Nipecotic acid and 2,4-diaminobutyric acid enhance the actions of muscimol on cerebral cortical neurons

Iontophoretically applied muscimol exerted a potent inhibitory action on the firing of spontaneously active cerebral cortical neurons of rats. On the basis of ejection currents employed, muscimol was considerably more potent than γ-aminobutyric acid (GABA), and the inhibitions produced by muscimol were frequently of a longer duration than those observed with GABA. Nipecotic acid and diaminobutyric acid (DABA) are potent inhibitors of high-affinity GABA uptake systems and muscimol is not thought to be a substrate for high-affinity GABA uptake (JOHNSTON, G. A. R. 1976. Physiolic pharmacology of GABA and its antagonists in the vertebrate nervous system. In GABA in nervous system function. Edited by E. Roberts, T. Chase, and D. B. Tower. Raven Press, New York). However, nipecotic acid and DABA consistently enhanced the inhibitory effects of both GABA and muscimol on cortical neurons while not affecting monoamine or adenosine 5′-monophosphate induced inhibitions. These findings suggest that iontophoretically applied nipecotic acid and DABA have some specificity for amino acid mechanisms in the cortex, but their actions appear to be more complex than can be explained by a selective blockade of GABA uptake processes. Thus, the uptake blockers may be exerting a weak and not readily detectable agonist action at amino acid receptors. Alternatively, the actions of iontophoretically applied muscimol may be partially terminated by uptake through GABA uptake systems.