Chronic phenmetrazine treatment promotes D(2) dopaminergic and α2-adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain
| Autor: | Steven R. Childers, Tammy Sexton, Allyn C. Howlett, Annie L Dreitzler, Linda J. Porrino, Bruce E. Blough, Bradley M Keegan, Thomas J.R. Beveridge, Mack D. Miller, Hilary R. Smith |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Chemistry G protein General Neuroscience Dopaminergic Article 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Neurochemical Desensitization (telecommunications) Dopamine Internal medicine Basal ganglia medicine Phenmetrazine Neurology (clinical) Molecular Biology 030217 neurology & neurosurgery Homeostasis Developmental Biology medicine.drug |
| Zdroj: | Brain Res |
| Popis: | Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2(Thr202/Tyr204), GSK3β(Tyr216), and DARPP-32(Thr34). Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[(14)C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN’s activity, we performed [(35)S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D(2) dopamine and α(2)-adrenergic, but not 5-HT(1A), receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3β levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use. |
| Databáze: | OpenAIRE |
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