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

Abstract

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.

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

“…One of the most commonly reported synthetic cathinones found in “Bath Salts” preparations is 3,4-methylenedioxypyrovalerone, or MDPV, a monoamine reuptake inhibitor that is ∼750 times more potent at inhibiting reuptake at the dopamine transporter than the serotonin transporter [10–13]. Consistent with reports of MDPV being widely used, it has been demonstrated to share discriminative stimulus properties with other commonly used stimulants (e.g., cocaine, methamphetamine) [14–19], and readily maintains self-administration, acting as a highly effective reinforcer in both rodents and non-human primates [11,20–25].…”

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

“…Caffeine, an adenosine receptor antagonist, can increase arousal and produce modest increases in locomotor and cardiovascular activity. In addition to these mild stimulant properties, caffeine also shares discriminative stimulus properties with stimulants, such as cocaine or MDPV (e.g., G. T. Collins et al, 2016; Harland et al, 1989; Justinova et al, 2009; Munzar et al, 2002; Seaman et al, 2021). Similarly, pretreatment with caffeine can increase cocaine self‐administration and reinstate extinguished responding for either cocaine or MDPV (Comer & Carroll, 1996; Doyle et al, 2021; Horger et al, 1991; Schenk et al, 1994).…”

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

“…Chemical analyses of the initial wave of “Bath Salts” preparations suggested that most preparations contained 3,4-methylenedioxypyrovalerone (MDPV; a selective dopamine and norepinephrine transporter reuptake inhibitor), 3,4-methylenedioxymethcathinone (methylone; a non-selective monoamine transporter substrate), or 4-methylmethcathinone (mephedrone; a non-selective monoamine transporter substrate) (Spiller et al, 2011; Shanks et al, 2012; Seely et al, 2013). Consistent with their popularity as recreational drugs, the discriminative stimulus effects of MDPV and methylone overlap with those of cocaine and methamphetamine (Fantegrossi et al, 2013; Gatch et al, 2013; Collins et al, 2016; DeLarge et al, 2017; Harvey et al, 2017; Smith et al, 2017; Gatch and Forster, 2020; Seaman et al, 2021), and both drugs are readily self-administered by rats (Aarde et al, 2013; Watterson et al, 2014; Schindler et al, 2016a; Gannon et al, 2017, 2018c) and non-human primates (Collins et al, 2019; de Moura et al, 2021). Since their emergence, the United States Drug Enforcement Agency has placed 13 synthetic cathinones, including MDPV, methylone, and mephedrone, under Schedule I regulations (Drug Enforcement Administration, Department of Justice 2011, 2014).…”

“…Subsequently, clandestine laboratories have attempted to skirt these regulations by making slight chemical modifications to these structures, resulting in a large number of “legal” synthetic cathinone derivatives that retain activity as substrates for monoamine transporters and monoamine reuptake inhibitors. Although the general mechanisms of action remain intact, the introduction of modest structural differences results in differences in the potencies and selectivities of these compounds to interact with monoamine transporters, resulting in changes in abuse-related effects, including discriminative stimulus and reinforcing effects (Gannon et al, 2018c, 2018a; Seaman et al, 2021).…”

“…Though the degree to which the subjective and/or adverse effects of “Bath Salts” preparations are influenced by caffeine is unclear, preclinical studies have begun examining the role of caffeine in the abuse-related effects of caffeine-containing drug mixtures. Indeed, drug discrimination studies in rats have demonstrated that the discriminative stimulus effects of caffeine not only overlap with those of cocaine and MDPV, but mixtures of cocaine+caffeine and MDPV+caffeine exhibit supra-additive interactions with respect to their cocaine-like discriminative stimulus effects (Collins et al, 2016; Seaman et al, 2021). Furthermore, interactions between MDPV and caffeine, and methylone and caffeine, have been demonstrated to be greater than additive with regard to reinforcing effectiveness, determined using progressive ratio and economic demand procedures in rats (Gannon et al, 2018b, 2019) as well as interact synergistically to reinstate extinguished responding for drug-paired stimuli (Doyle et al, 2021).…”