Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2

Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent findings with respect to the functional analysis of TPH2. Received 12 September 2005; received after revision 25 October 2005; accepted 31 October 2005     

Developmental pattern of the serotonin synthesizing enzyme in the brain of postnatally malnourished rats

Résumé Dans le cerveau de rats souffrant de malnutrition depuis la naissance, on a déterminé l'activité de l'enzyme 5-hydroxytryptophane-déscarboxylase pendant le premier mois du développement. Une différence significative a été observée le 21^ème jour par rapport aux contrôles. En même temps, la concentration endogène de 5-HT ne présenta qu'une tendence à diminuer.     

Studies on the hydrolysis of bradykinin by angiotensin-converting enzyme (kininase II)

Summary Arg-Pro-Pro-Gly-Phe, the N-terminal pentapeptide of bradykinin, is not an inhibitor of angiotensin-converting enzyme and is not hydrolyzed by the enzyme. Arg-Pro-Pro, the N-terminal tripeptide is a relatively potent (IC₅₀=2.3×10⁶ M) inhibitor but its higher homolog, Gly-Arg-Met-Lys-Arg-Pro-Pro is not an inhibitor of angiotensin-converting enzyme.This work was supported in part by grants from the US Public Health Service (HL 18415, HL 15691, HL 19764) and the John A. Hartford Foundation, Inc., and by the Medical Research Service of the Veterans Administration.     

Effect of the administration of (d-Ala)2methionine-enkephalin on the serotonin metabolism in rat brain

Summary The effect of cerebroventricular injection of [D-Alanine] methionine-enkephalin (DALA), a synthetic analog of met-enkephalin, on the serotonergic system of rat brain has been studied. This opioid peptide caused an increase in 5HT turnover which was particularly evident in the limbic forebrain. This effect was completely antagonized by naloxone pretreatment.Acknowledgments. Support received from Tecnofarmaci, Rome, is gratefully acknowledged.     

Influences of the chemical structure on the activity of new inhibitory compounds of the angiotensin-converting enzyme

The ACE inhibitory activity of some perimidines, chinazolinones and amidinohydrazones is described. Relations were found between the chemical structure and the inhibitory activity on the ACE.     

Influences of the chemical structure on the activity of new inhibitory compounds of the angiotensin-converting enzyme

Summary The ACE inhibitory activity of some perimidines, chinazolinones and amidinohydrazones is described. Relations were found between the chemical structure and the inhibitory activity on the ACE.     

Mechanism of the serotonin depressor response following BAS-phenol administration in the dog

Résumé Après l'administration de BAS-phénol à des chiens anesthésiés, l'effet usuel de la sérotonine d'augmenter la pression artérielle se convertit constamment en un abaissement prolongé de la pression. Cet effet d'abaissement n'est pas influencé par la section bilatérale des deux nerfs vagues, mais on peut le bloquer avec la diphénhydramine. Les données présentées suggèrent que la réponse d'abaissement de la pression artérielle de la sérotonine qui survient dans les chiens ayant été traités avec du BAS-phénol est dûe à une libération d'histamine endogène.     

Selective effects of gonadal steroids on the response of peripheral serotonin receptors

The maximal contraction provoked by serotonin (5-HT) in isolated stomach strips of adult rats, a functional index for peripheral 5-HT receptors, was sexually differentiated, androgen-sensitive, and estrogen refractory. This is at variance with the reported sensitivity of central 5-HT receptors to estrogen.     

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.     

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

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.     

Selective effects of gonadal steroids on the response of peripheral serotonin receptors

Summary The maximal contraction provoked by serotonin (5-HT) in isolated stomach strips of adult rats, a functional index for peripheral 5-HT receptors, was sexually differentiated, androgen-sensitive, and estrogen refractory. This is at variance with the reported sensitivity of central 5-HT receptors to estrogen.     

Influence of diet on plasma tryptophan and brain serotonin levels in mice

Groups of mice were maintained for up to 78 weeks on tryptophan restricted, protein restricted and control diets. Plasma tryptophan levels were significantly reduced by both forms of dietary restriction. Brain serotonin levels were significantly reduced only in mice on the tryptophan restricted diet, but not for mice on the protein restricted diet. The protein-restricted diet contains less of the large neutral amino acids which compete with tryptophan to enter the brain. It is known that protein restriction and tryptophan restriction extend lifespan. The results presented here suggest that extension of lifespan and lowering of brain serotonin are not related.     

Influence of diet on plasma tryptophan and brain serotonin levels in mice

Summary Groups of mice were maintained for up to 78 weeks on tryptophan restricted, protein restricted and control diets. Plasma tryptophan levels were significantly reduced by both forms of dietary restriction. Brain serotonin levels were significantly reduced only in mice on the tryptophan restricted diet, but not for mice on the protein restricted diet. The protein-restricted diet contains less of the large neutral amino acids which compete with tryptophan to enter the brain. It is known that protein restriction and tryptophan restriction extend lifespan. The results presented here suggest that extension of lifespan and lowering of brain serotonin are not related.     

Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain

In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling. This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%, or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT) expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion, cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh homeostasis. Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006     

Pharmacological effects of carbaryl II. Modification of serotonin metabolism in the rat brain

Zusammenfassung Nachweis, dass Carbaryl die Konzentration von Serotonin und 5-Hydroxyindolessigsäure im Rattenhirn steigert. Der Zusammenhang mit einem Stress wird als möglich angenommen.     

The effect of adrenalectomy on the norepinephrine and serotonin content of the brain and on reserpine action in rats

Zusammenfassung Sieben Tage nach Adrenalektomie ist der 5-HT-Gehalt des Rattengehirns vermindert, während der NA-Gehalt unverändert bleibt. Chronische Hydrocortisonbehandlung restituiert, DOCA-Behandlung bleibt wirkungslos. Nach 5-HTP-Behandlung steigt der 5-HT-Gehalt auch im Gehirn der adrenalektomierten Tiere.