Activity of the hippocampal somatostatinergic system following daily administration of melatonin.

If melatonin or its analogs are to be used therapeutically in humans, their chronic effects on responsiveness of melatonin target cells need to be assessed. We have previously demonstrated that acute melatonin treatment regulates the somatostatinergic system in the rat hippocampus. In the present study, we have investigated the effects of subchronic and chronic daily treatment with melatonin on the somatostatinergic system in the rat hippocampus. Male Wistar rats (200-250 g) were injected with melatonin (25 microg/kg body weight, subcutaneously) daily for 4, 7 or 14 days and sacrificed 24 h after the last injection. Melatonin administration for 4 days induced a decrease in the hippocampal somatostatin (SRIF)-like immunoreactivity content as well as a decrease in the number of SRIF receptors and an increase in their apparent affinity. The decreased number of SRIF receptors in the melatonin (4 days)-treated rats was associated with a decreased capacity of SRIF to inhibit both basal and forskolin-stimulated adenylyl cyclase activity. These melatonin-induced effects reversed to control values after 7 or 14 days of treatment. Hippocampal membranes from control and melatonin-treated rats showed similar Gi and Gs activities. Melatonin treatment altered neither the functional Gi activity nor the Gialpha 1 or Gialpha 2 levels at any of the time periods studied. The present results suggest that chronic exposure to melatonin results in a tolerance of the hippocampus to this hormone.

Acutely administered melatonin decreases somatostatin-binding sites and the inhibitory effect of somatostatin on adenylyl cyclase activity in the rat hippocampus.

Melatonin is known to increase neuronal activity in the hippocampus, an effect contrary to that of somatostatin (somatotropin release-inhibiting factor, SRIF). Thus, the aim of this study was to investigate whether the somatostatinergic system is implicated in the mechanism of action of melatonin in the rat hippocampus. One group of rats was injected a single dose of melatonin [25 microg/kg subcutaneously (s.c.)] or saline containing ethanol (0.5%, s.c.) and killed 5 hr later. Melatonin significantly decreased the SRIF-like immunoreactivity levels and induced a significant decrease in the density of SRIF receptors as well as in the dissociation constant (Kd). SRIF-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase activity was markedly decreased in hippocampal membranes from melatonin-treated rats. The functional activity of Gi proteins was similar in hippocampal membranes from melatonin-treated and control rats. Western blot analyses revealed that melatonin administration did not alter Gialpha1 or Gialpha2 levels. To determine if the changes observed were related to melatonin-induced activation of central melatonin receptors, a melatonin receptor antagonist, luzindole, was administered prior to melatonin injection. Pretreatment with luzindole (10 mg/kg, s.c.) did not alter the melatonin-induced effects on the above-mentioned parameters and luzindole, alone, had no observable effect. The present results demonstrate that melatonin decreases the activity of the SRIF receptor-effector system in the rat hippocampus, an effect which is apparently not mediated by melatonin receptors. As SRIF exerts an opposite effect to that of melatonin on hippocampal neuronal activity, it is possible that the SRIFergic system could be implicated in the mechanism of action of melatonin in the rat.

Effects of subchronic and chronic melatonin treatment on somatostatin binding and its effects on adenylyl cyclase activity in the rat frontoparietal cortex.

Melatonin and somatostatin are known to exert similar effects on locomotor activity. We have previously demonstrated that acute melatonin treatment regulates somatostatin receptor function in the rat frontoparietal cortex. However, the effects of subchronic and chronic melatonin treatment on the somatostatin receptor-G protein-adenylyl cyclase system in the rat frontoparietal cortex are unknown. Melatonin was administered subcutaneously at a daily dose of 25 microg/kg for 4 days, 1 wk or 2 wk. Twenty-four hours after the last injection, the animals were sacrificed. Melatonin did not alter the somatostatin-like immunoreactivity content in the frontoparietal cortex from control and melatonin-treated rats during any of the previously indicated periods. Four days of melatonin administration induced both an increase in the number of [(125)I]-Tyr11-somatostatin receptors and a decrease in the affinity of somatostatin for its receptors in frontoparietal cortical membranes. The increased number of somatostatin receptors in the melatonin-treated rats was associated with an increased capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity. Melatonin administration for 4 days induced a higher adenylyl cyclase activity both under basal conditions and after direct stimulation of the enzyme with forskolin. No significant differences were observed in the function of Gi proteins in the 4-day melatonin-treated rats. Western blot analyses showed that the 4-day melatonin treatment reduced Gialpha(2) levels, without altering the amount of Gialpha(1). These melatonin-induced changes reverted to control values after 7 or 14 days of treatment. Altogether, the present findings suggest that subchronic melatonin treatment modulates the somatostatin receptor/effector system in the rat frontoparietal cortex.