Nicolas Noyola
Member
- Joined
- Apr 5, 2018
- Messages
- 88
Central gabaergic mechanisms as targets for melatonin activity in brain.The pineal gland serves the function of a neuroendocrine transducer converting information about day length into the nocturnal release of melatonin. Melatonin acts on the brain, particularly on the hypothalamus, to affect several biological rhythms. By employing autoradiography and 2-[(125)I]melatonin as a radioligand, the hypothalamic suprachiasmatic nucleus (SCN) and the pars tuberalis of the adenohypophysis have been identified as sites for melatonin binding exhibiting dissociation constants (K(d)s) in the 10(?10) M range. These sites were also revealed in test-tube binding assays employing crude membrane fractions. Additionally, studies in either membrane or cytosol fractions using tritiated or radioiodine-labelled melatonin indicated location of another population of presumptive melatonin binding sites with K(d)s in the 10(?8) ?10(?9) M range in several other brain areas, including the hippocampus, cerebral and cerebellar cortexes, as well as the pineal gland. Signal transduction processes for melatonin presumably involve interaction with G proteins to inhibit adenylate cyclase. Also, a decrease of Ca(2+) uptake, stimulation of guanylate cyclase and inhibition of cyclooxygenase occur at 10(?8) M melatonin concentrations. The time of administration of melatonin is critical for hormone action. In rodents and humans, a major late afternoon-early evening period of sensitivity is found for several central and peripheral effects of melatonin. Results in rats suggest that central synapses employing ?-aminobutyric acid (GABA) as an inhibitory transmitter are a target for pineal melatonin activity because: (a) pinealectomy (Px) disrupts circadian rhythmicity of brain GABA and benzodiazepine (BZP) binding; (b) low doses of melatonin counteract Px-induced modifications of BZP and GABA binding; (c) chronic melatonin treatment increases brain BZP and GABA binding; (d) melatonin administration accelerates brain GABA turnover rate; (e) melatonin increases glutamic acid decarboxylase activity and Cl(?) ion conductance in the medial basal hypothalamus-preoptic area, with maximal activity in the evening. As BZP, melatonin could affect circadian rhythmicity by modifying GABAergic mechanisms in the endogenous oscillator. Additionally, the epileptoid state described after Px and the mild sedation and torpor that follow administration of pharmacological amounts of melatonin can be explained by an effect on central GABAergic circuits.
