Suppression of the immune response by drugs interfering with the metabolism of serotonin

Summary The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.     

Evidence for a correlation between the latency of an early component of auditory evoked potentials and the brain levels of serotonin in albino rats

Summary Changes in brain serotonin levels are correlated with the latency of an early component of auditory evoked potentials (EAEP) in rats. In fact 5-hidroxytryptophan provokes an increase both in serotonin brain synthesis and in the latency of EAEP. On the other hand, PCPA provokes an opposite effect.     

Evidence for a correlation between the latency of an early component of auditory evoked potentials and the brain levels of serotonin in albino rats.

Changes in brain serotonin levels are correlated with the latency of an early component of auditory evoked potentials (EAEP) in rats. In fact 5-hidroxytryptophan provokes an increase both in serotonin brain synthesis and in the latency of EAEP. On the other hand, PCPA provokes an opposite effect.     

Serotonergic and cholinergic interaction in the regulation of pituitary-adrenal function in rats

It has been proposed that the central serotonergic inputs which modulate pituitary-adrenal secretion are mediated by cholinergic neurons. We have tested this hypothesis in intact rats. Male Sprague-Dawley rats were injected with cholinergic and serotonergic agents which enhanced transmitter function and with receptor blocking agents. Agents were injected, singly and in combination, into both unstressed and stressed animals. Since the response to cholinergic agents might be due to changes to vasopressin release, Brattleboro (vasopressin deficient) rats were also injected with cholinergic agents. The level of plasma corticosterone at 1-h post-injection was determined. Results indicate that the serotonin receptor blockade decreased the stimulatory, cholinergic effect of physostigmine. Cholinergic receptor blockers did not significantly reduce the corticosterone rise induced by 5-hydroxytryptophan. These results do not support the hypothesis of cholinergic mediation of serotonergic input. Nicotinic and muscarinic receptors appeared to exert opposing influences on the system. The nicotinic receptor antagonist was able to block the stimulatory effect of physostigmine. The muscarinic receptor antagonist significantly elevated plasma corticosterone levels. No differences were found in the effect of physostigmine on Brattleboro rats as compared to controls. These data are interpreted as suggesting that 1) the acetylcholine-induced stimulation of pituitary-adrenal function is mediated, in part, by serotonergic neurons; and 2) stimulation of nicotinic receptors is facilitatory whereas stimulation of muscarinic receptors is inhibitory to pituitary-adrenal function.     

Effect of des-Tyr1-gamma-endorphin on serotonin metabolism in rat brain regions

Intracerebroventricular (i.c.v.) administration of des-Tyr1-gamma-endorphin (0.1 and 1.0 microgram) caused a decrease of the serotonin (5-HT) concentration of the hippocampus. The concentration of 5-HIAA and the pargyline-induced alterations in 5-HT and 5-HIAA were not affected. No effects were noticed in other brain regions.     

Immunohistological investigations of N-Acetylserotonin in the rat cerebellum after parachlorophenylalanine treatment

Summary The amount of N-acetylserotonin (NAS) in the granule layer of the rat cerebellum was investigated using immunohistologic double antibody technique. After 5 days of treatment with parachlorophenylalanine (PCPA) an increase of NAS was observed. The possibility of a differential effect of PCPA on serotonin synthesis in the neurons and the nerve terminals is discussed.     

Immunohistological investigation of N-acetylserotonin in the rat cerebellum after parachlorophenylalanine treatment.

The amount of N-acetylserotonin (NAS) in the granule layer of the rat cerebellum was investigated using immunolohistologic double antibody technique. After 5 days of treatment with parachlorophenylalanine (PCPA) an increase of NAS was observed. The possibility of a differential effect of PCPA on serotonin synthesis in the neurons and the nerve terminals is discussed.     

The involvement of noradrenaline, 5-hydroxytryptamine and acetylcholine in imipramine-induced seizures in mice

The influence of some noradrenergic, 5-hydroxytryptaminergic and cholinergic agents on imipramine-induced seizures were investigated in mice. DL-threo-3,4-dihydroxyphenylserine (DOPS) and pargyline significantly potentiated imipramine-induced seizures. Phentolamine and prazosin significantly attenuated seizures elicited by imipramine and significantly attenuated the seizure-enhancing effect of DOPS. -Methyl-p-tyrosine and reserpine significantly attenuated seizures induced by imipramine. Disulfiram significantly protected mice against imipramine-induced seizures. However, DOPS significantly potentiated seizures induced by imipramine in disulfiram-pretreated animals. Clonidine effectively protected mice against imipramine-induced seizures. Idazoxan, on the other hand, significantly protentiatied seizures induced by imipramine and significantly antagonised the protective effect of clonidine against the seizures. 5-HTP, PCPA, cyproheptadine, mianserin, ketanserin and trazodone did not affect imipramine-induced seizures to any significant extent. Physostigmine antagonised seizures induced by imipramine while atropine significantly potentiated the seizures, and significantly attenuated the protective effect of physostigmine against the seizures. These data suggest that enhancement and attenuation of central noradrenergic and cholinergic neurotransmissions respectively, and not 5-HT mechanisms, may underlie imipramine-induced seizures in mice.     

Pre- and postnatal lead exposure affects the serotonergic system in the immature rat brain.

The effect of pre- and postnatal lead exposure on the development of the serotonergic system in striatum and brain stem was investigated. Serotonin and its metabolite 5-HIAA where determined by HPLC-EC. A significant decrease of 5-HT was detected in the brain stem at postnatal day 28. At both days 6 and 28 postnatal, 5-HIAA was reduced in striatum and brain stem. The results provide support to the hypothesis that developing 5-HT neurons are sensitive to relatively low levels of lead exposure.     

Pre- and postnatal lead exposure affects the serotonergic system in the immature rat brain

Summary The effect of pre- and postnatal lead exposure on the development of the serotonergic system in striatum and brain stem was investigated. Serotonin and its metabolite 5-HIAA where determined by HPLC-EC. A significant decrease of 5-HT was detected in the brain stem at postnatal day 28. At both days 6 and 28 postnatal, 5-HIAA was reduced in striatum and brain stem. The results provide support to the hypothesis that developing 5-HT neurons are sensitive to relatively low levels of lead exposure.     

Effect of des-Tyr1-γ-endorphin on serotonin metabolism in rat brain regions

Summary Intracerebroventicular (i.c.v.) administration of des-Tyr¹-γ-endorphin (0.1 and 1.0 μg) caused a decrease of the serotonin (5-HT) concentration of the hippocampus. The concentration of 5-HIAA and the pargyline-induced alterations in 5-HT and 5-HIAA were not affected. No effects were noticed in other brain regions. Acknowledgement. The skilful technical assistance of Ms Henny de Vos Burchart-Lodewijks and Mrs H.A. Spierenburg and J.A. Meijer is gratefully acknowledged. Des-Tyr¹-γ-endorphin was a gift of Dr. H.M. Greven, Organon International B.V., Oss, The Netherlands. To whom reprint requests should be addressed.     

Serotonin and 5-hydroxyindoleacetic acid concentrations in individual hypothalamic nuclei and other brain areas of rat

Summary Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were measured in individual nuclei of rat hypothalamus and other brain areas using HPLC with electrochemical detection. 5-HIAA levels were first demonstrated in hypothalamic and some discrete brain areas. The 5-HIAA/5-HT ratio was highest in the n. caudatus putamen, high in the n. ventromedialis and lowest in the n. suprachiasmaticus.     

Circadian rhythms of serotonin and the electrical activity of the frontal ganglion of the cockroach,Periplaneta americana

Summary Rhythmic circadian variations in the spontaneous electrical activity of the frontal ganglion (FG) of the cockroach,Periplaneta americana, have been shown, and the neurotransmitter (NT) involved in this activity has been identified as serotonin (5-hydroxytryptamine, 5-HT). During the 24-h day, the diurnal variations in the electrical activity and the levels of 5-HT and its immediate metabolite 5-hydroxyindole acetic acid (5-HIAA) were maximal at 24.00 h and minimal at 12.00 h.     

Tetanus intoxication causes an increment of serotonin in the central nervous system

Mice injected with tetanus toxin (TTx) showed an increase of 5-hydroxytryptamine (serotonin, 5-HT) levels in the central nervous system. The increment was not uniform throughout the central nervous system. Particularly significant were the 25% and 80% increases observed, respectively, in whole brain and spinal cord. The levels of dopamine and norepinephrine remained unchanged. The subsequent studies of 5-HT turnover revealed a synthesis rate in the tetanic animals that was almost double that of controls. The degradation rate of the amine as well as the levels of 5-hydroxyindolacetic acid were unaffected.     

Tetanus intoxication causes an increment of serotonin in the central nervous system

Summary Mice injected with tetanus toxin (TTx) showed an increase of 5-hydroxytryptamine (serotonin, 5-HT) levels in the central nervous system. The increment was not uniform thoughout the central nervous system. Particularly significant were the 25% and 80% increases observed, respectively, in whole brain and spinal cord. The levels of dopamine and norepinephrine remained unchanged. The subsequent studies of 5-HT turnover revealed a synthesis rate in the tetanic animals that was almost double that of controls. The degradation rate of the amine as well as the levels of 5-hydroxyindolacetic acid were unaffected.     

A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action of parachlorophenylalanine by 5-hydroxytroptophan

Summary An acute reduction in the synaptic availability of serotonin (5HT) by p-chlorophenlalanine (PCPA) nullifies the decrease in the density of cortical beta adrenoceptors caused by desipramine (DMI) but does not appreciably alter the attenuation of the norepinephrine (NE) sensitive adenylate cyclase. The analysis of competition-binding curves of [³H]-dihydroalprenolol shows that the affinity of the agonist (–)-isoproterenol for cortical beta adrenoceptors is profoundly reduced following PCPA. This reduction in agonist affinity is enhanced by DMI. Resupplying 5HT by by-passing trptophan hydroxylase inhibition, by administering 5-hydroxytryptophan, converts a DMI non-responsive to a DMI responsive beta adrenoceptor population and shifts the markedly decreased agonist affinity towards the affinity values found in control preparations. The results demonstrate the pivotal role of 5HT in the regulation of the density and agonist affinity characteristics of cortical beta adrenoceptors and contribute to the scientific basis of the serotonin-norepinephrine link hypothesis of affective disorders.Acknowledgments. This work was supported by USPHS grant MH-29228 and the Tennessee Department of Mental Health and Mental Retardation. Present address of L. R. Sterank: NOVA Pharmaceutical Corporation, Baltimore (MD 21228, USA).     

Connection between 3H 5-HT and adenyl cyclase activation induced by 5-HT in preparations of cerebral glial membranes

Purified glial membrane preparations have been isolated from horse brain striatum. Tritiated 5-HT bound to these membranes with a high affinity (KD = 10 nM); the corresponding binding is reversible and appears specific of the serotoninergic structure. In parallel, 5-HT activates an adenylate cyclase with a low affinity (KD = 1 microM). The sites involved in this binding and in this adenylate cyclase activation appear different from the serotoninergic sites reported in the neuronal membrane preparations.     

Control of infection by pyroptosis and autophagy: role of TLR and NLR

Cells can die by distinct mechanisms with particular impacts on the immune response. In addition to apoptosis and necrosis, recent studies lead to characterization of a new pro-inflammatory form of cell death, pyroptosis. TLR and NLR, central innate immune sensors, can control infections by modulating host cell survival. In addition, TLRs can promote the induction of autophagy, thus promoting delivery of infecting pathogens to the lysosomes. On the other hand, activation of some NLR members, especially NLRC4 and NAIP5, leads to the infected cell death by pyroptosis, which is accompanied by secretion of the pro-inflammatory cytokines IL-1β, IL-18, and IL-33. Data presented here illustrate how the compartmentalization of the innate immune sensors can influence the outcome of infections by controlling the fate of host cells.     

Radioautographic identification of central monoaminergic neurons by local micro-instillation of tritiated serotonin or noradrenaline in cats]

Monoaminergic neurons in nuclei raphe dorsalis and locus coeruleus of the Cat may be visualized by radioautography after local micro-instillation of tritiated serotonin and noradrenaline. The concomitant administration of the appropriate tracer with the other biogenic amine in non radioactive form permits a specific identification of serotoninergic and catecholaminergic nerve cell bodies. A small contingent of presumptive serotoninergic neurons is thus demonstrated in the region of the locus coeruleus.     

Action de la Psilocybine sur le cerveau du lapin

Summary Psilocybin, the by-product of which Psilocin] has been identified as 4-hydroxy-dimethyl-tryptamine (4-HTP) develops in the waking rabbit a marked activation of the somatic behaviour and of the electrical brain activity. This stimulating action is due to a depression of the mediothalamic recruiting and moderating system rather than to an activation of the reticular arousal system. The electrophysiological effects of 4-HTP are compared with those of 5-HTP.