5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine

Abstract

1 The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-fIT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine.2 Administration of MDMA (20mgkg'1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-', i.p.) protected only the hippocampus. 3 Administration of a single dose of chlormethiazole (100 mg kg-') 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx + 2.5°C) induced by the MDMA injection. 4 Injection of PCA (5 mg kg-', i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100mg kg-', i.p.) or dizocilpine (1 mg kg-', i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg', i.p.) was given which produced only a 30% loss of 5-HT content. Chlormethiazole did prevent the hyperthermia induced by PCA (5 mg kg-'), while the lower dose of PCA (2.5 mg kg-') did not produce a change in body temperature. 5Neither chlormethiazole nor dizocilpine prevented the neurotoxic loss of hippocampal or cortical 5-HT neurones measured 4 days following administration of fenfluramine (25 mg kg', i.p.). 6 In general, chlormethiazole and dizocilpine were effective antagonists of the 5-HT-mediated behaviours of head weaving and forepaw treading which appeared following injection of all three neurotoxins. 7 Both chlormethiazole and dizocilpine have previously been shown to prevent the neurotoxic effects of a high dose of methamphetamine on cerebral 5-HT and dopamine pathways. These drugs also prevent MDMA-induced neurotoxicity of 5-HT pathways, but not that induced by injection of PCA or fenfluramine. This suggests that the mechanisms of neurotoxic damage to 5-HT pathways produced by substituted amphetamines cannot be identical. The monoamine loss does not appear to result from the hyperthermia produced by the neurotoxic compounds.

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

“…The temperature results agree with previous observations that MDMA increases body temperature (Colado et al 1993;Dafters 1994;Mechan et al 2001) and that this response diminishes across repeated days of administration (Cassel et al 2004;Marston et al 1999;Slikker et al 1989). Locomotor activity has been reported to decrease or not change after comparable regimens (Cassel et al 2004;Marston et al 1999;Slikker et al 1989).…”

“…The loss of serotonin in the present study occurred with only modest temperature increases. Elevated temperature exacerbates the serotonin loss after MDMA (Colado et al 1993;Malberg and Seiden 1998), but loss can occur without markedly elevated temperatures (McGregor et al 2003). The present results suggest that "harm reduction" approaches by limiting hyperthermia are not a guarantee against serotonin depletion.…”

Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration

“…However, recent data suggest that the predominant action of MDMA in this region may be that of inhibiting dopamine neuronal ®ring (Gi ord et al, 1996). Since the drug can induce Ca 2+ dependent dopamine release (Crespi et al, 1997) dopamine mediated function would be suppressed, thereby allowing the expression of 5-HT mediated behaviours including the serotonin syndrome (Spanos & Yamamoto, 1989;Colado et al, 1993;Green et al, 1995).…”

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

“…1b), then extended to MDMA in subsequent studies (Ricaurte et al 1988), and generally results in profound regional depletions in 5-HT, its metabolite 5-hydroxyindoleacetic acid, and decreased binding potential at serotonin transporters (SERT). Most other laboratory groups studying the effects of MDMA in primates also seem to have adopted this dosing procedure (see, for example, Slikker et al 1988Slikker et al , 1989Kleven et al 1989;DeSouza et al 1990;Ali et al 1993;Colado et al 1993;Frederick et al 1998;O'Shea et al 1998;Taffe et al 2002;Bowyer et al 2003). The consistency with which these serotonergic alterations are observed after repeated administrations of MDMA suggests that this compound certainly possesses the capacity to alter neurochemistry in a persistent manner, but considerable controversy exists surrounding the applicability of the dose regimen commonly utilized to induce these effects in comparison with recreational use of MDMA by humans.…”