Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Abstract

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.

Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus

“…Considering the close structural and mechanistic overlaps between mephedrone and the neurotoxic amphetamines, it was surprising to find that mephedrone does not cause damage to DA nerve endings of the striatum in mice (Angoa-Pérez et al, 2012; Baumann et al, 2012; den Hollander et al, 2013; Hadlock et al, 2011; Motbey et al, 2012b; Shortall et al, 2012). On the other hand, given the manner in which it interacts with DA and 5HT transporters, it has been predicted that mephedrone would protect against methamphetamine- or MDMA-induced neurotoxicity.…”

“…However, a number of studies have established that this drug does not cause persistent reductions in function of the DA neuronal system (Angoa-Pérez et al, 2012; Baumann et al, 2012; den Hollander et al, 2013; Hadlock et al, 2011; Motbey et al, 2012b; Shortall et al, 2012). The issue of whether mephedrone damages 5-HT nerve endings remains unsettled as one study documented possible neurotoxic effects (Hadlock et al, 2011) while others have been negative in this regard (Baumann et al, 2012; den Hollander et al, 2013; Motbey et al, 2012b; Shortall et al, 2012). The present studies were carried out to determine if mephedrone alone or combined with methamphetamine or MDMA would unmask a neurotoxic effect on 5HT nerve endings.…”

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

“…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).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Although a decrease in recognition performance in the novel object recognition test was observed 1 month after treatment with 4-MMC (Motbey et al, 2012), as well as a decrease in working memory measured using the T-maze spontaneous alternation test, there were no effects on spatial memory in the Morris water maze test. Furthermore, both 4-MMC and MDMC have no effect on anxiety-like behavior measured using the emergence test or elevated plus maze or on depressive behavior in the forced swim test and actually appear to improve aspects of spatial reversal learning (den Hollander et al, 2013).…”