Postsynaptic alpha-adrenergic receptors potentiate the beta-adrenergic stimulation of pineal serotonin N-acetyltransferase.

Abstract

The role played by postsynaptic et-adrenergic receptors in the stimulation of pineal N-acetyltransferase (EC 2.3.1.5) and [3H]melatonin production was investigated in the rat. In vivo studies indicated that phenylephrine, an a-adrenergic agonist, potentiated and prolonged the effects of isoproterenol, a P adrenergic agonist. Similar observations were made in organ culture with glands devoid of functional nerve endings. In addition, a combination of 1 FAM prazosin, an a1-adrenergic blocking agent, and 1 FM propranolol, a -adrenergic blocking agent, was many times more potent then either agent alone in blocking the stimulatory effects of norepinephrine on N-acetyltransferase activity and [3Hlmelatonin production. These findings establish that norepinephrine acting through ar-and (3-adrenergic receptors stimulates rat pineal N-acetyltransferase activity and, as a result, the production of melatonin. Apparently, (-adrenergic activation is an absolute requirement, and an et-adrenergic receptor mechanism potentiates -adrenergic activation. These findings are significant because they demonstrate a-adrenergic potentiation of (-adrenergic effects. In addition, they indicate that the widely held belief that melatonin production is regulated exclusively by a postsynaptic -adrenergic mechanism must be revised.A daily rhythm in circulating melatonin occurs in all mammals (1). In the rat this is generated by a large rhythm in the activity of pineal arylamine N-acetyltransferase (EC 2.3.1.5) (1-4), the enzyme that converts serotonin to the immediate precursor of melatonin, N-acetylserotonin.The activity of N-acetyltransferase is regulated by a neural circuit that stimulates the nocturnal release of norepinephrine from sympathetic nerves in the pineal gland (5)(6)(7)(8). Norepinephrine acts through an adrenergic mechanism to increase intracellular cyclic AMP (9, 10) which induces and activates Nacetyltransferase (3, 4), leading to an increase in melatonin production (11,12).It is now generally thought, based on a number of studies (11)(12)(13)(14)(15)(16)(17), that norepinephrine acts exclusively through postsynaptic /3-adrenergic receptors to increase cyclic AMP, N-acetyltransferase-activity, and melatonin production. We were surprised, therefore, by recent observations (unpublished data) which seem to indicate that norepinephrine increases pineal cyclic AMP through an action involving both a-and (3-adrenergic receptors. We found that a combination of isoproterenol (10 ,tM) and phenylephrine (10 ,uM) produced a stimulation at 10 min, of cyclic AMP and cyclic GMP equivalent to that produced by norepinephrine (10 ,uM) and that the effect of phenylephrine (10 ,uM) or isoproterenol (10 ,uM) alone was <20% of that produced by the combination of isoproterenol (10 UM) and phenylephrine (10 MM).This raised the obvious possibility that N-acetyltransferase activity and melatonin production are also regulated by both aand (3adrenergic receptors located on postsynaptic structures. We have studied this question and our results, pr...

Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy

“…Pharmacologic blockade of ␤ ARs suppresses melatonin production Cowen et al 1983). Stimulation of ␣ -adrenergic receptors potentiates the effects of ␤ AR stimulation on melatonin synthesis (Klein et al 1983;Sugden et al 1984;Sugden et al 1985). Thus, pineal gland melatonin production can provide a physiologic index of noradrenergic activity.…”

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

“…The inhibition of noradrenergic activity by GABA has been shown to be post and presynaptic in rat pineals (36). Our perifusion system was able to preserve post and presynaptic domains since the nerve terminals innervating the pineal gland are known to need Ͼ24 h to degenerate (37).…”

The Influence of Gonadectomy on Anxiolytic and Antidepressant Effects of Melatonin in Male and Female Wistar Rats: A Possible Implication of Sex Hormones

“…Norepinephrine released at night from sympathetic nerve endings in the pineal gland stimulates adrenergic recaptors and the cAMP pathway; the resulting induction and activation of pineal NAT activity leads to high nighttime melatonin levels [7]. Once synthesized, melatonin is released directly into general circulation to establish its endocrine function on blood glucose, appetite, and sleep.…”

“…Once synthesized, melatonin is released directly into general circulation to establish its endocrine function on blood glucose, appetite, and sleep. In addition to these functions, melatonin seems to exert psychotropic effects in rodents, such as sedative activeties, analgesic, anticonvulsionants, anxiolytic and antidepressant [7,8]. In humans, melatonin has been studied for possible application in disorders of mood disturbances that were evident in the circadian profile of melatonin in depressed patients [9].…”