Lack of neuroprotection to MDMA-induced neurotoxicity in the Neurokinin-1 receptor knockout mouse.

V. BISAGNO; E. DEL RIO; I. COLADO; S. P. HUNT; C. DE FELIPE

Arizona, USA

Congreso; 2006 NIDA International Forum; 2006

NIDA-NIH, USA

Lack of neuroprotection to MDMA-induced neurotoxicity in the Neurokinin-1 receptor knockout mouse. V. Bisagno, E. del Rio, I. Colado, S. P. Hunt and C. de Felipe. Instituto de Neurociencias, UMH-CSIC. Alicante, Spain and Department of Anatomy and Developmental Biology, UCL, London, England. 3,4 Methylenedioxymethamphetamine (MDMA) is an amphetamine analog and the major component of the street drug “Ecstasy”. MDMA targets serotonergic nerve terminal axons in rats and humans but MDMA toxicity appears to be limited to dopamine (DA) producing neurons in mice and causes nerve terminal degeneration in mouse striatum. Neurokinin 1 receptor (NK1) antagonists have been shown to protect methamphetamine neurotoxicity. We investigated the effect of toxic MDMA schedule (3X25mg drug base /kg, every 2 h) in the NK1 receptor knockout mice (NK1 -/- mice and wild type were obtained with C-57BL/6 x 129Sv Line crossed with an outbred MF-1 line). Rectal temperature was measured after each MDMA administration, and significant differences were found in the treatment factor, MDMA treated animals showed hyperthermia compared to saline treated animals, no genotype significant difference. Six days after MDMA toxic doses, dark-light box activity was evaluated, and the mutant mice spent less time in the white area (considered an anxiety measure) compared with the wild type animals. In order to establish the degree of dopaminergic toxicity, we measured DA content and its main metabolites in striatum as well as striatal dopamine transporter sites (DAT) by Western blots. Data shown a clear depletion of DA and metabolites, and a profound decreased in DAT sites to a similar extent in both genotypes. We also measured open field exploratory activity and anxiety parameters after a single acute MDMA dose of 10mg/kg and the MDMA NK1-/- group showed less time in the center of the field, also considered and anxiety-like response. The lack of neuroprotection shown in the NK1-/- MDMA treated group might be related to compensatory mechanisms exerted by other neurokinin receptors in the NK1 knockout. Another plausible explanation might be that the previously reported protective effects of NK1 receptor antagonists are not exerted only by the blockade of NK1 receptors but also by other pharmacological action not related to NK1 receptors. We are currently doing the same experiments that are being reported here in a pure C57BL/6 genetic background knockout mice of the NK1 receptor,  where NK1 -/- mice and NK1 +/+ were obtained by crossing C57BL/6 x 129Sv line onto C57BL/6 background  over 10 generations to obtain a NK1 knockout with more than 98% of C57BL/6 background.  Grant from the Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA).