title: Reduced striatal vesicular monoamine transporters after neurotoxic but not after behaviorally-sensitizing doses of methamphetamine.
abstract: Prior studies indicate long-term reductions of striatal dopaminergic markers after sustained, high dose methamphetamine exposures in vivo, suggesting a neurotoxic effect. We have reported lack of regulation of vesicular monoamine transporter type-2 expression, as opposed to other markers of striatal dopaminergic terminals, under conditions that alter dopaminergic transmission without synaptic terminal losses. In the present study, we evaluated the vesicular monoamine transporter and the neuronal membrane dopamine transporter in rat striata after in vivo exposure to neurotoxic or to intermittent, low dose (behaviorally-sensitizing, non-neurotoxic) methamphetamine administrations. Vesicular monoamine transporter binding was measured by autoradiography of (+)-[3H]dihydrotetrabenazine, the active isomer of (+/-)-[3H]dihydrotetrabenazine. (+)-Dihydrotetrabenazine bound to a homogeneous population of striatal sites in controls with a Kd of 1.5 nM and a Bmax of 3.8 fmol/microg protein. Neurotoxic methamphetamine treatment reduced both striatal vesicular monoamine transporter (-26%) and dopamine transporter (-39%) bindings. There were no changes after the non-neurotoxic treatment regimen. The vesicular monoamine transporter may thus be a valuable marker in the further clinical study of psychostimulant drug neurotoxicity.
authors.affiliation: Department of Internal Medicine, The University of Michigan, Ann Arbor, USA.
authors.forename: K
authors.initials: K
authors.lastname: Frey
authors.forename: M
authors.initials: M
authors.lastname: Kilbourn
authors.forename: T
authors.initials: T
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001345:Autoradiography; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015259:Dopamine Agents / Q000008:administration & dosage / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D008694:Methamphetamine; D013747:Tetrabenazine