Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

What turns CREB on

Objective: We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs.

Methods: We review results from various clinical and basic research studies.

Results: Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants up-regulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element-binding protein (CREB) and the neurotrophin, brain derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants.

Conclusions: These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival.

Antidepressants and neuroplasticity

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of long-term memories for emotionally arousing experiences but not that for less arousing or neutral information. However, previous studies have not determined the basis of such arousal-induced selectivity. Here we report the finding that endogenous noradrenergic activation of the basolateral complex of the amygdala (BLA) induced by emotional arousal is essential in enabling glucocorticoid memory enhancement. Corticosterone administered immediately after object recognition training enhanced 24-h memory of naive male rats but not that of rats previously habituated to the training context in order to reduce novelty-induced emotional arousal. The β-adrenoceptor antagonist propranolol administered either systemically or into the BLA blocked the corticosterone-induced memory enhancement. Further, in habituated rats, corticosterone activated BLA neurons, as assessed by phosphorylated cAMP response element binding (pCREB) immunoreactivity levels, and enhanced memory only when norepinephrine release was stimulated by administration of the α2-adrenoceptor antagonist yohimbine. These findings strongly suggest that synergistic actions of glucocorticoids and emotional arousal-induced noradrenergic activation of the BLA constitute a neural mechanism by which glucocorticoids may selectively enhance memory consolidation for emotionally arousing experiences.

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Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala

Arylalkylamine N-Acetyltransferase: “the Timezyme”

Norepinephrine (NE) regulates melatonin production and many other aspects of pineal function through actions involving cAMP. In the present study the effects of NE on the phosphorylation of the cAMP response element-binding protein (CREB) were studied to determine whether CREB phosphorylation might be involved in cAMP signal transduction in this tissue. CREB was detected using gel mobility-shift analysis with the radiolabeled Ca2+/cAMP response element of the c-fos promoter. CREB phosphorylation was estimated in the gel mobility-shift assay using an antiserum specific for phosphorylated CREB. This antiserum generates a supershifted CREB signal with protein extracts obtained from glands treated with NE (EC50 approximately equal to 10 nM) in organ culture, demonstrating that NE stimulates CREB phosphorylation. CREB phosphorylation peaks 30-45 min after NE treatment is initiated and then gradually returns to base-line values. Pharmacological studies show that NE-stimulated CREB phosphorylation is mediated primarily through beta 1-adrenergic receptor-stimulated increases in cAMP. Activation of alpha 1-adrenergic receptors, which is known to elevate the intracellular free Ca2+ concentration, does not cause CREB phosphorylation. However, it is possible to produce CREB phosphorylation with certain pharmacological agents that elevate the intracellular free Ca2+ concentration. In vivo studies show that CREB phosphorylation can be induced by treatment with isoproterenol (1 mg/kg), demonstrating that phosphorylation of pineal CREB occurs in intact animals. These studies indicate that cAMP-dependent CREB phosphorylation could play a role in the adrenergic regulation of gene expression in pinealocytes.

Norepinephrine stimulation of pineal cyclic AMP response element-binding protein phosphorylation: primary role of a beta-adrenergic receptor/cyclic AMP mechanism.

P H Roseboom

Papers

Norepinephrine stimulation of pineal cyclic AMP response element-binding protein phosphorylation: primary role of a beta-adrenergic receptor/cyclic AMP mechanism.