These data suggest that repeated MDMA exposure sensitized both the locomotor activating and reinforcing effects of MDMA. Activation of D receptors during MDMA pretreatment appears critical for the development of sensitization to MDMA-produced hyperactivity. The role of D receptor mechanisms in the development of sensitization to the reinforcing effects of MDMA is equivocal.

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Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague‐Dawley rats. The effects of extensive 3,4‐methylenedioxymethamphetamine (MDMA) self‐administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug‐naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor‐activating effect of MDMA (200 μg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self‐administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate‐putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate‐putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA‐produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate‐putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure.

<p>Rationale. ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a popular recreational drug of abuse. Like other drugs of abuse, a proportion of users develop symptoms that are characteristic of a Substance Use Disorder (SUD). The behavioural and neurobiological consequences of repeated misuse of MDMA are not well understood, however.  Objectives. The purpose of the present thesis was to investigate behaviourally relevant neuroadaptations that develop with repeated MDMA exposure in laboratory rats.  Methods. First, the effect of chronic, long-access (6 hour) self-administration of MDMA on the accumulation of the transcription factor, ΔFosB, in the nucleus accumbens (core, shell), dorsal striatum (dorsomedial, dorsolateral, ventromedial, ventrolateral), prefrontal cortex (anterior cingulate, prelimbic, infralimbic, orbitofrontal), amygdala (central, basolateral), ventral tegmental area (anterior, posterior), and raphe (dorsal, median) was measured using immunohistochemistry. Second, the behavioural relevance of these findings was determined by examining the effect of bi-lateral intra-striatal (nucleus accumbens, dorsomedial striatum, dorsolateral striatum) microinjections of MDMA (200 μg/1 μL/side) on the expression of behavioural sensitisation following two days of withdrawal from a regimen of repeated, systemic MDMA exposure (10 mg/kg/day, i.p., for 5 days). Third, a procedure was developed to examine neurochemical correlates of sensitised MDMA-produced behaviour (0, 5, 10 mg/kg, i.p.) following the same regimen of repeated MDMA exposure. Samples were collected from the medial striatum using in vivo microdialysis and the extracellular concentrations of serotonin, dopamine, MDMA, and their metabolites were quantified using liquid chromatography coupled with quadrupole time-of-flight (Q-TOF) mass spectrometry. Lastly, a unique untargeted metabolomics procedure was developed to further analyse these microdialysis samples and to identify novel or unexpected metabolites that were relevant to the sensitised behavioural response produced by MDMA.  Results. MDMA self-administration produced region-dependant increases in ΔFosB. Significant increases in ΔFosB were observed in the nucleus accumbens core, the medial areas of the dorsal striatum, as well as all areas of the prefrontal cortex and amygdala. Small, but significant increases were also observed in the dorsal raphe. Increases were observed in the nucleus accumbens shell and the posterior tail of the ventral tegmental area, but these increases were not significant following statistical correction for multiple comparisons. Acute exposure to MDMA increased locomotor activity only when the drug was infused into the nucleus accumbens. Following repeated systemic exposure, behavioural sensitisation was expressed when MDMA was infused into both the nucleus accumbens or the dorsomedial striatum, but not the dorsolateral striatum. Analysis of microdialysates from the medial striatum indicated that behavioural sensitisation was accompanied by small increases in baseline levels of extracellular serotonin and decreased MDMA-produced increases in serotonin, but these changes were not statistically significant. Behavioural sensitisation was also accompanied by increased extracellular concentrations of dopamine at baseline and following acute MDMA exposure, but these data were not statistically analysed due to small sample sizes. MDMA-produced extracellular concentrations of MDMA did not change with repeated exposure. Untargeted metabolomics revealed potential changes in MDMA and dopamine metabolism that might be relevant to the sensitised behavioural response.  Conclusions. The findings of the current research suggest that repeated MDMA exposure results in many of the same neuroadaptations that result from repeated exposure to other drugs of abuse. These included increased ΔFosB expression in many brain regions that are relevant to addiction, such as the nucleus accumbens, dorsal striatum, and prefrontal cortex. Dopaminergic mechanisms also appeared to be influenced and were associated with sensitised MDMA-produced behaviour. Surprisingly, serotonergic mechanisms were not significantly impacted by repeated MDMA exposure under the current conditions. Some of the procedures developed in this thesis are unique and may be of value for future research investigating the neurochemical underpinnings of addictive behaviour or other disease states.</p>