3,4‐Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine‐induced damage to dopamine nerve endings: β‐ketoamphetamine modulation of neurotoxicity by the dopamine transporter

Abstract

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

“…This binge treatment regimen has been established by multiple prior studies in this laboratory and others, and elicits significant neurotoxicity for amphetamine compounds. Doses of MeCa used fall within the range used in similar published studies (Gygi et al, 1996(Gygi et al, , 1997Sparago et al, 1996), whereas the range of 4MM doses used were comparable to studies involving METH and other b-ketoamphetamines (Angoa- Pérez et al, 2012Pérez et al, , 2013Pérez et al, , 2014Anneken et al, 2015). Mice were sacrificed 48 hours after the last drug treatment when amphetamine-associated neurotoxicity was known to reach maximal levels.…”

“…2. Typical toxicity over a range of doses for METH (2.5-10 mg/kg) as well as MEPH (20-40 mg/kg) is also included from a prior publication and supplemental experiments from our laboratory for comparison (Anneken et al, 2015). There was very little toxicity elicited by 4MM, with only the highest dose evoking a significant reduction (20%) in striatal DA ( Fig.…”

“…To this end, the bath salt MEPH can be particularly useful in studying METH toxicity. Although DA depletion when MEPH is given at elevated ambient temperatures has been reported, as well as a potentially toxic in vitro effect (den Hollander et al, 2014;Martínez-Clemente et al, 2014), numerous studies conducted in this laboratory and others under ambient conditions known to produce METH toxicity have reported no significant longterm in vivo dopaminergic neurotoxicity when MEPH is administered in a binge regimen (Angoa-Pérez et al, 2012Baumann et al, 2012;den Hollander et al, 2013;Motbey et al, 2013;Anneken et al, 2015). As shown in Fig.…”

“…Female C57BL/6 mice (Harlan, Indianapolis, IN) weighing 18-25 g at the time of experimentation were housed 5-7 per cage in large shoe-box cages in a light-(12-hour light/dark) and temperaturecontrolled room. Female mice were used, as they are very sensitive to neurotoxicity induced by amphetamines and to maintain consistency with our previous studies of METH and b-ketoamphetamine interactions (Angoa-Pérez et al, 2012Anneken et al, 2015). Mice had free access to food and water.…”

“…These effects are thought to be elicited by the release of dopamine (DA), serotonin (5-HT), and norepinephrine through their respective reuptake transporters, as the b-ketoamphetamines are known to have potent reuptake inhibition and releasing effects on these targets (Baumann et al, 2012;López-Arnau et al, 2012;Cameron et al, 2013;Eshleman et al, 2013;Simmler et al, 2013). The synthetic cathinones found in bath salts are less apt to produce lasting neurotoxicity compared with 3,4-methylenedioxymethamphetmine (MDMA) and methamphetamine (METH) (Angoa-Pérez et al, 2012;Baumann et al, 2012;den Hollander et al, 2013;Motbey et al, 2013;Anneken et al, 2015). This is despite a striking similarity in acute neurochemical and behavioral effects, including the aforementioned monoamine release, thermoregulation (Baumann et al, 2012;Fantegrossi et al, 2013;López-Arnau et al, 2014;Martínez-Clemente et al, 2014;Aarde et al, 2015;Kiyatkin et al, 2015;Shortall et al, 2016), hyperlocomotion (Baumann et al, 2012;López-Arnau et al, 2012;Marusich et al, 2012;Motbey et al, 2012;Wright et al, 2012;Aarde et al, 2013Aarde et al, , 2015Fantegrossi et al, 2013;Gatch et al, 2013), and measures of abuse potential (Hadlock et al, 2011;Lisek et al, 2012;Watterson et al, 2012;Aarde et al, 2013;Motbey et al, 2013;Karlsson et al, 2014).…”