Single or multiple injections of methamphetamine increased dopamine turnover but did not decrease tyrosine hydroxylase levels or cleave caspase-3 in caudate-putamen

Methamphetamine (METH), leading to striatal dopamine (DA) nerve terminal toxicity in mammals, is also thought to induce apoptosis of striatal neurons in rodents. We investigated the acute effects induced by multiple injections of METH (4 × 5 mg/kg, i.p.) at 2-h intervals or a single injection of METH (20 mg/kg, i.p.) on terminal dopaminergic toxicity markers, including DA levels, DA turnover, and tyrosine hydroxylase (TH) immunoreactivity in rat caudate-putamen (CPu). We further investigated whether both treatment paradigms would change Bax and activate caspase-3 expression, thus triggering striatal apoptotic mitochondria-dependent biochemical cascades. The first injection of METH (5 mg/kg, i.p.) produced a significant release of DA that peaked 30 min and stayed above control levels up to 1.5 h within CPu. In another set of experiments, rats were killed 1 and 24 h following the last injection, for tissue DA and metabolite content measurement and Western blot analysis (24 h). Multiple doses induced DA depletion and increased turnover at both endpoints. Single-dose METH reproduced these effects at 24 h; however, turnover was significantly higher than that evoked by the multiple doses at 24 h. Although both paradigms evoked similar DA depletion, however, none of the dosing regimens induced changes in TH expression at 24 h. The former paradigm produced an increase in Bax expression in CPu not sufficient to induce cleavage of caspase-3 proenzyme at 24 h. This study suggests that both paradigm induced changes in striatal dopaminergic markers that are independent of terminal degeneration and striatal apoptotic mitochondria-dependent caspase-3 driven cascade within 24 h. Synapse 60:185-193, 2006. Published 2006 Wiley-Liss, Inc.http://dx.doi.org/10.1002/syn.2028