Time‐Dependent Effect of Melatonin on Glutamic Acid Decarboxylase Activity and ³⁶CI⁻ Influx in Rat Hypothalamus

Abstract

The objective of the first series of experiments was to assess whether melatonin treatment modifies the activity of the y-aminobutyric acid synthesizing enzyme, glutamic acid decarboxylase, in the preoptic-medial basal hypothalamic area, cerebral cortex and cerebellar cortex of rats receiving 25 to 300 pg of melatonin in the early morning and late evening in the diurnal cycle. A significant increase of apparent V , , , and K , of the enzyme was found in the hypothalamus of rats killed at the 12th h of the light phase (i.e. the time when lights were turned off) and receiving 25 to 300 pglkg of melatonin 3 h earlier. In the early morning, only a 300 pglkg dose of melatonin (injected in the 1st h of the light phase) was effective to increase V , , , and K , of hypothalamic glutamic acid decarboxylase 3 h later. In cerebral and cerebellar cortices, increases in V , , , and K , of enzyme activity were apparent only in the evening and with the highest melatonin dose employed (300 pglkg). In a second series of experiments the activity of melatonin to modify in vitro3%-influx by 900 x g pellets of rat preoptic-medial basal hypothalamic area was studied at the 4th and 12th h of the light phase of daily photoperiod. Melatonin increased 36CI-influx at a minimum concentration of 100 nM (in the morning) or 10 nM (in the evening). The effect of melatonin on 36CI-influx was prevented by co-incubation with 100 pM picrotoxin. Addition of 10 to 100 pM of yaminobutyric acid to the resuspended 900 x g pellets brought about a dose-dependent increase of 36CI-influx. Preincubation with melatonin at threshold doses of 1 pM (in the morning) or 0.1 pM (in the evening) significantly augmented y-aminobutyric acid effect on 36CI-uptake. These results indicate that melatonin facilitates pre-and postsynaptic activities of y-aminobutyric acid neurons, particularly in the hypothalamus, through an effect that displays a diurnal sensitivity compatible with the documented activity of the hormone on a number of physiological functions.The pineal gland functions as a neuroendocrine transducer converting information about daylength into the nocturnal release of its hormone melatonin (1-3). In reptiles and birds the pineal gland is a major pacemaker for biologic rhythms, whereas in mammals this function is mediated principally by the hypothalamic suprachiasmatic nucleus (4-6). Melatonin acts on the suprachiasmatic nucleus to modulate mammalian circadian rhythmicity, as shown by the entrainment of locomotor activity in rats treated with the pineal hormone, an effect which is blocked by suprachiasmatic nuclei ablation (7-9). The time of administration of melatonin is critical for melatonin action. In hamsters (3, 10-12) and rats (13) a late afternoon-early evening period of sensitivity, and a brief period of sensitivity just preceding the time of lights on, were found. In the late evening an increase in brain membrane melatonin binding has been reported in rats (14-16) and hamsters (14). In a study on melatonin effect on 2-deoxyglucose uptake by...

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