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The scanning electron microscope has shown rich ramifications of the parenchymal canaliculi forming a three-dimensional network of anastomosing intercellular spaces in the rat pineal gland. Every pineal cell seems to be in contact with this channel system. An abundance of cellular processes can be found within the canaliculi which may play an important role in the histophysiology of the pineal body.
The effects of histamine (HA) and selective HA H1-, H2 and H3-receptor agonists on cyclic AMP formation were investigated in intact chick and duck pineal glands HA potently stimulated the pineal cycle AMP formation. The effect of HA was mimicked fully by N alpha-methylated histamines, and partially by several histaminergic drugs: 2-thiazolylethylamine (H1) amthamine (H2) and R alpha-methyl-histamine (H3). Dimaprit, another selective H2-agonist showed marginal activity. Forskolin highly potentiated the action of HA, and only weakly affected the effects of 2-thiazolylethylamine and amthamine. In the chick pineal, the stimulatory effects of HA and the tested histaminergic drugs were not blocked by mepyramine and thioperamide (H1- and H3-blockers, respectively), but they were antagonized by H2-receptor selective compounds ranitidine and aminopotentidine, which, however, acted in a noncompetitive manner. Another H2-selective blocker zolantidine antagonized the HA effect only when used at very high (30-100 microM) concentrations. In the duck pineal, the stimulatory effect of HA on cyclic AMP production was unaffected by mepyramine (H1), thioperamide (H3), and ranitidine (H2), and only partially inhibited by the H2-blocker aminopotentidine. Electrophysiological experiments revealed that HA is capable of evoking inward currents in most of the tested cells acutely isolated from chick pineal gland. The present findings further indicate that the pharmacological profile of the avian pineal HA receptor, whose stimulation leads to activation of cyclic AMP production, is different from any known HA receptor type (H1, H2, H3), and suggest the existence of either an avian-specific HA receptor, or a novel HA receptor subtype. Electrophysiological data suggest that the pineal HA receptor may be somehow linked to activation of an ionic channel.
The unusual occurrence of skeletal muscle in the pineal gland of the bat Rhinopoma microphyllum is described. Individual muscle fibres were centrally placed and were incompletely encapsulated by a labyrinthine network of widened spaces filled with electron-dense material. The 2.4 micron long sarcomeres consisted of well developed A, I, H, M, and Z bands. A few myofibrils were oriented transversely within the same fibre. T system components, mitochondria and glycogen appeared normally distributed. Unmyelinated nerve bundles impinged upon the fibre but neuromuscular junctions were not observed. Several possible sources of origin for this tissue in the pineal gland are reviewed.
The rhythmic nocturnal production of melatonin in pineal glands is controlled by the periodic release of norepinephrine from the superior cervical ganglion. Norepinephrine binds to the beta-adrenergic receptor and stimulates an increase in intracellular cAMP levels, leading to the transcriptional activation of serotonin N-acetyltransferase, which in turn promotes melatonin production. In the present study, we report that bradykinin inhibits basal- and forskolin-stimulated adenylyl cyclase activity, norepinephrine-induced cAMP generation, and N-acetyltransferase expression in a calcium-dependent manner. These effects were blocked by pretreatment with U73122 (a selective phospholipase C inhibitor), and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (a Ca(2+) chelator), but not pertussis toxin. The calcium ionophore, ionomycin, inhibited isoproterenol-mediated cAMP generation, similar to bradykinin. Interestingly, the inhibitory effect of bradykinin was evident only during the daytime. At midday, bradykinin inhibited the cAMP level by approximately 50% but markedly stimulated cAMP production (by approximately 50%) at night. Northern blotting and immunoblotting data disclosed circadian expression of calcium-inhibitable adenylyl cyclase type 6. Expression of adenylyl cyclase type 6 was maximal at Zeitgeber Time (ZT) 01 and very low at ZT 13. Our results suggest that bradykinin-induced calcium inhibits melatonin synthesis through the mediation of adenylyl cyclase type 6 expression.
In mammals, the photoperiodic information, received by the retina, is transmitted to the pineal gland. In both organs, melatonin is produced and functions as a neurohormone giving temporal information to the organism. A four-step enzymatic pathway, involving in particular the tryptophan hydroxylase (TPOH), the rate-limiting enzyme in serotonin synthesis, and the serotonin N-acetyltransferase (NAT) that converts serotonin to N-acetylserotonin, allows the synthesis of melatonin. Many studies on melatonin synthesis modulation have focused on the enzyme NAT, but the regulation of TPOH is less well understood. We report here a quantitative study, using a reverse transcription polymerase chain reaction (RT-PCR) analysis, of the nycthemeral expression of TPOH and NAT mRNAs in the ovine retina and pineal gland. In both organs, we show a nocturnal increase in mRNA levels of the two enzymes. suggesting a role of transcriptional mechanisms in the regulation of melatonin synthesis. However, the amplitude of the observed increase in TPOH and NAT mRNAs expression can not entirely explain the 7-fold nocturnal increase in the plasma melatonin level. Our results suggest that, in the sheep, post-transcriptional mechanisms might also be involved in the day/night modulation of melatonin production.
The pineal gland is known to play a central role in the photoperiodic control of reproduction in seasonal breeders. The present review, based on experimental data obtained in four different species of hamster, the Syrian or golden, the Djungarian or Siberian, the Turkish and the European, attempts to evaluate the role of the pineal in this phenomenon, the message which is conveyed from this gland as well as the mechanism of action of this message. Melatonin one of the 5-methoxyindoles rhythmically synthesized in the pineal gland, appears to be the pineal hormone conveying the photoperiodic message. The importance of the duration of the nocturnal peak of circulating melatonin is now well established, but our knowledge on the sites of action and on the mechanisms of action of melatonin is still rather poor. The presently available data suggest that melatonin can act at different levels, either on specific receptors, on receptors of other transmitters, on various molecular processes after diffusion in the cell or indirectly via effects on other endocrine hormones, e.g. gonadal steroids.
The 24 h profile of the activity of the antioxidant enzyme superoxide dismutase (SOD) in the pineal gland of rats was studied. Rhythmic analysis showed a significant 24 h rhythm with an amplitude of oscillation of 25% of the 24 h mean value, that was 100.34 +/- 1.6 U SOD (nitrite). An ultradian rhythm of 9 h was also detected. The diurnal profile of superoxide dismutase activity is discussed in relation to the oxidative metabolism of the pineal gland.
Three experiments were carried out on male Wistar-King rats to determine if 6 weeks of exposure to horizontally- or vertically-oriented 1-microT, 50-Hz magnetic fields suppresses melatonin content in plasma and pineal gland, as does 6 weeks of exposure to circularly-polarized, 50-Hz, 1-microT magnetic fields. In each experiment, a concurrent sham-exposed control group was exposed to a stray field of 0.02 microT. In addition, a separate control experiment was completed between the horizontal and vertical field experiments in which cage-controls were housed in the exposure facility for 6 weeks without activation of the magnetic field coils. Subjects were sacrificed at 12:00 or at 24:00 h for collection of plasma and pineal gland; melatonin was determined by radioimmunoassay. In contrast to the results of experiments with rotating-vector magnetic fields, there were no significant differences among 1-microT, 0.02-microT and control groups in melatonin concentration of pineal gland or plasma.
Specific binding sites for [3H]-1,3 di-ortho-tolylguanidine ([3H]-DTG), a selective radiolabeled sigma receptor ligand, were detected and characterized in sheep pineal gland membranes. The binding of [3H]-DTG to sheep pineal membranes was rapid and reversible with a rate constant for association (K+1) at 25 degrees C of 0.0052 nM-1.min-1 and rate constant for dissociation (K-1) 0.0515 min-1, giving a Kd (K-1/K+1) of 9.9 nM. Saturation studies demonstrated that [3H]-DTG binds to a single class of sites with an affinity constant (Kd) of 27 +/- 3.4 nM, and a total binding capacity (Bmax) of 1.39 +/- 0.03 pmol/mg protein. Competition experiments showed that the relative order of potency of compounds for inhibition of [3H]-DTG binding to sheep pineal membranes was as follows: trifluoperazine = DTG greater than haloperidol greater than pentazocine greater than (+)-3-PPP greater than (+/-)SKF 10,047. Some steroids (testosterone, progesterone, deoxycorticosterone) previously reported to bind to the sigma site in brain membranes were very weak inhibitors of [3H]-DTG binding in the present study. The results indicate that [3H]-DTG binding sites having the characteristics of sigma receptors are present in sheep pineal gland. The physiological importance of these sites in regulating the synthesis of the pineal hormone melatonin awaits further study.
In birds, the mediobasal hypothalamus (MBH) including the infundibular nucleus, inferior hypothalamic nucleus, and median eminence is considered to be an important center that controls the photoperiodic time measurement. Here we show expression patterns of circadian clock genes in the MBH, putative suprachiasmatic nucleus (SCN), and pineal gland, which constitute the circadian pacemaker under various light schedules. Although expression patterns of clock genes were different between long and short photoperiod in the SCN and pineal gland, the results were not consistent with those under night interruption schedule, which causes testicular growth. These results indicate that different expression patterns of the circadian clock genes in the SCN and pineal gland are not an absolute requirement for encoding and decoding of seasonal information. In contrast, expression patterns of clock genes in the MBH were stable under various light conditions, which enables animals to keep a steady-state photoinducible phase.
The cellular proliferative activity in the adult rat pineal gland was studied using bromodeoxyuridine immunohistochemistry during the light and dark phases of an artificial 12L:12D photoperiod. The results showed statistically significant differences in the number of labeled cells between the light and dark phases, with the labeled cells being almost threefold more abundant in the light period. Minor changes were also found in the pineal gland volume between both periods. The decrease in the number of labeled cells in the dark phase of the cycle could be related to the well-documented antimitotic action of melatonin.
Evidence is clear that each melatonin-producing cell in the chick pineal gland contains a circadian oscillator that continues to function in vitro, resulting in a prominent day/night rhythm of melatonin secretion. The aim of the present investigation was to examine whether the circadian organization of the gland has an electrophysiological correlate. To this end, single-cell recordings were made from isolated chick pineal glands kept in vitro under a light/dark cycle of 12:12 h, identical to that of the donors, or under continuous light or darkness. In all the glands investigated, a very small percentage of cells exhibited sodium-dependent spontaneous spike activity with a mean frequency below 10 Hz. The cells revealed rhythms with periods in the 15- to 60-min range and, additionally, exhibited ultradian and circadian rhythms in firing, with periods of 10.75+/-1.06 h and 26.25+/-1.26 h (mean +/- standard deviation), respectively. Most of the cells exhibited circadian rhythms with higher activity during daytime than at night, showing that the electrical activity and melatonin rhythm were out of phase. Under constant light or darkness, the circadian rhythm persisted. When the light/dark cycle of the donors was phase-advanced by 5 h, the cells revealed complete entrainment. We discuss whether the cells, albeit small in number, could function as a secondary ultradian/circadian oscillator contributing to the ultradian/circadian organization of the gland.
Methotrexate at 1 microM stimulated increase of serotonin N-acetyltransferase (NAT) activity in chick pineal glands cultured under each of three conditions of illumination. The peak of the circadian rhythm in NAT activity and the "spike" in content of cyclic GMP were both advanced in pineal glands cultured in the dark from midphotoperiod. In contrast, the time of peak NAT activity in glands cultured in the dark from late photoperiod was unaffected. In addition, methotrexate did not affect times of reaching maximum NAT activities in glands cultured from midphotoperiod in the light or under diurnal illumination. Doubling the concentration of methotrexate also eliminated the lag phase in increase of NAT activity in glands cultured in the dark. However, at a concentration of 5 microM methotrexate the curve depicting increase of NAT activity was biphasic, and neither time nor level of peak NAT activity differed from those of control glands. Results of attempts to demonstrate persistent effects of exposure to methotrexate were inconclusive.
Effects of alloxan treatment on the levels of pineal melatonin, pineal N-acetylserotonin, and serum melatonin were investigated. Male rats were housed under a photoperiod of 12 h light: 12 h darkness and a temperature of 23 +/- 3 degrees C. Three weeks after alloxan (170 mg/kg) or carrier injection (s.c.), the animals were killed at mid-light (1200 h) and mid-dark (2400 h). Pineal and serum indoles were extracted and quantified by radioimmunoassays. It was found that pineal levels of N-acetylserotonin in the diabetic rats were significantly higher (P less than 0.05) than those of the controls. Conversely, pineal and serum levels of melatonin in the control rats were significantly higher (P less than 0.05) than those of the alloxan-induced diabetics. Our results suggest that alloxan-induced diabetes may decrease pineal melatonin synthesis in rats by reducing the activity of hydroxyindole-O-methyltransferase, resulting in a decrease in pineal melatonin secretion.
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Three distinct subtypes of vesicular glutamate transporters (VGLUTs) have been identified to date that are expressed basically in a cell type-specific manner. We have found a splice variant of VGLUT1 mRNA that is expressed almost exclusively in photosensitive tissues, i.e. the retina and the pineal gland. The variant mRNA, termed VGLUT1v, contains an additional 75 base pair sequence derived from part of a second intron (designated as exon IIa) between exons 2 and 3. The variant accounted for approximately 70% and 25%of VGLUT1 mRNA in the adult retina and pineal gland, respectively. The expression of VGLUT1v was developmentally regulated in both tissues. Organ culture showed that expression of the variant in the retina increased in association with the development of rod cells, suggesting that VGLUT1v is expressed in rod cells. In situ hybridization with variant-specific probes showed expression of VGLUT1v in the inner segment layer of photoreceptor cells. On the other hand, variant expression did not parallel the development of rhodopsin-positive cells in the pineal gland. As rod cells and pinealocytes are known to release glutamate continuously at ribbon synapses, it is possible that the variant has some functional advantage over the wild-type transporter in such a specialized manner of glutamate release.
The developmental expression of the glial antigens, vimentin (VIM), glial fibrillary acidic protein (GFAP), and S-100 protein is described in the rat pineal gland from the first postnatal day to adulthood. Thick VIM immunopositive cell cords forming a network throughout the pineal gland were observed from the first postnatal days. These cords progressively disappeared during the first postnatal month as their cells dispersed into the pineal parenchyma. From 20 to 25 postnatal days, pineal glial cells appeared as isolated star-shaped VIM immunopositive cells. Immunostaining for GFAP and S-100 protein showed a similar developmental expression pattern. Both antigens appeared later than VIM (15-20 postnatal days) and were restricted to the pineal glial cells located in the proximal third of the gland, close to the pineal stalk.
Microglia in the pineal gland of 1-day-old Sprague-Dawley rats were examined by OX-42 immunocytochemistry and DiI-acetylated-LDL uptake in pineal cell suspension and were found to comprise 3-5% of the total cells in the pineal gland of the neonates. In order to investigate the effects of microglia on pinealocyte structure and function, microglia-depleted and microglia-enriched pineal cell cultures were generated from 1-day-old neonate by fluorescence activated cell sorting (FACS). After 7 days of culture, tissues were processed for either immunocytochemistry for pinealocyte S-antigen and serotonin or high performance liquid chromatography to measure serotonin. Morphometric analysis of immunoreacted cells revealed that pinealocyte neurite length was enhanced in microglia-depleted cultures and was inhibited in a microglia-enriched environment (ANOVA, P < 0.001). Serotonin content of pineal cultures decreased in microglia-depleted cultures and was elevated in microglia-enriched cultures (ANOVA, P < 0.001) without any significant change in pinealocyte numbers. These findings are consistent with a working hypothesis that microglia function to mediate neuroendocrine-immune interactions of the gland.