Fluoxetine protects MDMA-induced neurotoxicity in rat brain

Abstract

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Objectives: The MDMA is a popular illicit drug that produces toxic effect to brain serotonin neurons. We recently reported that 4-¹⁸F-ADAM (1) is a potent serotonin transporter imaging agent. The purpose of this study was to examine the effect of fluoxetine (FX) on MDMA-induced toxicity of serotonin transporters in rat brain using 1 and Micro-PET.

Methods: Male S-D rats were treated with FX (5 mg/kg, s.c.) followed by a neurotoxic regimen of MDMA (twice/day × 4 days, 10 mg/kg, s.c.). The neuroprotective effects of FX in serotonergic neurons were evaluated using 1 and Micro-PET one to four weeks after the treatment. The ROI (Regions of Interest) were drawn on the midbrain (MB), thalamus (TH), hypothalamus (HT), hippocampus (HC), caudate putamen (CP), and frontal cortex (FC) according to the atlas of rat brain and MRI. The specific uptake ratios (SUR) were expressed as (ROI-cerebellum) / cerebellum. Ex vivo autoradiography (ARG) were performed at the end of the study. Results of the ARG were compared to the Micro-PET images.

Results: In MDMA alone treated rats, the SUR of 1 in almost all the brain regions were about 50% lower than the normal controls at first week. This effect lasted for four weeks after the treatment. In contrast, co-administration of FX with MDMA resulted in a recovery of SUR in the MB ( 2.24 vs 3.43 ), TH ( 2.05 vs 3.18 ), HT ( 2.18 vs 3.39 ), HT ( 1.59 vs 2.56 ), CP ( 1.87 vs 3.01 ), and FC ( 1.43 vs 2.36 ) at fourth week. Ex vivo ARG study confirmed the Micro-PET imaging results.

Conclusions: The results suggest that FX can protect MDMA-induced neurotoxicity in rat brain, and 1 and Micro-PET may be feasible in monitoring therapeutic responses of MDMA-induced neurotoxicity.

Research Support: Supported by grants NSC 95-2811-B-016-002 ,NSC 95-2321-B-016-001-MY2 (CYS), and NSC 96-NU-7-016-001.