Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain
| Autor: | Steven R. Childers, Jeffrey J. Pezor, Thomas J.R. Beveridge, Bradley M Keegan, Ruoyu Xiao, Tammy Sexton, Allyn C. Howlett |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Baclofen Dopamine and cAMP-Regulated Phosphoprotein 32 medicine.medical_specialty Time Factors Stimulation Nucleus accumbens GABAB receptor Biology Article Rats Sprague-Dawley Glycogen Synthase Kinase 3 Random Allocation Cellular and Molecular Neuroscience chemistry.chemical_compound GTP-Binding Proteins Dopamine Internal medicine medicine Animals Phosphorylation Prefrontal cortex Pharmacology Glycogen Synthase Kinase 3 beta Brain Endocrinology medicine.anatomical_structure Globus pallidus Receptors GABA-B nervous system chemistry Cerebral cortex Focal Adhesion Kinase 1 GABA-B Receptor Agonists Autoradiography Tyrosine medicine.drug |
| Zdroj: | Neuropharmacology. 95:492-502 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2015.02.021 |
| Popis: | The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3β(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system. |
| Databáze: | OpenAIRE |
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