Central-type benzodiazepines inhibit release of alpha-melanocyte-stimulating hormone from the rat hypothalamus.
In a previous work, we have shown that GABA inhibits the release of alpha-melanocyte-stimulating hormone (alpha-melanotropin) from hypothalamic neurons through activation of GABAA receptors [Delbende et al. (1989) Brain Res. 497, 86-93]. Since GABA-gated channel activity can be allosterically modulated by a variety of compounds including benzodiazepines, we have investigated the effect of benzodiazepines in the control of alpha-melanotropin release by the rat basal hypothalamus. This study was conducted in vitro using perifused rat hypothalamic slices and the amount of alpha-melanotropin release was monitored with a sensitive and highly specific radioimmunoassay. Infusion of clonazepam (50 microM), a selective agonist for central-type benzodiazepine binding sites, induced an inhibition of KCl (50 mM)-evoked alpha-melanotropin release. The inhibitory effect of clonazepam was rapid and reversible. Administration of Ro 15-1788 (100 microM), a specific antagonist for central-type benzodiazepine receptors or SR 95531, a GABAA receptor antagonist, completely reversed the inhibitory effect of clonazepam. In addition, Ro 15-1788 and SR 95531 both enhanced the amplitude of the response observed during prolonged KCl infusion on alpha-melanotropin neurons, suggesting the existence of a tonic inhibitory effect of endogenous GABA and/or benzodiazepines in the release of alpha-melanotropin by hypothalamic neurons. To investigate further the effect of benzodiazepines in the regulation of alpha-melanotropin neurons, rats were treated in vivo with clonazepam (5 mg/kg) or the non-selective benzodiazepine receptor agonist diazepam (3 mg/kg). Both compounds caused a significant increase in the content of alpha-melanotropin and beta-endorphin in the rat hypothalamus within 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Blasquez
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Groupe de Recherche en Endocrinologie Moléculaire, CNRS URA 650, Unité Affiliée à l'INSERM, Université de Rouen, Mont-Saint-Aignan, France.
Jégou
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S
Tranchand Bunel
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D
Delbende
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C
Braquet
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P
Vaudry
H
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism*; D010477:Perfusion; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D001615:beta-Endorphin / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D018756:GABA Antagonists; D011724:Pyridazines; D005442:Flumazenil; D002998:Clonazepam; D001615:beta-Endorphin; D011189:Potassium Chloride; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones; C049853:gabazine; D003975:Diazepam