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Central type benzodiazepines and the octadecaneuropeptide modulate the effects of gaba on the release of alpha msh from frog neurointermediate lobe in vitro



Central type benzodiazepines and the octadecaneuropeptide modulate the effects of gaba on the release of alpha msh from frog neurointermediate lobe in vitro



Neuroscience 31(2): 485-494



The involvement of the GABA-benzodiazepine receptor complex in the regulation of melanotropin secretion has been investigated using perfused frog neurointermediate lobes. The GABAA agonist 3-amino-1 propane sulfonic acid mimicked the biphasic effect of GABA on .alpha.-melanocyte-stimulating hormone secretion: a brief stimulation followed by an inhibition of melanotropin secretion. The GABAA antagonist SR 95531 (10-4 M) inhibited both stimulation and inhibition of .alpha.-melanocyte-stimulating hormone release induced by GABA (10-4 M). Since the inhibitory effect of baclofen (10-4 M) was partially antagonized by SR 95531 (10-4 M), it appears that the GABAergic control of .alpha.-melanocyte-stimulating hormone release is mainly achieved through activation of GABAA receptors. GABA-induced stimulation of .alpha.-melanocyte-stimulating hormone release was inhibited by tetrodotoxin (10-5 M), an Na+-channel blocker, or nifedipine (10-5 M), a voltage-dependent Ca2+-channel blocker, suggesting that Na+ and Ca2+ ions are involved in the stimulatory phase of GABA action. Only central-type benzodiazepine binding site agonists such as clonazepam (10-4 M) modified .alpha.-melanocyte-stimulating hormone release. In fact, clonazepam (10-7 to 10-5 M) led to a dose-dependent potentiation of both GABA-induced stimulation and inhibition of .alpha.-melanocyte-stimulating hormone release. This potentiating effect was antagonized by the GABAA antagonist SR 95531 (10-4 M) or by the central-type benzodiazepine binding site antagonist flumazenil (10-4 M), whereas picrotoxin (10-4 M) abolished only the stimulatory phase. In contrast, the peripheral-type benzodiazepine binding site agonist Ro 5-4864 (10-4 M) was unable to potentiate the effects of GABA on .alpha.-melanocyte-stimulating hormone secretion. To investigate the possible involvement of endogenous benzodiazepine binding site ligands in the control of .alpha.-melanocyte-stimulating hormone secretion, a radioimmunoassay for the octadecaneuropeptide, a putative endogenous benzodiazepine binding site inhibitor, has been developed. High concentrations of octadecaneuropeptide-like material were found in neurointermediate lobe extracts, suggesting that this peptide may act as a regulator of the GABA-benzodiazepine receptor complex. The administration of synthetic octadeaneuropeptide (10-6 to 10-4 M) to perifused neurointermediate lobes markedly reduced the effects of GABA on .alpha.-melanocyte-stimulating hormone release. In addition, flumazenil (10-4 M) reversed the inhibitory action of octadecaneuropeptide on GABA-induced modulation of .alpha.-melanocyte-stimulating hormone release. Taken together, these results indicate that GABA acts on frog melanotrophs through a GABA receptor complex including a GABA, recognition site, a Cl- channel and a central-type benzodiazepine binding site. Activation of benzodiazepine receptors has the potential to modulate the effects of GABA on .alpha.-melanocyte-stimulating hormone secretion, the final response depending on the properties of the benzodiazepine-receptor ligand used: central-type benzodiazepine binding site agonists cause an enhancement of the response to GABA, whereas the endogenous peptidergic ligand octadecaneuropeptide attenuates the action of GABA.

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