of MDPV + caffeine and methylone + caffeine. METHODS: Male Sprague-Dawley rats acquired methylone self-administration (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement and generated full dose-response curves for methylone (0.01-1 mg/kg/inf) under an FR5 schedule of reinforcement. Demand curves were then obtained for methylone, MDPV, caffeine, and methylone + caffeine and MDPV + caffeine mixtures by increasing the FR across sessions according to the following series: 3, 10, 18, 32, 56, 100, 178, etc. RESULTS: Self-administration of methylone was rapidly acquired by 87.5% of rats and was maintained across a range of doses, producing an inverted U-shaped dose-response curve. Rank order demand for the individual constituents was MDPV > methylone > caffeine. Demand for the 3:1 (but not 10:1) methylone + caffeine mixture was greater than that for methylone alone, and demand for MDPV alone was similar to both MDPV + caffeine mixtures evaluated. CONCLUSIONS: These studies provide additional evidence that although methylone is an effective reinforcer, combining methylone with caffeine results in an enhanced reinforcing effectiveness compared to methylone alone. Thus, abused "bath salts" preparations containing synthetic cathinones and caffeine may have higher abuse liability than preparations containing only synthetic cathinones.

Effects of lorcaserin on reinstatement of responding previously maintained by cocaine or remifentanil in rhesus monkeys.

Drug abuse remains a serious public health issue, underscoring the need for additional treatment options. Agonists at serotonin (5-HT)2C receptors, particularly lorcaserin, are being considered as pharmacotherapies for abuse of a variety of drugs, including cocaine and opioids. The current study compared the capacity of lorcaserin to attenuate reinstatement of extinguished responding previously maintained by either cocaine or an opioid; this type of procedure is thought to model relapse, an important aspect of drug abuse. Six rhesus monkeys responded under a fixed-ratio schedule for cocaine (0.032 mg/kg/infusion) or remifentanil (0.00032 mg/kg/infusion). Reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.32 mg/kg) or heroin (0.0032-0.1 mg/kg) combined with response-contingent presentations of the drug-associated stimuli, or heroin alone without presentation of drug-associated stimuli. When combined with drug-associated stimuli, cocaine and heroin increased extinguished responding. On average, monkeys emitted fewer reinstated responses following 0.32 mg/kg cocaine, compared with the number of responses emitted when cocaine was available for self-administration or when extinguished responding was reinstated by 0.032 mg/kg heroin. When drug-associated stimuli were not presented, heroin did not increase responding. Lorcaserin dose dependently attenuated reinstated responding, and its potency was similar regardless of whether cocaine or heroin was given before reinstatement sessions. The generality of this effect of lorcaserin across pharmacological classes of abused drugs might make it particularly useful for reducing relapse-related behaviors in polydrug abusers. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter.

Synthetic cathinones are common constituents of abused "bath salts" preparations and represent a large family of structurally related compounds that function as cocaine-like inhibitors or amphetamine-like substrates of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters. Preclinical evidence suggests that some cathinones (e.g., MDPV and α-PVP) are more effective reinforcers than prototypical stimulant drugs of abuse, such as cocaine or methamphetamine. Although the reinforcing potency of these cathinones is related to their potency to inhibit DAT, less is known about the pharmacological determinants of their unusually high reinforcing effectiveness. To this end, we tested the hypothesis that reinforcing effectiveness of cathinone stimulants is positively correlated with their selectivity for DAT relative to SERT. Uptake inhibition assays in rat brain synaptosomes were used to directly compare the potency of MDPV, MDPBP, MDPPP, α-PVP, α-PPP, and cocaine at DAT, NET, and SERT, whereas intravenous self-administration in rats was used to quantify relative reinforcing effectiveness of the drugs using progressive ratio (PR) and behavioral economic procedures. All cathinones were more potent at DAT than NET or SERT, with a rank order for selectivity at DAT over SERT of α-PVP > α-PPP > MDPV > MDPBP > MDPPP > cocaine. These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT. Together, these studies provide strong and convergent evidence that the abuse potential of stimulant drugs is mediated by uptake inhibition at DAT, with activity at SERT serving as a negative modulator of reinforcing effectiveness.

Effects of lorcaserin and buspirone, administered alone and as a mixture, on cocaine self-administration in male and female rhesus monkeys.

Cocaine use disorder is a serious public health issue for which there is no effective pharmacotherapy. One strategy to speed development of medications for cocaine use disorder is to repurpose drugs already approved for use in humans based on their ability to interact with targets known to be important for addiction. Two such drugs, lorcaserin (Belviq; a drug with serotonin [5-HT]2C receptor agonist properties) and buspirone (Buspar; a drug with 5-HT1A receptor partial agonist and dopamine D3/D4 receptor antagonist properties) can produce modest decreases in cocaine self-administration in rhesus monkeys. The current study evaluated the effectiveness of mixtures of lorcaserin and buspirone (at fixed dose ratios of 3:1, 1:1, and 1:3 relative to each drug's ID50) to reduce responding for 0.032 mg/kg/inf cocaine under a progressive ratio schedule of reinforcement in 2 male and 2 female rhesus monkeys. Dose addition analyses were used to determine if the effects of the drug mixtures differed from those predicted for an additive interaction between lorcaserin and buspirone. Dose-dependent reductions of cocaine self-administration were observed when lorcaserin and buspirone were administered alone, as well as when they were administered as 3:1, 1:1, and 1:3 fixed ratio mixtures of lorcaserin + buspirone. The effects of the 1:1 mixture of lorcaserin + buspirone on cocaine self-administration were supraadditive, whereas the effects of 3:1 and 1:3 mixtures were additive. Together, these results indicate that a combination therapy containing a mixture of lorcaserin and buspirone might be more effective than either drug alone at treating cocaine use disorder. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats.

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'