The alpha2C-adrenoceptor modulates GABA release in mouse striatum.
The alpha(2C)-adrenoceptor occurs in high density in the striatum relative to other brain regions, but its biological role in striatal physiology is perplexing because of the paucity of noradrenergic terminals in this region. In this study, mice with a targeted inactivation of the alpha(2C)-adrenoceptor gene (alpha(2C)-KO mice), and genetically related mice (WT mice), were used to study the potential role of the striatal alpha(2C)-adrenoceptor in modulating GABA release. Perfused brain slices were pre-loaded with [(3)H]GABA and were stimulated electrically. In WT mice, the alpha(2)-adrenoceptor agonist, UK14304 (brimonidine), significantly enhanced [(3)H]GABA release from striatal slices, while the alpha(2)-adrenoceptor antagonist, RX821002, alone evoked a significant decrease in [(3)H]GABA release. In alpha(2C)-KO mice, the effect of RX821002 was absent, while UK14304 retained its ability to enhance [(3)H]GABA release. Pharmacological depletion of monoamines in WT mice also abolished the effect of RX821002 on [(3)H]GABA release. In hippocampal slices, RX821002-induced reduction in [(3)H]GABA release was present in WT and alpha(2C)-KO mice. In the presence of tetrodotoxin, RX821002 increased [(3)H]GABA release in striatal slices from both WT and alpha(2C)-KO mice. Together, these data imply that alpha(2A)- and alpha(2C)-adrenoceptors are located on different neurons in the striatum, that alpha(2C)-adrenoceptor-mediated effects on striatal GABA release are mediated by an endogenous catecholamine that could be dopamine, and that the alpha(2C)-adrenoceptor effect of RX821002 does not occur at the GABAergic terminal.
Zhang
Weilie
W
Departments of Psychiatry and Behavior and Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Ordway
Gregory A
GA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D014316:Tritium; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D009638:Norepinephrine