Introduction

The mammalian pineal gland is densely innervated by noradrenergic nerve fibres originating from the superior cervical ganglia (1) that plays an essential role in synthesis of melatonin (2). It is well established that NPY occurs together with noradrenaline in the postganglionic sympathetic fibres (3), and several studies have shown that the NPY-containing nerve fibres in the pineal gland, at least partly, originate from noradrenergic neurons in the superior cervical ganglia (4-6). NPY and noradrenaline are co-released from the nerve terminal (7,8) and it is therefore tempting to speculate how these transmitters interact postsynaptically on the pinealocyte.

Noradrenaline is the major neurotransmitter regulating melatonin synthesis and release and it is considered to be responsible for activation of CAMP-dependent signalling pathways and for the circadian variation in melatonin secretion and release. A possible role for NPY may be either to modulate the actions of noradrenaline in the early night and/or to regulate the decline in melatonin secretion in the late night. The purpose of this report is to cover the literature and extend with our own studies a clearer definition of the nature of NPY, the origin of NPYergic innervation, the NPY receptors, and the activity of NPY in the rat pineal gland.

As illustrated in Figure 1, the NPY precursor undergoes cleavage at a single dibasic site Lys38-Arg39 resulting in the formation of 1-39 amino acid NPY and a C-flanking peptide of NPY (CPON). The NPY fragment is further processed successively by carboxypeptidase-like and peptidylglycine alpha-amidating monooxygenase enzymes. The nature of NPY-immunoreactivity has not been examined in the pineal gland, thus gel filtration and site specific antisera were used to determine the processing of the NPY precursor.

Some intrapineal NPY fibres remain after superior cervical ganglionectomy (6,9). NPY is present in ocular nerves originating from the parasympathetic system (10) though it remains to be shown that the non-sympathetic nerves in the rat pineal gland also originate from a parasympathetic ganglion. Hence, while the NPYergic input in

Figure 1. Schematic illustration of the used antisera and their specificity for distinct epitopes of the NPY precursor, NPY, or CPON.

the pineal is considered to be sympathetic, a central input may also play a role in some species. In order to understand what systems innervate the pineal gland, histological and radioimmunological analyses were carried out in normal and superior cervical gan-glionectomised rats.

NPY exerts its actions through at least six different receptors subtypes, designated Y1-Y6 (11,12). These receptor subtypes are differently expressed in rat tissues. Y1,Y2 and Y5 are expressed in the brain, whereas Y4 has been found in some circumventric-ular organs (13-16).Y1 and Y2 receptors are activated by different NPY peptide analogues and considered to be post- and presynaptic, respectively (17). Y4 and Y5 receptors are postsynaptic, and shows affinity for pancreatic polypeptide. Binding of NPY has been shown on pinealocytes and the Y1 mRNA shown to be expressed in rat pineal tissue (18,19). Since these studies were reported, additional NPY specific receptors have been cloned and pharmacologically characterised (10). We have analysed the level of specific binding of NPY in the rat pineal gland and used reverse transcriptase polymerase chain reaction to determine which NPY receptors that are expressed in rat pineals.

NPY modulates the noradrenergic transmission in the rat pineal gland at both pre- and postsynaptic levels (18,19). Unequivocal results have been reported on the role of NPY alone (18-20), and little evidence for NPY activating transcriptional events is available. Given that NPY activates the pineal ocyte through Y1 receptors, several possible signalling pathways may be activated that are important in pineal function, and in particular related to how NPY may interact with noradrenergic signalling.

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