Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure.
Methamphetamine (METH)-induced neurotoxicity within the striatum and substantia nigra of the vervet monkey was characterized by heterogeneous decreases in immunoreactivity (IR) for dopamine system phenotypic markers. Decreases in IR for tyrosine hydroxylase (TH), dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) were observed 1 week after METH HCI (2x2 mg/kg; 24 h apart). Regional changes throughout the rostrocaudal extent of the striatum were characterized by a gradient of neurotoxic effect (lateral greater than medial) and the preservation of patches of IR. The decreases in IR in the caudate and putamen were greater than those in the nucleus accumbens. The reduced IR in the METH-exposed striatum allowed for the visualization of dopamine phenotype cell bodies. Within the ventral midbrain, the METH-exposed substantia nigra pars compacta (SNc) also showed a heterogeneous loss of IR (lateral greater than medial). In contrast, the ventral tegmental area (VTA) showed only minor decreases in IR. The magnitude of the decreases in the SNc and VTA subregions corresponded to those observed in their respective striatal projection areas, suggesting that nigrostriatal neuron subpopulations were differentially reactive to METH. The profile of these drug-induced nigrostriatal dopamine system deficits resembles aspects of Parkinson's disease pathology and, as such, may provide a useful model with which to evaluate neuroprotective and neurorestorative strategies.
Harvey
D C
DC
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-1735, USA.
Laćan
G
G
Melegan
W P
WP
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010300:Parkinson Disease / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D002352:Carrier Proteins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase