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Receptors for many neurotransmitters including catecholamines and acetylcholine (ACh) have been detected on the cell surface of lymphocytes. It has been demonstrated that a human T cell line synthesizes ACh and suggested that ACh may be an autacoid modulating T cell-dependent immune responses. However, the biochemical interactions of the ACh system with the immune system have not been elucidated in detail. We have shown that m1 and m2 muscarinic receptor mRNAs are expressed in human peripheral blood lymphocytes and in human T cell line Jurkat cells and that pretreatment of these cells with a muscarinic receptor agonist enhances interleukin-2 (IL-2) production. We also postulated possible intracellular signaling pathways via which muscarinic receptors regulate IL-2 production in Jurkat cells. The findings suggest that M1 muscarinic receptors are involved in muscarinic receptor-mediated enhancement of IL-2 production in Jurkat cells and that the transcription factor AP-1 and pathways via mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase and c-Jun N-terminal kinase, but not via p38 MAPK, may be involved in the muscarinic receptor-mediated enhancement of IL-2 production. Our findings demonstrate a neuro-immune interaction through muscarinic receptor signaling in immune cells.

The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previous studies reported that SAMP10 exhibits age-related learning impairments and behavioral depression in a tail suspension test after 7 months. We investigated the changes in emotional behavior in a forced swimming test and in receptors for dopamine and 5-hydroxytryptamine (5-HT) in SAMP10. SAMP10 at 8 months showed an increase of immobility in the test compared with SAMR1. Treatment with desipramine (25 mg/kg, i.p., 3 days) in SAMP10 caused a decrease in immobility. In the cortex from SAMP10, [3H]quinpirole binding to D2/D3 dopamine receptors increased significantly compared with control SAMR1. In the hippocampus from SAMP10, [3H]8-hydroxy DPAT binding to 5-HT1A receptor increased. In midbrains from SAMP10, bindings of [3H]quinpirole and [3H]8-hydroxy DPAT increased. [3H]SCH23390 binding to D1/D5 receptors and [3H]ketanserin binding to 5-HT2 receptor in brain regions examined in SAMP10 were similar to those in SAMR1. The present findings represent the first neurochemical evidence of an increase of D2/D3 and 5-HT1A receptors in SAMP10. SAMP10 may be a useful model of aging associated depressive behavior.

ntracerebroventricularly (i.c.v.) administered nitric oxide (NO) donors, 3-morpholinosydnonimine (SIN-1) (100-500 microg/animal) and sodium nitroprusside (SNP) (100-250 microg/animal) dose-dependently inhibited the rat gastric acid secretion evoked by vagal stimulation at 3 Hz. Furthermore, the inhibitory effect of SIN-1 (250 microg/animal) was more marked and its onset was more rapid than that of SNP (250 microg/animal). The SIN-1 (250 microg/animal)-induced antisecretory effect was abolished by both splanchnicotomy and phentolamine (5 mg/kg, i.m.), and also by indomethacin (500 microg/animal, i.c.v.). These results suggest that i.c.v. administered NO donors inhibit vagally evoked gastric acid secretion by activation of central sympathetic outflow. Central prostaglandin is probably implicated in this NO-mediated antisecretory effect.

Effect of rat alpha-calcitonin gene-related peptide (alpha-CGRP) microinjected into various hypothalamic nuclei on plasma levels of catecholamines and arterial blood pressure were investigated in urethane-anesthetized rats. alpha-CGRP (0.05 and 0.25 nmol) microinjected into the hypothalamic paraventricular nucleus (PVN) increased the plasma level of noradrenaline (NA), but not that of adrenaline (AD), in a dose-dependent manner. A similar increase in plasma level of NA was also observed by alpha-CGRP (0.05 nmol) microinjected into the preoptic area (POA), anterior hypothalamus (AH), dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). A significant increase in arterial blood pressure was observed by microinjection of alpha-CGRP (0.05 nmol) into the PVN, POA, AH and DMH, and the most prominent increase was caused by its microinjection into the PVN. Microinjection of the same dose of this peptide into the VMH, lateral hypothalamic area and posterior hypothalamus was without effect. The increase in plasma level of NA induced by alpha-CGRP (0.05 nmol) into the PVN was not affected by bilateral adrenalectomy. Electrical stimulation of the PVN elicited increases in plasma levels of both NA and AD. This increase in NA was abolished by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.v., 3 days before experiments). These results suggest that activation of the PVN by electrical stimulation elicits both sympathetic and adrenomedullary outflow. alpha-CGRP microinjected into the PVN selectively activates the sympathetic outflow.

Receptors for many neurotransmitters including catecholamines and acetylcholine (ACh) have been detected on the cell surface of lymphocytes. It has been demonstrated that a human T cell line synthesizes ACh and suggested that ACh may be an autacoid modulating T cell-dependent immune responses. However, the biochemical interactions of the ACh system with the immune system have not been elucidated in detail. We have shown that m1 and m2 muscarinic receptor mRNAs are expressed in human peripheral blood lymphocytes and in human T cell line Jurkat cells and that pretreatment of these cells with a muscarinic receptor agonist enhances interleukin-2 (IL-2) production. We also postulated possible intracellular signaling pathways via which muscarinic receptors regulate IL-2 production in Jurkat cells. The findings suggest that M1 muscarinic receptors are involved in muscarinic receptor-mediated enhancement of IL-2 production in Jurkat cells and that the transcription factor AP-1 and pathways via mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase and c-Jun N-terminal kinase, but not via p38 MAPK, may be involved in the muscarinic receptor-mediated enhancement of IL-2 production. Our findings demonstrate a neuro-immune interaction through muscarinic receptor signaling in immune cells.

To elucidate the fundamental mechanism of age-related deficiencies of learning and to develop effective drugs for intervention in age-related diseases such as learning dysfunctions, pertinent animal models that have characteristics closely similar to human dysfunctions should be established. SAM (senescence-accelerated mouse) has been established as a murine model of the SAM strains, groups of related inbred strains including nine strains of accelerated senescence-prone, short-lived mice (SAMP) and three strains of accelerated senescence-resistant, long-lived mice (SAMR). SAMP-strain mice show relatively strain-specific age-associated phenotypic pathologies such as shortened life span and early manifestation of senescence. Among the SAMP-strain mice, SAMP8 mice show an age-related deterioration in learning ability. Here, the neuropathological, neurochemical and pharmacological features of SAM are reported, especially for SAMP8. Moreover, the effects of several drugs on the biochemical and behavioral alterations in SAMP8 and the etiologic manifestation of accelerated senescence are also discussed.

We characterized the voltage-activated Ca2+ channels involved in noradrenaline (NA) release from gastric sympathetic neurons using isolated, vascularly perfused rat stomach. The evoked NA release by electrical stimulation of periarterial nerves was abolished by calcium removal from the perfusion medium and by cadmium. Omega-conotoxin GVIA (N-type Ca2+-channel blocker) effectively and omega-conotoxin MVIIC (N/P/Q-type blocker) slightly inhibited the evoked NA, while omega-agatoxin IVA (P-type blocker) had no effect. These results suggest that omega-conotoxin GVIA and omega-conotoxin MVIIC-sensitive N-type Ca2+ channels are involved in NA release from the rat gastric sympathetic nerve terminals.

Irsogladine maleate (IM) has been used as a mucosal protective agent, whose action is partially explained as enhancement of mucosal blood flow, increase of cellular cyclic AMP and facilitation of gap-junctional intercellular communication. Effect of IM on rat gastric mucosal hydrophobicity, one of the mucosal barrier properties, was investigated, in comparison with that of 16,16-dimethyl prostaglandin E2 (dmPGE2). IM alone had no effect on mucosal hydrophobicity and mucosal phospholipids content. dmPGE2 alone did not change mucosal hydrophobicity significantly, but remarkably increased mucosal surface-active phospholipids. Intragastric administration of absolute ethanol significantly decreased gastric mucosal hydrophobicity and mucosal phospholipids content. IM could prevent the decrease in mucosal hydrophobicity by ethanol, maintaining the surface mucus gel layer and mucosal surface phospholipids almost as non-damaged control levels, whereas dmPGE2 also prevented the decrease in mucosal hydrophobicity by ethanol, with the surface epithelium being partially exfoliated and mucosal surface-active phospholipids showing remarkable enhancement. These results suggest that IM may preserve gastric mucosal hydrophobicity against ethanol, not through enhancement of mucosal phospholipids content like prostaglandin, but possibly through its reported stabilization action to the epithelial cell lining, which may preserve the surface epithelium with the mucous gel layer containing surface-active phospholipids, a possible origin of mucosal hydrophobicity.

We reported that centrally applied bombesin probably excites both the gastric sympathetic and adrenomedullary systems and thus induces inhibition of gastric acid secretion. In the present study, therefore, we examined whether or not centrally applied bombesin directly affects sympathetic nerve activities in rats anesthetized with urethane. Intracerebroventricular administration of bombesin (0.3 and 3.0 nmol) increased discharge rates of the sympathetic branch as well as those of the adrenal branch of preganglionic greater splanchnic nerves. These effects were not secondary to changes in arterial blood pressure by bombesin. In conclusion, centrally applied bombesin directly activates both the sympathetic and adrenomedullary systems.

Effect of rat alpha-calcitonin gene-related peptide (alpha-CGRP) microinjected into various hypothalamic nuclei on plasma levels of catecholamines and arterial blood pressure were investigated in urethane-anesthetized rats. alpha-CGRP (0.05 and 0.25 nmol) microinjected into the hypothalamic paraventricular nucleus (PVN) increased the plasma level of noradrenaline (NA), but not that of adrenaline (AD), in a dose-dependent manner. A similar increase in plasma level of NA was also observed by alpha-CGRP (0.05 nmol) microinjected into the preoptic area (POA), anterior hypothalamus (AH), dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). A significant increase in arterial blood pressure was observed by microinjection of alpha-CGRP (0.05 nmol) into the PVN, POA, AH and DMH, and the most prominent increase was caused by its microinjection into the PVN. Microinjection of the same dose of this peptide into the VMH, lateral hypothalamic area and posterior hypothalamus was without effect. The increase in plasma level of NA induced by alpha-CGRP (0.05 nmol) into the PVN was not affected by bilateral adrenalectomy. Electrical stimulation of the PVN elicited increases in plasma levels of both NA and AD. This increase in NA was abolished by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.v., 3 days before experiments). These results suggest that activation of the PVN by electrical stimulation elicits both sympathetic and adrenomedullary outflow. alpha-CGRP microinjected into the PVN selectively activates the sympathetic outflow.