Presynaptic serotonin mechanisms in rats subjected to inescapable shock.

After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive control rats do. The present studies were designed to examine the correlations between the behavioral differences and the changes of presynaptic serotonergic activity, seen in these groups of rats. The major findings concerned presynaptic serotonergic effects in the hippocampus and hypothalamus of learned helpless rats. In the hippocampus, these included a statistically significant increase in three presynaptic 5-hydroxytryptamine (5-HT) mechanisms: K(+)-induced release of [3H]serotonin, high affinity uptake of [3H]serotonin and maximum density of binding sites for uptake of 5-HT, measured with [3H]paroxetine. In the hypothalamus, there was a differential modulation of all three presynaptic 5-HT mechanisms. A significant decrease in: K(+)-induced release of [3H]serotonin, in high affinity uptake of [3H]serotonin and the maximum binding site density of [3H]paroxetine binding was observed. No changes in uptake site binding was seen in other regions of the brain examined. These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the behavioral response to stress.     

Selective serotonin reuptake inhibitors and hyponatraemia: review and proposed mechanisms in the elderly

The association between selective serotonin reuptake inhibitors (SSRIs) and hyponatraemia has been well documented, the elderly appearing to be at greatest risk. An analysis of data of hyponatraemia in the elderly using SSRIs from all published cases and from the Committee on Safety of Medicines found that the mean time to detection was about 3 weeks after commencing SSRIs. A wide range of time to detection (1-253 days) and non-specific symptoms suggest hyponatraemia is detected by chance rather than being specifically looked for. In the elderly there are physiological changes, a high prevalence of medical illnesses and concomitant drug use, which may precipitate hyponatraemia. Together with a risk of altered water regulation in psychiatric illness this may account for the particular susceptibility of the elderly to hyponatraemia whilst using SSRIs.     

Studies on the mechanisms underlying amiloride enhancement of 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats

Amiloride and several of its congeners known to block the Na(+)/Ca(2+) and/or Na(+)/H(+) antiporters potentiate methamphetamine-induced neurotoxicity without altering methamphetamine-induced hyperthermia. We now examine whether amiloride also exacerbates 3,4-methylenedioxymethamphetamine (MDMA)-induced long-term serotonin (5-HT) loss in rats. Amiloride (2.5 mg/kg, every 2 h x 3, i.p.) given at ambient temperature 30 min before MDMA (5 mg/kg, every 2 h x 3, i.p.), markedly exacerbated long-term 5-HT loss. However, in contrast to methamphetamine, amiloride also potentiated MDMA-induced hyperthermia. Fluoxetine (10 mg/kg i.p.) completely protected against 5-HT depletion caused by the MDMA/amiloride combination without significantly altering the hyperthermic response. By contrast, the calcium channel antagonists flunarizine or diltiazem did not afford any protection. Findings with MDMA and amiloride were extended to the highly selective Na(+)/H(+) exchange inhibitor dimethylamiloride, suggesting that the potentiating effects of amiloride are probably mediated by the blockade of Na(+)/H(+) exchange. When the MDMA/amiloride combination was administered at 15 degrees C hyperthermia did not develop and brain 5-HT concentrations remained unchanged 7 days later. Intrastriatal perfusion of MDMA (100 microM for 8 h) in combination with systemic amiloride caused a small depletion of striatal 5-HT content in animals made hyperthermic but not in the striatum of normothermic rats. These data suggest that enhancement of MDMA-induced 5-HT loss caused by amiloride or dimethylamiloride depends on their ability to enhance MDMA-induced hyperthermia. We hypothesise that blockade of Na(+)/H(+) exchange could synergize with hyperthermia to render 5-HT terminals more vulnerable to the toxic effects of MDMA.     

Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota

Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan → 5-hydroxytryptophan (5-HTP) → serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood–brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.     

Methionine enkephalin-induced shaking behavior in rats: Dissociation from brain serotonin mechanisms

Intracerebroventricular injection of methionine enkephalin (met-enkephalin) caused dosedependent shakes in rats. The role of endogenous 5-hydroxytryptamine (5-HT) in met-enkephalin-induced shakes was investigated since shaking behavior has been associated with activation of 5-HT receptors. Met-enkephalin-induced shakes were not affected significantly by pretreatment with p-chlorophenylalanine, 5,7-dihydroxytryptamine, or methysergide. Naloxone inhibited the shakes caused by met-enkephalin. The results suggest that met-enkephalin elicits shaking behavior by a mechanism independent of central 5-HT.     

Pharmacological characterization of serotonin receptors involved in the control of prolactin secretion

The present study was undertaken to characterize the type of serotonin (5-HT) receptors involved in the control of prolactin (PRL) secretion in male rats. d-Fenfluramine (10 mg/kg i.p.), a potent 5-HT releaser and quipazine, (20 mg/kg i.p.) a 5-HT agonist, caused a marked increase in serum PRL levels. Ritanserin (200 micrograms/kg i.p.), a specific antagonist of 5-HT2 receptors, administered 1 h before the administration of d-fenfluramine or quipazine, completely prevented the PRL-releasing effect of these drugs. Furthermore, the administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) (1.5, 3 and 6 mg/kg i.p.), a compound considered to be a prototypical 5-HT1A agonist, failed to induce any change in serum PRL levels. The same lack of effect on PRL secretion was observed after the administration of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridin-4-yl)-1-H-indole (RU 24969) (1, 3 and 10 mg/kg i.p.), a compound which has been shown to possess a higher selectivity for 5-HT1B receptor subtypes than for 5-HT1A subtypes. These results suggest that 5-HT receptors involved in the control of PRL secretion are of the 5-HT2 type.     

Presynaptic control of serotonin on striatal dopamine function

Rationale

The influences of the serotonergic system on dopamine (DA) neuron activity have received considerable attention during the last three decades due to the real opportunity to improve disorders related to central DA neuron dysfunctions such as Parkinson??s disease, schizophrenia, or drug abuse with serotonergic drugs. Numerous biochemical and behavioral data indicate that serotonin (5-HT) affects dopaminergic terminal function in the striatum.

Objective

The authors propose a thorough examination of data showing controversial effects induced by striatal 5-HT on dopaminergic activity.

Results

Inhibitory and excitatory effects of exogenous 5-HT have been reported on DA release and synthesis, involving various striatal 5-HT receptors. 5-HT also promotes an efflux of DA through reversal of the direction of DA transport. By analogy with the mechanism of action described for amphetamine, the consequences of 5-HT entering DA terminals might explain both the excitatory and inhibitory effects of 5-HT on presynaptic DA terminal activity, but the physiological relevance of this mechanism is far from clear. The recent data suggest that the endogenous 5-HT system affects striatal DA release in a state-dependent manner associated with the conditional involvement of various 5-HT receptors such as 5-HT_2A, 5-HT_2C, 5-HT₃, and 5-HT₄ receptors.

Conclusion

Methodological and pharmacological issues have prevented a comprehensive overview of the influence of 5-HT on striatal DA activity. The distribution of striatal 5-HT receptors and their restricted influence on DA neuron activity suggest that the endogenous 5-HT system exerts multiple and subtle influences on DA-mediated behaviors.     

Oversensitivity to serotonin of the collateralized vascular bed in rat hindquarters: mechanisms of increased vasoconstriction

A buffered solution was perfused at a constant flow rate (2 ml/min) through both iliac arteries in rat hindquarters. Perfusion pressures were measured in normal and collateralized vascular beds of the left and right hind-leg, respectively. Bolus injections of various agonists produced concentration-dependent increases in perfusion pressure in both collateralized and normal circulatory beds. Serotonin, in particular, and noradrenaline, to a lesser extent, produced more pronounced vasoconstriction on the collateral side than on the normal side. The difference in vasoreactivity to serotonin was related to a difference in both vascular structure and sensitivity of both types of vascular bed. Vasoconstriction induced by serotonin was inhibited by 5-HT2 antagonists. Selective blockade of alpha 1,alpha 2,beta 1-beta 2 adrenoceptors and amine uptake blockade were ineffective. This study indicates that, in rat hind-legs, the collateralized vascular bed is superreactive to serotonin in comparison with the normal bed. This resetting of reactivity to serotonin is due to the specific vascular structure as well as to an increased 5-HT2 receptor-mediated sensitivity.     

Interaction between naloxone and serotonin in the control of the cardiovascular system in hemorrhaged cats

We investigated the mechanism for the pressor effect of intravenous administration of naloxone in pentobarbital-anesthetized cats. Comparisons were made between groups of hemorrhaged animals that received either naloxone or an equivalent volume of saline after 1 h of hemorrhage. Two other groups of hemorrhaged animals were depleted of serotonin by pretreatment with para-chlorophenylalanine 40-48 h before the experiment. One group of serotonin-depleted animals received naloxone after 60 min of hemorrhage and the other group received saline. Animals with normal brain serotonin content showed a significant pressor effect following naloxone when compared with animals given saline. Animals with reduced brain serotonin content also had a pressor response following naloxone administration. Serotonin-depleted animals showed an increase in maximum left ventricular dP/dt following naloxone administration when compared to serotonin-depleted animals given saline. Our data are consistent with the hypothesis that naloxone can exert a pressor effect in hemorrhaged cats by actions at central and at peripheral sites. In cats with normal serotonin values, the peripheral action of naloxone is predominant. In serotonin-depleted animals given naloxone, central and peripheral sites contribute to the pressor effect.     

Role of central serotonin and melanocortin systems in the control of energy balance

Body weight homeostasis is critically dependent upon the convergence and integration of multiple central and peripheral signalling systems that collectively function to detect and elicit physiological and behavioural responses to nutritional state. To date, only a minority of these signals have been pharmacologically targeted for the treatment of human obesity. One signal that has been effectively manipulated to reduce body weight is the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT); however, the relevant downstream signalling pathways are incompletely understood. Recently, the melanocortin system, a nexus for multiple modulators of energy balance, has emerged as one key mediator of serotonin's effects on appetite. Here we review the serotonin and melanocortin systems with reference to their roles in energy balance and discuss the evidence that the two systems are functionally linked.     

Neurogenic mechanisms in control of the rabbit iris sphincter muscle

The iris sphincter muscle is supplied with cholinergic, adrenergic and substance P-containing nerve fibers, all with a possible role in the control of pupil size. The functional significance of the various nervous components in the rabbit iris sphincter muscle was examined in vitro and in vivo. The contractile response to electrical stimulation is composed of several contractions, occurring along different time scales. Single pulse stimulation produced an atropine-sensitive twitch. Pulse train stimulation revealed two successive atropine-sensitive twitches followed by a slow, long-lasting contraction, sensitive to Spantide, an antagonist of tachykinins such as substance P. A guanethidine- and phentolamine-sensitive contractile response to pulse train stimulation could be demonstrated in the presence of both atropine and Spantide. Only the Spantide-sensitive response could be completely exhausted by prolonged electrical stimulation. In vivo, neither the adrenergic nor the substance P-containing nerve fibres appeared to contribute to the miotic response to light since Spantide and guanethidine were without effect. This response was inhibited by atropine only.     

Plasticity mechanisms in vestibular compensation in the cat are improved by an extract of Ginkgo biloba (EGb 761).

The effects of administration of an extract of Ginkgo biloba (EGb 761) on vestibular compensation was studied in unilateral vestibular neurectomized cats. This experimental model of CNS plasticity was investigated by using behavioral tests (postural disorders compensation, locomotor balance recovery), electrophysiological (spontaneous and evoked neck muscle activity) and neurophysiological (spontaneous firing rate recovery of deafferented vestibular cells) recordings, and immunocytochemical methods (synaptic loss and synaptic reoccupation within the deafferented vestibular nuclei). In all experiments, EGb 761 was administered over 30 days at daily doses of 50 mg/kg IP. The results showed a faster recovery in the EGb-treated group of cats as compared to an untreated control group. EGb administration strongly accelerated postural and locomotor balance recovery. Concomitantly, spontaneous neck muscle activity, vestibulo-collic reflexes and spontaneous firing rate of vestibular units located on the lesioned side were restored earlier. Morphological correlates characterized by a more rapid synaptic reoccupation were found in the deafferented medial vestibular nucleus by means of immunoreactive labelling using an antibody against a synaptic vesicle-associated protein (synaptophysin), but they displayed a longer time-constant in comparison with the behavioral and neurophysiological data. These results clearly demonstrate that EGb 761 acts on recovery mechanisms considered as key processes in vestibular compensation. They suggest that this substance would possess neurotrophic and/or neuritogenic properties improving functional recovery after CNS injury.     

Effects of serotonin in failing cardiac ventricle: signalling mechanisms and potential therapeutic implications

Previously, cardioexcitation by serotonin (5-hydroxytryptamine, 5-HT) was believed to be confined to atria in mammals including man, and mediated through 5-HT₄ receptors in pig and man, but 5-HT_2A receptors in rat. Recent studies, reviewed here, demonstrate that functional 5-HT₄ receptors can be revealed in porcine and human ventricular myocardium during phosphodiesterase inhibition, and that 5-HT₄ receptor mRNA is increased in human heart failure. In rats, functional 5-HT₄ and 5-HT_2A receptors appear in the cardiac ventricle during heart failure and mediate inotropic responses through different mechanisms. 5-HT_2A receptor signalling resembles that from α₁-adrenoceptors and causes inotropic effects through increased myosin light chain phosphorylation, resulting in Ca²⁺ sensitisation. 5-HT₄ receptor signalling resembles that from β-adrenoceptors and causes inotropic effects through a pathway involving cAMP and PKA-mediated phosphorylation of proteins involved in Ca²⁺ handling, resulting in enhanced contractility through increased Ca²⁺ availability. Cyclic AMP generated through 5-HT₄ receptor stimulation seems more efficiently coupled to increased contractility than cAMP generated through β-adrenoceptor stimulation. Increasing contractility through cAMP is considered less energy efficient than Ca²⁺ sensitisation and this may be one reason why β-adrenoceptor antagonism is beneficial in heart failure patients. Treatment of heart failure rats with the 5-HT₄ antagonist SB207266 (piboserod) resulted in potentially beneficial effects, although small. Further studies are needed to clarify if such treatment will be useful for patients with heart failure.     

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

RationaleBased upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT_2A receptors, with serotonergic receptors of the 5-HT_1A and 5-HT_2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT_2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT_2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter.ObjectiveDetermine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice.MethodsSERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle.ResultsThe visual stimulus exerted control in both genotypes. LSD-induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital-induced stimulus control in 80% of WT mice and 54% of knockout mice.ConclusionsAlthough SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT_1A and/or 5-HT_2A receptors underlies the absence of stimulus control by LSD.