Abstract
In the last years, considerable efforts have been devoted to examine the participation of brain γ-aminobutyric acid (GABA) neurons in circadian phenomena. The importance of gabaergic neurons in circadian organization of brain function is underlined by the fact that almost every single neuron in the suprachiasmatic nucleus contains GABA. In addition, drugs affecting GABA function, like benzodiazepines (BZP) or melatonin, are effective to phase-shift circadian rhythms. Several data point out to a melatonin interaction with GABA-containing neurons in the CNS. Melatonin injection decreases brain GABA concentration, modifies GABA-BZP binding to brain membranes, and increases GABA turnover rate, GABA-induced chloride influx in rat hypothalamus, and the electrophysiological effects of GABA in rabbit cerebral cortex. As other GABA-positive ligands, melatonin inhibited cage-convulsant (TBPS) binding to rat brain membranes. Under long photoperiods, a significant rhythm of GABA turnover was detected in the areas studied (cerebral cortex, preoptic-medial basal hypothalamus, cerebellum and pineal gland) of Syrian hamsters, with maxima at night. Under short photoperiods the synchronization in turnover rate among the remaining regions was lost. This effect was attributed to the different melatonin secretory patterns under both lighting environments. In a number of studies carried out to define the participation of gabaergic mechanisms in behavioral effects of melatonin in rodents, we found that: (1) The administration of the central-type BZP antagonist flumazenil blunted the analgesic response to melatonin in mice, indicating that time-dependent melatonin analgesia was sensitive to central-type BZP antagonism. (2) Flumazenil although unable by itself to modify locomotor activity or induced seizures in rodents, significantly attenuated the inhibitory effects of melatonin. (3) The anxiolytic and pro-exploratory melatonin properties assessed in rats in a plus-maze indicated maximal effects of melatonin at night, with absence of effects at noon and a weak activity at the beginning of the light phase, an effect blunted by administration of flumazenil. (4) In Syrian hamsters, flumazenil inhibited melatonin-induced re-entrainment of locomotor activity and body temperature rhythms of Syrian hamsters after phase-advancing the L:D cycle. Collectively, the results are compatible with the view that melatonin activity on circadian rhythmicity was sensitive to central-type BZP antagonism. Melatonin and BZP seem to have in common an activity on central gabaergic neurons participating in circadian organization.
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Cardinali, D.P., Golombek, D.A., Rosenstein, R.E., Kanterewicz, B.A., Fiszman, M. (1995). Chronobiological Activity of Melatonin: Mediation by Gabaergic Mechanisms. In: Fraschini, F., Reiter, R.J., Stankov, B. (eds) The Pineal Gland and Its Hormones. NATO ASI Series, vol 277. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1911-9_11
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