Effect of levodopa/carbidopa on stress response in zebrafish.

The dopaminergic system of zebrafish is complex and the numerous pathways and receptors in the central nervous system (CNS) are being extensively studied. A critical factor for the synthesis, activation and release of catecholamines (CAs) is the presence of tyrosine hydroxylase, an enzyme which converts L-tyrosine into levodopa. Levodopa thus is the intermediary in the synthesis of dopamine (DA) and norepinephrine (NE) and promotes its release; therefore, CAs play an important role in the CNS with hormonal functions. Here, we use levodopa/carbidopa to clarify the involvement of the dopaminergic pathway in the stress response in zebrafish submitted to an acute stress challenge. Acute stress was induced by chasing fish with a net for 2 min and assessed by measuring whole-body cortisol levels. Two experiments were carried out, the first with exposure to levodopa/carbidopa and the second with exposure to AMPT and levodopa/carbidopa. Levodopa/carbidopa balances the stress response through its action on the zebrafish hypothalamic-pituitary-adrenal (HPA) axis. Changes in cortisol levels suggest that DA was related to the balance of the stress response and that NE decreased this response. These effects were specific to stress since levodopa/carbidopa did not induce changes in cortisol in non-stressed fish.

Absence of neurotoxicity of chronic L-DOPA in 6-hydroxydopamine-lesioned rats.

We investigated the effects of 6 months' oral treatment with L-dihydroxy-phenylalanine (L-DOPA)/carbidopa on the remaining dopaminergic neurones of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) of rats with moderate or severe 6-hydroxydopamine (6-OHDA)-induced lesions and sham-operated animals. Using a radioimmunohistochemical method we counted tyrosine hydroxylase (TH)-radioimmunoreactive cells in the SNC and the VTA in emulsion-coated sections and measured the remaining surface area of both structures on autoradiograms. The sole difference observed was a significant increase of the remaining surface area of TH radioimmunolabelling in the SNC of moderately lesioned rats treated with L-DOPA/carbidopa compared with the untreated animals, while the rest of the parameters recorded, in both structures and groups of animals, were unchanged. This suggest that in vivo, this treatment is not toxic either to healthy dopaminergic neurones of the ventral mesencephalon or to those surviving after a 6-OHDA lesion.

Tratamento crônico com L-Dopa e MK-801: efeitos comportamentais e neuroquímicos em um modelo experimental de parkinsonismo / Chronic treatment with L-Dopa and MK-801: behavioral and neurochemical effects in animal model of parkinsonism

O presente estudo investigou o efeito dos tratamentos crônicos com L-DOPA e MK-801 no desenvolvimento do processo de supersensibilidade dopaminérgica, utilizando um modelo de hemiparkinsonismo. Rotaçoes contralaterais à lesao foram utilizadas como medida comportamental do processo de supersensibilidade. Ratos lesados unilateralmente com 6-OHDA na substância negra foram tratados sistemicamente com L-DOPA/carbidopa e MK-801 durante 13 dias consecutivos, seguidos por um período de retirada de droga de 10 dias. Após esse período, os animais foram testados com salina e no dia seguinte testados com L-DOPA. Resultados mostraram que o tratamento com L-DOPA e o pré-tratamento com MK-801 nao impediram o aparecimento do processo de supersensibilidade, mas retardaram o início do mesmo. Entretanto, uma vez iniciado, o processo se tornou mais acentuado, visto que, após um período de retirada, a administraçao de L-DOPA produziu rotaçoes contralaterais equivalentes àquelas do 13§ dia. O grupo pré-tratado com MK-801, entretanto, apresentou um número de rotaçoes contralaterais semelhante ao apresentado pelo grupo salina. Ensaios bioquímicos utilizando a técnica de cromatografia líquida de alta eficiência (HPLC-EC) indicaram que o tratamento com L-DOPA nao produziu mudanças nos níveis dopaminérgicos estriatais. Entretanto, as razoes dopaminérgicas DOPAC/DA e HVA/DA dos grupos tratados com L-DOPA se encontravam aumentadas. Houve aumento nos níveis dopaminérgicos corticais. Em conclusao, o presente trabalho sugere que a administraçao crônica de L-DOPA nao é suficiente para impedir o desenvolvimento do processo de supersensibilidade, porém retarda o aparecimento deste. O pré-tratamento com MK-801, além de retardo, produz também a atenuaçao do processo.

Dopamine and serotonin turnover rate in the retina of rabbit, rat, goldfish, and Eugerres plumieri: light effects in goldfish and rat.

The concentration of dopamine, and its metabolites 3,4-dihydroxyphenylacetic and homovanillic acids, as well as serotonin and its metabolite 5-hydroxyindoleacetic acid, were determined in the retina of two teleosts, C. auratus (goldfish) and E. plumieri (mojarra), and two mammals, R. norvegicus (rat) and O. cuniculus (rabbit). The turnover rate of these monoamines were investigated in the four species by the calculation of the ratio monoamine/metabolite as an indirect index, and in goldfish and rat by the inhibition of the synthesis with alpha-methyl-p-tyrosine or p-chlorophenylalanine, by the increase in dopamine or serotonin by the corresponding precursors, 3,4-dihydroxyphenylalanine or 5-hydroxytryptophan, and by inhibition of monoaminooxidase with pargyline. The modulation by light and dark stimulation was studied in the goldfish and the rat. Differences in the concentration and turnover rate were observed among the species. Serotonin concentration was higher in the teleosts. The administration of inhibitors of dopamine and serotonin synthesis differentially decreased the levels of the monoamines in the retina of goldfish and rat. The rate of formation of dopamine and serotonin by the corresponding precursors was much higher in the goldfish than in the rat. Pargyline administration decreased 3,4-dihydroxyphenylacetic and 5-hydroxyindoleacetic acids at different rates and time dependency in the retina of goldfish and rat. Dopamine and serotonin concentration did not exhibit high modifications by the inhibitor, suggesting the function of regulatory mechanisms or additional effect of pargyline at other sites different from monoaminooxidase.(ABSTRACT TRUNCATED AT 250 WORDS)

Parkinsonismo: aspéctos clínicos, biológicos e terapêuticos / Parkinsonism: clinical, biological and therapeutical aspects

O parkinsonismo idiopático (doença de Parkinson) e secundário, ou seja, que apresenta etiologia conhecida (pós-encefalítico, por toxinas, por drogas ou por algumas doenças degenerativas) såo processos neurodegenerativos que afetam progressivamente as funçÆes motoras normais do indivíduo. Neste trabalho, os aspéctos clínicos, etiológicos, fisiopatológicos e principalmente a descriçåo do arsenal farmacológico e as medidas utilizadas no combate ou retardo medicamentoso do parkinsonismo såo abordados e discutidos

Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs normal children.

The neuroendocrine response to L-5-hydroxytryptophan was compared in 37 prepubertal children who met the Research Diagnostic Criteria for major depressive disorder with that in 23 normal children with no lifetime history of any psychiatric disorder and very low rates of depression in both first- and second-degree relatives. Intravenous L-5-hydroxytryptophan (0.8 mg/kg) was given over a 1-hour interval after preloading with oral carbidopa, an inhibitor of peripheral but not central L-5-hydroxytryptophan metabolism. L-5-Hydroxytryptophan, a precursor of serotonin, increases serotonin turnover in the central nervous system when given after carbidopa. Seven (19%) of the 37 children with major depressive disorder and two (9%) of the 23 normal children had nausea or vomiting and therefore did not complete the full infusion. They were subsequently excluded from data analysis. After this stimulation, prolactin, cortisol, and growth hormone secretion were compared between diagnostic groups. The depressed children secreted significantly less cortisol (effect size, 0.70) and significantly more prolactin (effect size, 0.83). There was a sex-by-diagnosis interaction in prolactin response to L-5-hydroxytryptophan and, on examination, the prolactin hypersecretion was seen in depressed girls but not in depressed boys compared with same-sex controls. There was no significant stimulation of growth hormone in either group. These findings are consistent with dysregulation of central serotonergic systems in childhood major depression.

Stimulation of the hypothalamo-pituitary-adrenocortical axis by the central serotonergic pathway: involvement of endogenous corticotropin-releasing hormone but not vasopressin.

Many reports indicate that serotonin plays a role in the regulation of the hypothalamo-pituitary-adrenocortical axis. The present study was designed to elucidate whether the activation of the central serotonergic pathway enhances adrenocorticotropin and corticosterone secretion, and if so, whether the CRH and vasopressin neuronal systems could be mediating this effect. Intraperitoneal administration of a low dose of L-5-hydroxytryptophan (an aromatic L-amino acid precursor of serotonin synthesis; 20 mg/kg bw, 30 minutes before the sacrifice) in rats pretreated with pargyline (a brain monoamine oxidase inhibitor, which enhances monoamine activity; 75 mg/Kg bw, 16 hours before the sacrifice) and carbidopa (a peripheral active inhibitor of the decarboxylation of aromatic L-amino acids, which would permit more monoamine precursor to be available to the brain; 50 mg/Kg bw, 90 minutes before the sacrifice) increased ACTH and corticosterone secretion in plasma. Such an effect was partially blocked by metergoline (a serotonin type-1 and-2 receptor blocker; 1 mg/Kg bw, 90 minutes before the sacrifice), but not by spiperone (a serotonin type-2 and dopamine receptor antagonist; 0.5 mg/Kg bw. 90 minutes before the sacrifice). The activation of the central serotonergic system enhanced the CRH content in the median eminence, whereas it decreased the content of this neuropeptide in the medial basal hypothalamus. These effects were fully abolished by metergoline, but not by spiperone pretreatment. The activation of the serotonergic pathway did not influence the vasopressinergic neuronal system. In vitro experiments using hypothalamic-median eminence fragments incubated with serotonin solutions indicate that this monoamine possesses a CRH releasing effect at concentrations of 1 microM or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of the increase in apomorphine-induced stereotypy and aggression in REM sleep deprived rats by dopamine agonist pretreatments.

REM sleep deprivation (REMSD) induces augmented responses to dopaminergic agonists. Prolonged administration of neuroleptics induces a similar state, probably by the production of supersensitivity of dopaminergic receptors. Such a supersensitive state could be induced by REMSD as a result of impairment of dopamine neurotransmission. In order to test this hypothesis, bromocriptine, nomifensine, amphetamine, L-dopa, imipramine and electroconvulsive shock (ECS) were administered to rats during REMSD, and aggressive and stereotyped behaviors were measured. Amphetamine and L-dopa pretreatment attenuated the increases in apomorphine-induced stereotypy and aggression in REMSD rats, but ECS selectively reduced apomorphine-induced aggression. The other drugs tested were ineffective on both behavioral tests. Such a selective action may reflect different effects of ECS on different dopaminergic systems such as those involved with stereotypy and aggression. The results suggest that REMSD induces an increase in dopaminergic sensitivity which may be reversed by pretreatment with some dopaminergic agonists.

The urinary excretion of 5-hydroxyindoleacetic acid does not reflect brain levels of this metabolite of 5-hydroxytryptamine.

The present study was undertaken to determine if changes in the serotonergic central nervous system can be reflected by urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Cerebral, spinal and urinary levels of 5-HIAA were determined and compared in rats whose cerebral 5-HIAA concentration had been depleted by nucleus raphe dorsalis and medialis lesion or increased by L-tryptophan loading. Since no differences were observed in the urinary excretion of 5-HIAA we conclude that this parameter cannot be used to detect changes in the serotonergic central nervous system.