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

Abstract

Aims Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus. Main methods The status of 5HT nerve endings in hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4. Key findings Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone. Significance Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.

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.…”

Neurotoxicology of Synthetic Cathinone Analogs

“…Mephedrone alone did not cause persistent reductions in the levels of DA, 5-HT, or TPH-2 [18, 19, 22, 28, 69] aside from a small decrease in the DA metabolite HVA in the mouse striatum [28]. Mephedrone is considered a more potent releaser of DA than MDMA [15, 70].…”

“…Studies in mice indicate that combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5-HT nerve endings to an extent that was different from either drug alone [18]. Methamphetamine and MDMA alone caused mild reductions in 5-HT but did not change SERT and TPH2 levels [23].…”

“…Mephedrone administration alone did not cause persistent reductions in the levels of SERT [18]. Uptake inhibition studies using rat synaptosomes found that mephedrone potently inhibits DAT and SERT [35, 70], and the drug is a substrate for DAT, SERT, and the norepinephrine transporter (NET) [24].…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…High ambient temperatures produce a general increase in amphetamine neurotoxicity (see below), and these studies indicate that this also holds true for cathinones. Furthermore, there is evidence that 4-MMC can increase the loss of striatal DA induced by METH when the two drugs are coadministered (Angoa- Perez et al, 2013b), but does not exacerbate the loss of 5-HT after METH or MDMA (Angoa- Perez et al, 2013a).…”