| Methamphetamine (METH) is a potent psychostimulant known to cause extensive neural damage in the central nervous system. Continued characterization of its neural effects showed that single intraperitoneal injection of METH (10-40 mg/kg of body weight) induces striatal apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) dose-dependently. Single bolus doses of METH generated higher levels of TUNEL-positive neurons compared to a binge of METH (4 x 10 mg/kg of body weight at 2-hour intervals). METH-induced (30 mg/kg of body weight) apoptosis peaks at 24 hours after treatment, and occurs prior to the depletion of dopamine nerve terminal markers and the increases in reactive astrocytes. Nissl staining confirmed neuronal loss at this time point. Since the striatum is a heterogeneous structure known to exhibit selective vulnerabilities towards different insults, a series of immunohistochemical and cell quantification studies were carried out to identify the phenotypes of cells affected by METH. METH induced death of GABAergic projection neurons. METH also damaged GABAergic and cholinergic interneurons in the dorsal striatum. Interestingly, somatostatin interneurons were spared.; Since METH augments striatal substance P (SP) levels, it was hypothesized that signaling through the neurokinin-1 (NK-1) receptor by SP activates the apoptotic cascade. To determine the role of NK-1 receptor in METH-induced apoptosis, the effects of pharmacological blockade and local ablation of receptor-expressing neurons were examined. Administration of NK-1 receptor antagonist, WIN 51,708, 30 minutes prior to METH exposure, prevented METH-induced apoptosis and peroxynitrite generation. Pretreatment with WIN 51,708 had no effect on METH-induced hyperthermia. To confirm that local activation of NK-1 receptors within the striatum are contributing to METH-induced apoptosis of striatal neurons, NK-1 receptor-expressing interneurons were selectively ablated by intrastriatal injections of NK-1 receptor agonist, [Sar9,Met(O2)11]substance P, conjugated to a ribosomal-inactivating cytotoxin saporin (SSP-SAP). Ablation of NK-1 receptor-expressing striatal interneurons prevented METH-induced apoptosis. These results provide the first pharmacological evidence that tachykinins, particularly SP, acting through NK-1 receptors, play a crucial role in the pathogenesis of METH-induced cell death in the striatum. These findings also suggest a novel approach for therapeutic interventions in the treatment of neurodegenerative disorders including Parkinson's and Huntington's diseases. |
