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PubMedDate not supplied

Role of serotonin in tolerance to ethanol and barbiturates: evidence for a specific vs. non-specific concept of tolerance.

The results of our recent investigations have suggested that tolerance and cross-tolerance development to motor-impairing and hypothermic effects of ethanol was slowed when brain serotonin (5-HT) was extensively depleted by treatment with p-chlorophenylalanine (p-CPA). These findings have been extended by the observation that p-PCA also slowed the development of tolerance to motor-impairing effects of barbital whether tolerance was tested repeatedly in the same animal or in separate subgroups being tested only once. Additional support was provided by the demonstration that intracerebral injection of 5,7-dihydroxytryptamine (-DHT), which is known to deplete 5-HT markedly, also slowed the development of tolerance to motor-impairing and hypothermic effects of ethanol. In addition, when brain 5-HT level was elevated by administration of L-tryptophan, the rate of tolerance development to ethanol, as measured by motor impairment and hypothermia, was accelerated. In contrast to 5,7-DHT, intracerebral injection of 5,6-DHT was surprisingly found to accelerate the development of tolerance to ethanol. Upon further investigation, however, it was determined that the 5,6-DHT treatment depleted brain 5-HT levels by only 20% and, in addition, resulted in the development of supersensitivity. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives. The possibility of a non-specific vs. specific effect of the serotoninergic system (as well as other aminergic systems) in tolerance and neuroplasticity deserves further investigation. The possible significance of these findings and the role of 5-HT (and noradrenaline) in the mechanism of tolerance are discussed in terms of analogy to enzyme or receptor mechanism.

5,6-Dihydroxytryptamine↗

PubMed1979

Selective response of rat peripheral sympathetic nervous system to various stimuli.

1. We utilized the induction of tyrosine hydroxylase, a catecholamine-synthesizing enzyme, in sympathetic ganglia and adrenal medullae to explore the central and peripheral mechanisms through which choline, various environmental stresses, and drugs that alter blood pressure or central neurotransmission affect various portions of the sympathetic nervous system. Animals received each treatment chronically, and enzyme activity was measured in the superior cervical, stellate, and coeliac ganglia and in the adrenal medullae.2. Choline administration increased tyrosine hydroxylase activity in all four tissues, probably by increasing the release of acetylcholine from preganglionic sympathetic neurones that synapse on catecholamine-producing ganglion and chromaffin cells; carbachol and nicotine had similar effects.3. Insulin enhanced tyrosine hydroxylase activity primarily in the coeliac ganglion and the adrenal medullae, but not in the superior cervical ganglia.4. Reserpine and phenoxybenzamine increased the activity of the enzyme in all four tissues.5. Prolonged exposure to a cold environment increased enzyme activity in all four tissues, but especially in the stellate and coeliac ganglia; forced swimming affected tyrosine hydroxylase only in these two ganglia.6. Several drugs known to modify central neurotransmission were found to increase tyrosine hydroxylase activity in some portions of the sympathetic nervous system but not in others. 5,7-Dihydroxytryptamine, which destroys terminals of serotoninergic neurones, enhanced enzyme activity in all four tissues, but primarily in the coeliac ganglion and adrenal medullae. ET-495 (a dopaminergic agonist), D-amphetamine, and morphine induced tyrosine hydroxylase activity in the adrenal medullae and the coeliac ganglion, but not in the superior cervical ganglia. Oxotremorine, a centrally acting muscarinic agonist, increased tyrosine hydroxylase activity only in the adrenal medullae; its effect was not blocked by methylatropine, a peripheral muscarinic blocker.7. These data indicate that specific neurones in the central nervous system, which utilize specific neurotransmitters and which are differentially affected by drugs and environmental inputs, selectively influence the outflows through the various zones of the sympathetic nervous system.

5,7-Dihydroxytryptamine↗

PubMed1979

Serotonin and the control of ventilation in awake rats.

In awake, unrestrained, intact rats, reserpine, para-chlorophenylalanine, 6-fluorotryptophan, and para-chloroamphetamine depleted whole brain serotonin and produced a substantial and sustained hyperventilation as evidenced by a 5--9 torr drop in PaCO2. Administration of 5-hydroxytryptophan to rats treated with para-chlorophenylalanine partially alleviated the hyperventilation. No change in ventilation was observed after alpha-methyltyrosine. 5,7-Dihydroxytryptamine produced contradictory results. On the basis of these pharmacological studies, we propose that some serotonin-mediated nerve transmissions might function under physiological conditions to inhibit the central nervous system output which controls normal breathing.

5,7-Dihydroxytryptamine↗

PubMed1979

Effects of brain serotonin alterations on prostaglandin E1-induced bradycardia in rats.

The vasodepressor and bradycardia responses of saline control, serotonin-depleted and serotonin-potentiated rats to an intravenous dose of prostaglandin E1 (PGE1) were assessed under the urethane anesthesia. Elevation of serotonin concentration in brain with either 5-hydroxytryptophan (a serotonin precursor) or chlorimipramine (an inhibitor of serotonin reuptake), although causing no changes in vasodepressor reuptake), although causing no changes in vasodepressor response, did enhance the PGE1-induced bradycardia in contrast, depleting serotonin concentration in brain with either p-chlorophenylalanine or 5,7-dihydroxytryptamine greatly reduced the PGE1-induced bradycardia without changes in vasodepressor response. Moreover, the reduced PGE1 bradycardia induced by p-chlorophenylalanine treatment was readily reversed by the replacement of the depleted brain serotonin with 5-hydroxytryptophan in combination with a peripheral decarboxylase inhibitor Ro4-4602. The data indicate that brain serotonergic systems play a role in the elaboration or modulation of the PGE1-induced bradycardia. Specifically, brain serotonin seems to facilitate the PGE1-induced bradycardia since its depletion causes a decrease and its potentiation or elevation causes an increase in the PGE1-induced bradycardia.

5,7-Dihydroxytryptamine↗

PubMed1979

Ontogenesis of tryptophan transport in the rat brain.

During the first three postnatal weeks, the levels of tryptophan in the brain are exceptionally high, 2--4 times those found in adult rats. This is related to two main peculiarities concerning tryptophan transport in young animals: 1. the lack of tryptophan binding onto serum albumin which makes its diffusion from plasma to tissues easier for the early life period; 2. the greater capacity of synaptosomes from neonates to accumulate tryptophan. Experiments consisting of electrolytic lesioning of the midbrain raphé or 5, 7-dihydroxytryptamine treatment clearly demonstrate that the uptake or tryptophan during postnatal development is not more active in serotoninergic than in other types of nerve terminals. In adult rats, changing the concentration of tryptophan induces parallel modifications in the rate of 5-HT synthesis in the brain since the rate limiting enzyme, tryptophan hydroxylase, is not saturated by its substrate. In contrast, neither tryptophan loading, nor parachlorophenylalanine administration (resulting in a marked decrease in brain tryptophan levels) alters the rate of 5-HT synthesis in the CNS of neonates, indicating that tryptophan hydroxylase is saturated during the early life period. These results are discussed in relation to the possible non-transmitter role of 5-HT during brain growth.

Aging↗

PubMed1975

Involvement of brain monoamines in the stimulant and paradoxical inhibitory effects of methylphenidate.

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with alpha-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-beta-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by alpha-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.

5-Hydroxytryptophan↗

PubMed1979

Evidence against serotonin involvement in the tonic component of electrically induced convulsions and in carbamazepine anticonvulsant activity.

Intraventricular injection of 5,7-dihydroxytryptamine, selective destruction of descending serotoninergic neurons by 5,6-dihydroxytryptamine or electrolytic and chemical lesions of the nucleus raphe dorsalis did not affect the electroconvulsive threshold in rats. No effect was observed after the systemic administration of drugs known to increase central serotonin transmission, such as quipazine, m-chlorophenylpiperazine, and moderate doses of d-fenfluramine, whereas p-chlorophenylalanine, an inhibitor of serotonin synthesis, decreased seizure susceptibility. The anticonvulsant activity of carbamazepine was not modified in animals with the same experimental lesions. The results, in relation to the high selectivity of the experimental procedures employed to deplete brain and spinal cord serotonin, do not bear out any involvement of serotonin in the tonic component of electrically induced convulsions or in the action of carbamazepine.

Animals↗

PubMed1977

Inhibiton of neurons in the amygdala by dorsal raphe stimulation: mediation through a direct serotonergic pathway.

This study presents data showing that the dorsal raphe nucleus (DRN) has a marked inhibitory influence upon neurons in the amygdala and that this inhibitory effect is mediated by a direct DRN-amygdala serotonergic pathway. The evidence may be briefly summarized as follows:(1) on the same amygdaloid cells, both iontophoresis of serotonin (5-HT) and electrical stimulation of the DRN markedly inhibited spontaneous single unit activities; (2) the latency of DRN-induced inhibition was relatively short and is compatible with the conduction velocities (which were determined by antidromic activation of the 5-HT pathway) of unmyelinated 5-HT fibers; (3) destruction of 5-HT projections by 5,7-dihydroxytryptamine (5,7-DHT) or pharmacological depletion of 5-HT by parachlorophenylalanine (PCPA) prevented the inhibitory responsed to DRN stimulation in the great majority of cells studied; (4) in PCPA-pretreated animals, injection of 5-hydroxytryptophan (5-HTP) reversed the PCPA effect, restoring the responses of amygdaloid cells to DRN stimulation. In the amygdala, the presumptive 5-HT antagonists which we tested did not block the inhibitory effects of 5-HT except that intravenously administered LSD blocked the inhibitory responses produced by submaximal DRN stimulation. The implications of these results for the possible functions of 5-HT in the amygdala is discussed.

5-Hydroxytryptophan↗

PubMed1977

A quantitative rotational model for studying serotonergic function in the rat.

Unilateral injection of 5,7-dihydroxytryptamine (4 mug/4 mul) into the medial forebrain bundle of rats produced serotonin depletions of 65% and 70% in the ipsilateral corpus striatum and ipsilateral forebrain, respectively. These animals showed a dose-dependent increase in contralateral turning (rotational behavior) when pretreated with a peripheral decarboxylase inhibitor and then injected with L-5-hydroxytryptophan in doses ranging from 5 to 100 mg/kg i.p. Injections of p-chloroamphetamine, which releases endogenous stores of serotonin, produced ipsilateral turning which could be blocked by prior serotonin depletion. Systemic administration of the catecholamine drugs L-DOPA, apomorphine and D-amphetamine never elicited consistent turning in either direction in these animals. These data indicate that the turning response of rats with unilateral destruction of brain serotonin nerve terminals provides a sensitive tool for quantifiably studying changes in serotonergic function.

5-Hydroxytryptophan↗

PubMed1979

Effect of brain 5-hydroxytryptamine alterations on reflex bradycardia in rats.

The vasopressor and bradycardia responses to an intravenous dose of epinephrine were assessed in saline-controlled, 5-hydroxytryptamine-(5-HT) depleted, and 5-HT-potentiated rats. Regardless of the previous treatment epinephrine produced an insignificant change in the basal levels of mean arterial pressure and heart rate. However, brain serotonin alteration did produce some influences on the reflex bradycardia in response to an elevation in arterial pressure. Elevating 5-HT contents in brain with 5-hydroxytryptophan (5-HTP) after peripheral decarboxylase inhibition with Ro 4-4602 produced a significant reduction in reflex bradycardia compared to the controls. In contrast, depleting 5-HT contents in brain with either p-chlorophenylalanine (PCPA) or 5,7-dihydroxytryptamine (5,7-DHT) led to an enhancement of epinephrine-induced bradycardia. Moreover, the enhanced reflex bradycardia induced by PCPA treatment was readily blocked by the replacement of the depleted brain 5-HT with 5-HTP and Ro 4-4602. The results suggest that serotoninergic systems play a role in the elaboration or modulation of reflex bradycardia. Specifically, 5-HT appears to inhibit reflex bradycardia since its depletion facilitated and its elevation inhibited reflex bradycardia.

Animals↗

PubMed1976

Stimulatory role for brain serotoninergic system on prolactin secretion in the male rat.

Systemic administration of parachlorophenylalanine (PCPA, 100 mg/kg sc on alternate days X two times), a blocker of serotonin (5-HT) synthesis, considerably decreased brain 5-HT and plasma prolactin (PRL) levels in young male rats. Intraventricular (IVT) administration of 5,7-dihydroxytryptamine (5,7-DHT, 200 mug/20 mul), a neurotoxic drug which destroys 5-HT nerve terminals, induced, 3, 12, and 30 days after treatment, a marked depletion of brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and considerably reduced plasma PRL levels at each time interval. Feeding of rat for up to 4 days with a tryptophan (TP)-deficient diet, caused a depletion of brain 5-HT and 5-HIAA contents and did not modify plasma PRL levels. Addition of TP (2 g/kg of diet) to the TP-deficient diet resulted in increased brain 5-HT and 5-HIAA contents and significantly increased PRL levels. These data provide evidence for the role of the 5-HT system in the maintenance of tonic PRL secretion.

5,6-Dihydroxytryptamine↗

PubMed1975

Microspectrofluorimetric analysis of the formaldehyde induced fluorescence in midbrain raphe neurons.

The formaldehyde induced fluorescence in perikarya localized in the midbrain rephe nuclei was investigated using the Falck-Hillarp technique in combination with qualitative (spectral analysis) and quantitative microspectorfluorimetry. The spectral evidence obtained after various pharmacological and lesion experiments with the neurotoxic compounds 5,6-dihydroxytryptamine and 5,7-dihydroxytryptamine, strongly favours the view that the vast majority of the perikarya in the cell groups B-7, B-8 and B-9 (according to Dahlström and Fuxe) are 5-hydroxytryptamine neurons, defined as structures capable of synthesizing, metabolizing, and storing 5-hydroxytryptamine. The spectral data indicate that the 5-hydroxytryptamine neurons might contain in addition to 5-hydroxytryptamine another indolealkylamine, possibly tryptamine, in low concentrations. The perikarya were shown to be able to take up and accumulate exogenously administered 6-hydroxytryptamine provided that monoamine oxidase was inhibited. Quantitative microfluorimetric analysis disclosed that the tryptophan hydroxylase inhibitor p-chlorophenylalanine was unable to block effectively this enzyme in the 5-hydroxytryptamine perikarya, although acutely a partial blockade was observed. The 5-hydroxytryptamineerogenously to the action of p-chlorophenylalanine and this might be associated with different states of neuronal activity. The difference in potency of p-chlorophenylalanine as regards tryptophan hydroxylase inhibition in perikarya and in nerve terminals may be related to different properties of tryptophan hydroxylase in various parts of the neuron and/or to a high turnover of the enzyme in the perikarya.

5-Hydroxytryptophan↗

PubMed1979

A method of quantitating aggressive behaviour revealing possible dissociation of motor activity and aggression.

A method is described for quantitating isolation-induced aggression in wild male mice by measuring coarse motor activity. It is based on the operational definition that aggression is the form of motor activity in which two (or more) animals are involved in behaviour patterns, such as physical attack and/or defence including pursuit and flight. Both coarse and fine motor activity were measured by means of an electromagnetic activity meter. Four hundred ninety-two fights occurring among mice treated with various hormones, neurotransmitter antagonists, hashish, and cyproterone acetate were recorded; a positive significant correlation (P less than 0.001) between indices of fighting behaviour as well as fighting time and coarse motor activity were found. The simultaneous measurement of motor activity and aggression revealed dissociated effects of some drugs on non-aggressive fine motor activity and aggression.

5,7-Dihydroxytryptamine↗

PubMed1979