Paroxetine MDMA

Dr. Gibb s hypothesis regarding dopamine involvement, we thought that perhaps MBDB would not be neurotoxic because of a lack of effect on dopamine. But, in fact, it is neurotoxic as well, measured by whole-brain serotonin 5-HIAA and tritiated paroxetine binding sites. It is perhaps two-thirds the toxicity, on a molecular weight basis, of MDMA, but it is toxic. 

TABLE 2. Effects of repeated systemic administration of MDMA on the regional decreases in [ H]paroxetine-labeled serotonin uptake sites... 

H]MDMA interacted with multiple sites in rat brain. A low affinity pH]MDA binding site (apparent Kd>1.0 mM) was found to be resistant to boiling of the synaptosomal preparation for 15 minutes. This site was saturable, as indicated by a 30 pereent inhibition of [ H]MDA binding to boiled synaptosomes by 1.0 mM MDA and a 56 pereent inhibition of the binding by 0.1 mM of the serotonin uptake bloeker paroxetine. The indication of a saturable, nonspecific binding site for [ H]MDA in boiled membranes necessitated that we use boiled tissue to assess nonspecific binding in all subsequent experiments. 

In initial ICC studies, animals were treated with MDA or MDMA using the protocol described by Ricaurte et al. (1985). Adult Sprague-Dawley rats (150 to 200 g) reeeived subcutaneous injections of racemic MDA or MDMA every 12 hours for 4 days. Each dose was equivalent to 20 mg/kg of the free base. The rats were sacrificed by intracardiac aldehyde perfusion 2 weeks after the final dose. In order to study subacute effects for evidence of degeneration, additional rats received MDA every 12 hours for 2 days and were sacrificed 24 hours after the last injection. Additional experimental details are described elsewhere (O Heam et al. 1986 O Heam et al. 1988). A series of animals treated identically and in parallel were analyzed for changes in 5-HT levels and density of uptake sites using paroxetine binding (Yeh et al. 1986 Battaglia et al. 1987). 

Battaglia, G. Yeh, S.Y. O Heam, E. Molliver. M.E. Kuhar, M.J. and De Souza, E.B. 3,4-Methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) preferentially destroy serotonin terminals in rat brain Quantification of neurodegeneration by measurement of H-paroxetine-labeled serotonin uptake sites. 

SLC6A4 (SERT) SERT plays a role in the reuptake and clearance of serotonin in the brain. Like the other SLC6A family members, SERT transports its substrates in a Na+-dependent fashion and is dependent on CL and possibly on the countertransport of K+. Substrates of SERT include serotonin (5-HT), various tryptamine derivatives, and neurotoxins such as 3,4-methylene-dioxymethamphetamine (MDMA ecstasy) and fenfluramine. SERT is the specific target of the selective serotonin reuptake inhibitors (e.g., fluoxetine and paroxetine) and one of several targets of tricyclic antidepressants e.g., amitriptyline). Genetic variants of SERT have been associated with an array of behavioral and neurological disorders. The precise mechanism by which a reduced activity of SERT, caused by either a genetic variant or an antidepressant, ultimately affects mood and behavior is not known. 

The psychological effects of ecstasy (MDMA, methylenedi-oxymethamfetamine) may be reduced if citalopram has previously been given. It seems likely that other SSRIs will also reduce or block some of the effects of ecstasy, but increased serotonin effects may, in theory, also be possible. An isolated report describes a neurotoxic reaction in a man taking citalopram when he took unknown amounts of ecstasy. Fluoxetine and paroxetine may decrease the metabolism of ecstasy. 

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