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Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone (MDPV) and Structurally Related Synthetic Cathinones

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Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone (MDPV) and Structurally Related Synthetic Cathinones Research report 1 Discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones Robert W. Seaman Jra,b, Michelle R. Doylea,b, Agnieszka Sulimac, Kenner C. Ricec and Gregory T. Collinsa,b 02/22/2021 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= by http://journals.lww.com/behaviouralpharm from Downloaded The 3,4-methylenedioxypyrovalerone (MDPV), and other agonists, phenylephrine and clonidine, respectively, Downloaded structurally related synthetic cathinones, are popular failed to increase MDPV-appropriate responding at alternatives to prototypical illicit psychostimulants, such doses smaller than those that suppressed responding from as cocaine and methamphetamine. These drugs are often altogether. Although these studies do not support a role http://journals.lww.com/behaviouralpharm referred to as ‘bath salts’ and function either as cocaine- for serotonergic or adrenergic systems in mediating/ like inhibitors of monoamine uptake, or amphetamine-like modulating the discriminative stimulus effects of MDPV, substrates for dopamine, norepinephrine and serotonin convergent evidence is provided to suggest that the transporters. These studies used male Sprague–Dawley discriminative stimulus effects of MDPV are primarily rats trained to discriminate MDPV from saline to evaluate mediated by its capacity to inhibit dopamine uptake, the substitution profiles of structurally related synthetic and the subsequent activation of dopamine D2 or D3 by cathinones, cocaine, and other direct-acting dopamine and receptors. Behavioural Pharmacology XXX: 000–000 BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= noradrenergic receptor agonists in order to characterize Copyright © 2021 Wolters Kluwer Health, Inc. All rights the relative contributions of dopamine, norepinephrine and reserved. serotonin to the discriminative stimulus effects of MDPV. Behavioural Pharmacology 2021, XXX:000–000 As expected, each of the cathinones and cocaine dose- dependently increased MDPV-appropriate responding, Keywords: 3,4-Methylenedioxypyrovalerone, drug discrimination, structure activity relationship, synthetic cathinones with a rank-order potency that was positively correlated a with their potency to inhibit dopamine and norepinephrine, Department of Pharmacology, The University of Texas Health Science Center at San Antonio bResearch Service, South Texas Veterans Health Care System, but not serotonin, a relationship that is consistent with the San Antonio, Texas and cDrug Design and Synthesis Section, Molecular Targets rank order to maintain self-administration. The dopamine and Medications Discovery Branch, NIDA- and NIAAA-Intramural Research Programs, Bethesda, Maryland, USA D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, Correspondence to Gregory T. Collins, PhD, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr - whereas the dopamine D1/5 receptor agonist, SKF 82958, MC 7764, San Antonio, Texas 78229, USA nonselective dopamine receptor agonist, apomorphine, Tel: +(210) 567 4199; fax: +(210) 567 4303; e-mail: [email protected] as well as the α–1, and α–2 adrenergic receptor Received 11 September 2020 Accepted as revised 29 December 2020 Introduction physiological (tachycardia and hyperthermia) symptoms Synthetic cathinones emerged on the illicit drug market that sometimes resulted in death. The United States in the early 2000s in the form of ‘bath salts’ preparations Drug Enforcement Agency (US DEA) currently lists 13 and quickly became popular alternatives to psychostim- synthetic cathinones as Schedule I compounds (Drug on 02/22/2021 ulants, such as cocaine and methamphetamine. Indeed, Enforcement Administration, Department of Justice synthetic cathinones function as either cocaine-like 2011, 2014), including 3,4-methylenedioxypyrovaler- inhibitors of monoamine uptake or amphetamine-like one (MDPV), α-pyrrolidinopentiophenone (α-PVP) substrates for dopamine, norepinephrine and serotonin and other pyrrolidine-containing cathinones. However, transporters (Baumann et al. 2012, 2013; Simmler et al. clandestine laboratories have skirted these regulations 2013, 2014; Eshleman et al. 2013, 2017). They garnered by introducing slight chemical modifications to these attention in the popular press because of their status structures, resulting in a large number of ‘legal’ synthetic as ‘legal highs’ as well as the large number of adverse cathinone derivatives. In addition to differences in their effects, emergency room visits and abnormal behaviors regulatory status, structurally-distinct synthetic cathinone associated with the use of various ‘bath salts’ prepara- derivatives have important functional differences in their tions (Spiller et al. 2011; Kyle et al. 2011; Murray et al. mechanisms of action. The modest structural differences 2012; Johnson and Johnson 2014). Those admitted to produced by chemical modifications convey both differ- LWW the emergency room were reported to exhibit both ences in potency to inhibit uptake at and selectivity for psychiatric (paranoia, hallucinations and agitation) and dopamine, norepinephrine and serotonin. For instance, 0955-8810 Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000624 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 2 Behavioural Pharmacology 2021, Vol XXX No XXX the monoamine uptake inhibitor, MDPV, inhibits uptake between reinforcing effectiveness, as assessed by either at dopamine and norepinephrine with ~750-fold more a progressive ratio schedule of reinforcement or demand potency than at serotonin but upon regulation by the US curve analyses and selectivity to inhibit uptake at dopa- DEA, was quickly replaced in ‘bath salts’ preparations mine relative to serotonin (Gannon et al. 2018a). with other pyrrolidine-containing cathinones, such as α-PVP (Baumann et al. 2012, 2013; Simmler et al. 2013; Although the discriminative stimulus effects of MDPV Eshleman et al. 2013, 2017; Gannon et al. 2018a) (Fig. 1). have been described in numerous studies (Fantegrossi et Functional studies have suggested that cathinones con- al. 2013; Gatch et al. 2013; Collins et al. 2016; Gannon et al. taining a pyrrolidine ring (e.g. MDPV) generally function 2016; Harvey and Baker 2016; Berquist and Baker 2017; as uptake inhibitors at monoamine transporters whereas Berquist et al. 2017; DeLarge et al. 2017; Harvey et al. 2017; those lacking a pyrrolidine ring or containing smaller Risca and Baker 2019; Gatch and Forster 2020), the vast substituents (e.g. methylone) function as substrates majority of these studies have characterized these effects for monoamine transporters. Furthermore, potency to in subjects trained to discriminate other stimulants from inhibit uptake at dopamine has been demonstrated to be saline. From these studies, it is clear that the discrimina- enhanced by the presence of a methylenedioxy moiety tive stimulus effects of MDPV overlap with those pro- (e.g. MDPV versus α-PVP) or a longer α-alkyl side chain duced by d-amphetamine (Harvey et al. 2017), cocaine [e.g. MDPV versus 3,4-methylenedioxy-α-pyrrolidin- (Gatch et al. 2013; Collins et al. 2016; Gannon et al. 2016), obutyrophenone (MDPBP)] on pyrrolidine-containing methamphetamine (Gatch et al. 2013), and 3,4-methyl cathinones whereas selectivity for dopamine over sero- enedioxy methamphetamine (MDMA) (to a lesser tonin is greater for compounds lacking a methylenedi- extent) (Gatch and Forster 2020). Similarities between oxy moiety and having a longer α-alkyl side chain (e.g. the discriminative stimulus effects of MDPV and other α-PVP > α-pyrrolidinopropiophenone (α-PPP) >MDPV). commonly abused stimulants led to further investiga- Potency to inhibit uptake at norepinephrine has also been tion of the mechanism(s) mediating the discriminative demonstrated to be primarily influenced by the length stimulus effects of MDPV. In those studies, rodents of the α-alkyl side chain, but the absence of a methyl- trained to discriminate MDPV from saline were used to enedioxy moiety also results in modest increases in demonstrate that the discriminative stimulus effects of potency to inhibit uptake at norepinephrine (Eshleman cocaine (Fantegrossi et al. 2013; Risca and Baker 2019) et al. 2017). Our laboratory has previously demonstrated and methamphetamine (Fantegrossi et al. 2013; Berquist that the rank-order potencies of structurally-related syn- and Baker 2017) overlap with those of MDPV, while sub- thetic cathinones to maintain responding under a fixed stitution studies with MDMA, a drug with strong sero- ratio schedule of reinforcement are consistent with their tonin releasing properties, were mixed, with one study potencies to inhibit uptake at dopamine (Gannon et al. reporting MDMA producing high levels (Fantegrossi et 2018b), and that there is a significant positive correlation al. 2013), and another reporting low levels (Berquist and Fig. 1 Chemical structure of the synthetic cathinone 3,4-methylenedioxypyrovalerone (upper) and structurally related synthetic cathinones 3,4-methylene- dioxy-α-pyrrolidinobutyrophenone (MDPBP) (middle left), 3,4-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) (lower left) α-pyrrolidinopenti- ophenone (α-PVP) (middle right) and α-PPP (lower right).
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