title: Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion.
abstract: It has been proposed that glutamatergic and dopaminergic systems are functionally opposed in their regulation of striatal output. The present study tested the effects of drugs that enhance AMPA-receptor-mediated glutamatergic transmission (ampakines) for their effects on dopamine-related alterations in cortical activity and locomotor behavior. Rats with unilateral 6-hydroxydopamine lesions of the ascending nigro-striatal dopamine system were sensitized to methamphetamine and then tested for methamphetamine-induced circling behavior in the presence and absence of ampakines CX546 and CX614. Both ampakines produced rapid, dose-dependent reductions in circling that were evident within 15 min and sustained through 1 h of behavioral testing. In situ hybridization maps of c-fos mRNA expression showed that in the intact hemisphere, ampakine cotreatment markedly increased c-fos expression in parietal, sensori-motor neocortex above that found in rats treated with methamphetamine alone. Ampakine cotreatment did not augment c-fos expression in frontal, sensori-motor cortex or striatum. Still larger ampakine-elicited effects were obtained in parietal cortex of the dopamine-depleted hemisphere where labeling densities were increased by approximately 60% above values found in methamphetamine-alone rats. With these effects, the hemispheric asymmetry of cortical activation was less pronounced in the ampakine-cotreatment group as compared with the methamphetamine-alone group. These results indicate that positive modulation of AMPA-type glutamate receptors 1) can offset behavioral disturbances arising from sensitized dopamine receptors and 2) increases aggregate neuronal activity in a regionally selective manner that is probably dependent upon behavioral demands.
authors.affiliation: Department of Anatomy and Neurobiology, Gillespie Neuroscience Research Facility, University of California at Irvine, Irvine, CA 92697-4292, USA.
authors.forename: U S
authors.initials: US
authors.lastname: Hess
authors.forename: S P
authors.initials: SP
authors.lastname: Whalen
authors.forename: L M
authors.initials: LM
authors.lastname: Sandoval
authors.forename: G
authors.initials: G
authors.lastname: Lynch
authors.forename: C M
authors.initials: CM
authors.lastname: Gall
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal; D002452:Cell Count; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007839:Functional Laterality; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D019579:Neocortex / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D010078:Oxazines / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists*; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D018663:Adrenergic Agents; D000697:Central Nervous System Stimulants; D004149:Dioxoles; D010078:Oxazines; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D008694:Methamphetamine; C414782:2H,3H,6aH-pyrrolidino(2'',1''-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1, 4-dioxan-10-one; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase