5.1. The NPY Precursor is Cleaved and NPY is Amidated

The studies showed that the nerve fibres in the pineal gland contain only NPY in a final and processed form. Termination of processing has been observed in other tissues

An (.Pituitary Hippocampus Pineal Gland Y1Y2Y4Y5 Y1V2Y4Y5 Y1 Y2 Y4 Y5

Figure 8. Expression of Y receptor mRNA in the pineal gland, the anterior pituitary and the hippocampus using a reverse transcriptase-polymerase chain reaction. The reactions were performed in the three tissues simultanously. It shows that Y1 is the dominant, if not the only postsynaptic receptor that is expressed in the rat pineal.

such as the suprachiasmatic nucleus (21,22). In contrast to other peptide precursors, ProNPY is fully processed to active molecules. Because CPON has not been associated with any function in the organs studied, we conclude that NPY in the nerve fibres are amidated NPY.

5.2. NPY Originates Predominantly from the Sympathetic Superior Cervical Ganglia

It is known that the superficial pineal gland of the rat is densely innervated by nerve fibres containing NPY (4,6). Further, it was revealed that the vast majority of the NPY-immunoreactivity (97%) originates from the superior cervical ganglia and a minority from elsewhere.

Notably, the NPYergic innervation of the pineal gland is found to be species dependent. High amounts ofNPY nerve fibres have been observed in the rat and sheep (4,6,9), whereas little innervation is seen in the mink and primate (27,28). Further, while pineal NPYergic fibres originate mainly from a sympathetic source in rat and sheep, NPY originates to a large extent also from neurones in the brain in the mink and monkey.

The presence of NPY in the central input of the rat pineal is supported by the observation that most of the NPY/CPON-immunoreactive fibres remaining after gan-glionectomy was seen in that part of the pineal complex that is known to receive a central innervation, namely the deep pineal gland. Also a parasympathetic innervation cannot be excluded (29-31).

5.3. NPY in the Deep Pineal and the Central Innervation

The origin of the NPY/CPON-immunoreactive neurons contained in the central pinealopetal projection have not been identified yet with certainty. It is shown that the majority of the central input contains NPY and not noradrenaline, which excludes cat-echolaminergic neurons in the brain stem costoring NPY (32). A NPYergic projection originating from the intergeniculate leaflet of the lateral geniculate nucleus to the suprachiasmatic nucleus has been demonstrated (33-36)and this projection has been shown to mediate phase advances to the pacemaker (37,38). Since the intergeniculate leaflet projects to the pineal gland (24), it is likely that this projection supplies the deep pineal with NPY/CPON-positive afferents, and thereby connects the pineal gland directly with the circadian timing system.

5.4. The Pinealocyte Expresses Only Y1 Receptors

The NPY receptor subtypes are differently expressed in the organism. In the pineal gland, only the Y1 receptor subtype was found to be expressed. This finding is in accordance with a previous study report in binding of NPY to aY1 preferring binding site in a primary culture of pinealocytes (18). The level of total binding in the pineal is low compared to other tissues. Other known NPY receptors were not expressed in the rat pineal gland.

Noteworthy, postsynaptic Y4 and Y5 receptors were not found in the pineal. The Y4 receptor is expressed in the periphery and in some circumventricular organs considered to be a target for blood borne pancreatic polypeptide (39). The Y5 receptor is expressed in the hypothalamus and not in peripheral tissues (16) and is apparently not playing any role in pineal. However, presynaptic Y receptors expressed in the sympathetic cell body or in other neurons innervating the pineal are probably present (see below) and undetectable in the used mRNA assay.

5.5. NPY Neurotransmission in the Rat Pineal Complex:

Functional Considerations

A major question related to these observations is how NPY via the postsynaptic receptor inhibits melatonin release. It has been demonstrated that NPY inhibits P adrenergic, VIPergic and cholera toxin-induced cAMP accumulation in pineal cultures, through a pertussin toxin sensitive Gi protein (40). This raises interesting perspectives, because two transmitters in the same nerve terminal, or even in the same vesicle, activate and inhibit the pinealocyte. Whether impulse frequency affect the proportional release of NPY and noradrenaline from sympathetic endings in the pineal gland remains to be established.

The role of NPY in other organs has been attributed to its co-transmission with catecholamines, because they are costored in the same postganglionergic nerves (3). In peripheral sympathetic nerve endings, noradrenaline is stored in two different types of vesicles, the large and the small dense core vesicles (41). Single electrical stimulation of other sympathetic nerves, such as splenic and mesenteric nerves (at frequencies lower than 20 Hz), produced release of both noradrenaline and NPY from the nerve endings that increased with the frequency of stimulation, but the ratio of noradrena-line to NPY remained constant (7,8). It is not known under what conditions nora-drenaline is released alone, and if similar mechanisms occur in pineal nerves. However, the co-localisation of NPY noradrenaline implies that NPY is released together with noradrenaline.

The sympathetic nervous system is rhythmic in many organs (42). Its role in pineal function is unclear—in particular the mechanisms involved in the inhibition of the melatonin secretion in the late dark-phase are poorly understood. It is speculated that altered impulse frequencies during the night could affect the release of noradrenaline and NPY in such a way that noradrenaline had a major effect in the beginning of the dark phase, and NPY plays a role later resulting in the decline of N-acetyl transferase activity and subsequent of melatonin secretion.

The pineal tissue shares the characteristics of a sympathetic input with many other peripheral organs. Thus, there may be a functional component of this input that relates to regulation of the vascular system, and another related to the neuroendocrine regulation. In general, NPY contracts isolated peripheral blood vessels, but the responses

Figure 9. Schematic illustrations of possible effect of NPY and noradrenaline (NA) at the synaptic level. NPY acts either via a post-synaptic receptor in concert with NA to regulate melatonin synthesis and secretion or pre-synaptically to inhibit further release of NA to the extracellular space.

in terms of dose-response relationships are different from organ to organ (43). Using the radioactive microsphere technique for measurements of regional blood flow, the effects of NPY was among many organs studied also in the pineal gland of the rabbit (44). After 2 minutes of NPY, there was a marked blood flow reduction in the pineal gland (44).

In summary, NPY seems to have at least three effects on the sympathetic neuro-effector junction (Figure 9). There is a presynaptic effect (expressed as inhibition of norepinephrine release), and two postsynaptic effects; a direct response, and a potentiation/inhibition of the noradrenergic response (17,45,46). Apart from the direct effect, the same appears to be true for the pineal gland. However, it remains to be understood how this input can drive the circadian rhythm, which is unique for pineal physiology.

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