PHARMACOLOGICAL INHIBITION OF THE VESICULAR MONOAMINE TRANSPORTER 2 ATTENUATES 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED HYPERTHERMIA, LOCOMOTOR ACTIVITY AND NEUROTOXICITY.

picture of Andy Phan presenting his/her poster: PHARMACOLOGICAL INHIBITION OF THE VESICULAR MONOAMINE TRANSPORTER 2 ATTENUATES 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED HYPERTHERMIA, LOCOMOTOR ACTIVITY AND NEUROTOXICITY.

Andy Phan , Lucina E. Lizarraga, Aram B. Cholanians, Joseph M. Herndon, Serrine S. Lau, and Terrence J. Monks

PHARMACOLOGICAL INHIBITION OF THE VESICULAR MONOAMINE TRANSPORTER 2 ATTENUATES 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED HYPERTHERMIA, LOCOMOTOR ACTIVITY AND NEUROTOXICITY.

3,4- Methylenedioxymethamphetamine (MDMA, or more commonly known as Ecstasy) is a synthetic psychostimulant that is highly abused as a recreational drug. Upon consumption, the drug prompts the acute pharmacological effects. Such effects consist of acute synaptic monoamine release, especially the release of serotonin (5-HT), leading to hyperactivity and hyperthermia. On the contrary, long-term serotonergic neurotoxicity is seen in lasting depletion of 5-HT and structural damage to 5-HT-related nerve terminals. The underlying molecular mechanisms behind these opposing effects are not well understood. The vesicular monoamine transporter 2 (VMAT2) functions as an intra-neuronal storage vesical and as a transporter of monoamine neurotransmitters, specifically dopamine and 5-HT. The role that VMAT2 plays is essential for its prevention of neurotransmitter oxidation within the cytosol by monoamine oxidases. With this in consideration, we investigated the effect of pharmacological inhibition of VMAT2 in Sprague-Dawley rats with the use of Ro4-1284 on both the MDMA-mediated neurotoxic acute and long-term effects. Rats that were given a pretreatment of the VMAT2 inhibitor (10 mg/kg, ip) one hour prior to MDMA treatment (20 mg/kg, sc) showed increases in 5-HT levels in the cortex and striatal regions of the brain in comparison to rats treated with MDMA and no pretreatment. Animals dosed with MDMA without Ro4-1284 pretreatment displayed increased hyperactivity, measured as total horizontal movement distance and mean velocity. Pretreatment with Ro4-1284 delayed and attenuated this hyperactivity. MDMA-induced hyperthermia was also significantly reduced in animals pretreated with Ro4-1284 as core body temperatures in these rats were significantly reduced compared to MDMA-treated rats. In summary, the use of Ro4-1284 to pharmacologically inhibit VMAT2 is able to mitigate MDMA-induced depletion of 5-TH/5-HIAA, locomotion activity, and hyperthermia in rats. It is proposed that VMAT2 plays a role in regulating the acute and long-term neurotoxic effects of MDMA. (NIDA Award DA023525). 

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