Distinct mechanisms mediating methamphetamine-induced neuronal apoptosis and dopamine terminal damage share the neuropeptide substance p in the striatum of mice.
Methamphetamine (METH) is an addictive psychostimulant that induces damage to the dopamine terminals and the apoptosis of some neurons of the striatum. Our laboratory demonstrated using either a single bolus dose (30 mg/kg) or a binge (10 mg/kg 4x at 2-h intervals) of METH that pharmacological blockade of the substance P receptor (neurokinin-1) attenuates METH-induced damage to both the presynaptic dopamine terminals and the apoptosis of some neurons of the striatum. To determine the phenotype of striatal neuron ablated by METH, we combined TUNEL (Terminal Deoxyncleotidyl Transferase-Mediated dUTP Nick End Labeling) with immunofluorescence for selective markers of projection and interneurons. METH induces the loss of approximately 20% of the projection neurons. The cholinergic and gamma-aminobutyric acid (GABA)-parvalbumin interneurons sustain losses of 30% and 50%, respectively. The somatostatin/neuropeptide Y (NPY)/nitric oxide synthase (NOS) interneurons are not impacted by METH. To investigate the mechanism by which substance P mediates METH-induced damage in this part of the brain, we ablated the striatal interneurons that express the neurokinin-1 receptor (NK-1R) with the selective neurotoxin substance P-SAP. Ablation of the NK-1R-expressing interneurons prevented METH-induced apoptosis in the striatum but was without effect on depletion of dopamine terminal markers. We propose that substance P mediates the apoptosis of some striatal neurons via the intrastriatal activation of nitric oxide synthesis. In contrast, substance P may mediate damage of the dopamine terminals via an extrastriatal mechanism involving the substantia nigra and cortical glutamate release.
Zhu
Judy P Q
JP
Department of Biological Sciences, Hunter College, 695 Park Avenue, New York, NY 10021, USA.
Xu
Wenjing
W
Angulo
Jesus A
JA
D000818:Animals; D017209:Apoptosis; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009479:Neuropeptides / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
D015259:Dopamine Agents; D009479:Neuropeptides; D018040:Receptors, Neurokinin-1; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C454685:SSP-SAP fusion protein, recombinant; D008694:Methamphetamine; D000076985:Saporins; D004298:Dopamine