Long-term GABA treatment elicits supersensitivity of quisqualate-preferring metabotropic glutamate receptor in cultured rat cerebellar neurons.
In primary cultures of rat cerebellar granule neurons, GABA treatment (50 microM, 7 days) caused a withdrawal supersensitivity selective for the metabotropic glutamate receptors that mainly prefer L-glutamate, quisqualate and, to a lesser extent, kainate. The withdrawal supersensitivity was absent when 10 microM SR-95531 was coadministered with GABA during the treatment period, an event that suggests the GABAA receptors primarily produced the GABA treatment effect. This was supported further by the inability of baclofen treatment to mimic completely the treatment effect of GABA. Withdrawal from 7 days of baclofen treatment only produced a slight increase in the metabotropic effect of L-glutamate and carbachol. In addition, in untreated neurons, baclofen had no acute effect, whereas GABA inhibited the effect of L-glutamate and carbachol. The inhibitory effect of GABA was reversed by SR-95531 and was absent in neurons treated with GABA. These observations suggest the involvement of GABAA receptors and the apparent development of tolerance to GABA, respectively. Also, dependence on GABA may have occurred; the metabotropic effects of glutamate, kainate, and quisqualate were not altered in neurons maintained with GABA treatment.
Yu
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Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
Chuang
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DM
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D004361:Drug Tolerance; D058787:GABA-A Receptor Antagonists; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D058787:GABA-A Receptor Antagonists; D005971:Glutamates; D011724:Pyridazines; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D011189:Potassium Chloride; D016318:Quisqualic Acid; D002217:Carbachol; C049853:gabazine; D001418:Baclofen; D007608:Kainic Acid