Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys

Abstract

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(À)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S( þ )-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

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

“…For S(+)-MDMA, however, decreased reinforcing effects were observed in only one monkey (Fantegrossi et al 2004a). It is important that responding for cocaine was remarkably stable in all monkeys, suggesting that there was some pharmacological specificity to these observed behavioral changes.…”

“…Comparing the first and last dose-effect curves for racemic and R(−)-MDMA generally revealed shifts to the right and down, indicating reduced reinforcing effects for these compounds (Fantegrossi et al 2004a). For S(+)-MDMA, however, decreased reinforcing effects were observed in only one monkey (Fantegrossi et al 2004a).…”

“…Subsequent self-administration experiments with MDMA were conducted over an approximately 18-month period to assess the persistence of these reinforcing effects (Fantegrossi et al 2004a) because diminished subjective effects over repeated uses have often been reported by human ecstasy users (see, for example, the recent review of chronic tolerance to MDMA in Parrot 2005). In these studies, monkeys were given the opportunity to selfadminister one of several MDMA doses about twice per week under the single-dose FR10 schedule described above, and dose-effect curves were repeatedly determined in this manner over the duration of the experiment.…”

“…Although a single report suggests that even a relatively brief period of MDA self-administration results in the depletion of hippocampal 5-HT at least 2 weeks after discontinuing drug access in the rat (Markert and Roberts 1991), the persistence of this effect was not determined, and only one previous study has examined the neurochemical consequences of selfadministered MDMA (Fantegrossi et al 2004a). The behavioral data obtained from this later study were presented above, but a significant effort was made to uncover neurochemical correlates of these observed behavioral changes, the results of which are described below.…”

“…Ordinates: monoamine concentration (nanogram per milligram tissue). Brain concentrations of 5-HT and dopamine were measured by reverse phase HPLC coupled with electrochemical detection using the method previously described in Fantegrossi et al (2004a). See text for further details…”