Central Serotonin Receptors Research Articles

8-Hydroxy-2-(alkylamino)tetralins and related compounds as central 5-hydroxytryptamine receptor agonists

A series of 2-(alkylamino)tetralins related to 8-hydroxy-2-(di-n-propylamino)tetralin (21) were prepared and tested as dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists. Several of the compounds were potent 5-HT agonists devoid of DA-mimetic effects. N-Ethyl or N-propyl substitution of 8-hydroxy-2-aminotetralin gave the most potent agonists. It was shown that the most potent compound, (+)-21, has the 2R configuration. 5,8-Di-methoxy-2-(di-n-propylamino)tetralin (31) was found to be a weak DA agonist devoid of 5-HT activity. The corresponding indan derivative, 4,7-dimethoxy-2-(di-n-propylamino)indan (39), has been reported to be active on both DA and 5-HT receptors. The 5-HT-stimulating properties of compounds 21 and 39 as compared to the incapability of compound 31 to activate the 5-HT receptor is tentatively explained by the assumed mode of binding of the compounds to the 5-HT receptor.

Influence of ergot derivatives on prolactin secretion in rats. Mechanisms of action and clinical implications

Ergot derivatives are the most effective compounds in the treatment of migraine attacks. It has been proposed that these compounds exert this effect by direct action on skull arteries or arteriovenous anastomoses, or by interfering with peripheral or central serotonin receptors. It is also possible that these compounds influence monoaminergic neurotransmission and, thereby, endorphins modulating the threshold for pain or sensory perception. In testing these hypotheses, changes in receptor sensitivity or function have to be considered since we have observed simultaneous tolerance and supersensitivity development in the same animal treated chronically with lisuride. We therefore propose that ergot derivatives can reduce the well documented higher sensitivity of migraine sufferers to various stimuli. In humans, prolactin-levels can be used for determining bioavailability of some ergot derivatives and for studying whether dopaminergic mechanism plays a role in their antimigraine effect.

Chemical denervation produces supersensitivity of central serotonergic receptors involved in the control of TSH secretion in the rat

m-Chlorophenylpiperazine, a serotonin receptor agonist, produced dose-related decrease of TSH plasma levels in the rat. This effect was prevented by a pretreatment with metergoline, a serotonin receptor blocker. Chemical destruction of central serotonin pathways, induced by intraventricular injection of 5,7-dihydroxytryptamine, significantly increased the TSH-inhibiting effect of m-CPP. These findings suggest the possible development of supersensitivity of central serotonin receptors involved in the control of TSH secretion.

Antagonism of vascular serotonin receptors by m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine

m-Chlorophenylpiperazine and m-trifluoromethylphenylpiperazine, two compounds that act as agonists at central serotonin receptors mediating certain neuroendocrine, behavioral and serotonin turnover effects, lacked appreciable agonist activity at serotonin receptors mediating contraction of the rat jugular vein. Instead, these compounds were potent antagonists of serotonin-induced contraction of the jugular vein. Apparently these non-indole compounds affect serotonin receptors in various tissues differently, being agonists in brain but mainly antagonists at some peripheral serotonin receptor sites.

Opioidergic regulation of thyroid activity: Possible interference with the serotonergic system

Acute systemic administration of ( d-Met 2, pro 5-NH 2)-enkephalin (ENKamide), a very potent enkephalin analog, and of morphine not only diminished the basal levels of serum TSH under resting conditions, but also significantly reduced the enhanced serum TSH concentrations induced by goitrogen treatment or by bilateral thyroidectomy. Acute administration of opiates failed to inhibit the pituitary TSH response to exogenous TRH administration. The TSH release-inhibiting effect of ENKamide was reversed by pretreatment with the serotonin synthesis inhibitor, parachlorophenylalanine (pCPA) or with the central serotonin receptor blocker, metergoline. These results furnish evidence in favour of the following concepts: (a) opioid compounds equally influence the tonic release of the TRH - TSH system under resting conditions, and also suppress the reactive changes of this circuit following specific loads, leading to an activation of this system; (b) opioids do not act directly at the pituitary level in inhibiting TSH secretion, but rather seem to suppress the release of TRH from the hypothalamus; (c) they may exert their inhibitory effect on the activity of the TRH - TSH - thyroid system by increasing the activity of the central nervous serotonergic system.

Ca2+-guanine nucleotide interactions in brain membranes. I. Modulation of central 5-hydroxytryptamine receptors in the rat.

Abstract: The present study indicates that central 5‐hydroxytryptamine (5‐HT; serotonin) receptors can be modulated in opposite directions by Ca2+ and guanine nucleotides [guanosine triphosphate (GTP), β, γ‐imidoguanosine 5′‐triphosphate (GppNHp)]. Thus CaCl2 (≥0.5 mm) inhibited whereas GTP and GppNHp (10 μm) stimulated the 5‐HT‐sensitive adenylate cyclase in the hippocampus of newborn rats. Both the affinity (Kd−1) and the number (Bmax) of [3H]5‐HT binding sites in hippocampal membranes from adult rats were increased in the presence of Ca2+ (≥0.25 mm); GTP (≥0.1 mm) and GppNHp (≥0.3; μm) produced reverse effects. The efficacy of guanine nucleotides in inhibiting specific [3H]5‐HT binding was counteracted by Ca2+: the addition of this cation (5mm‐CaCl2) to the assay mixture resulted in a 40‐fold increase in the IC50 for GTP; the IC50 for GppNHp increased five‐fold under the same condition. The examination of the respective effects of Ca2+ and of GTP on the specific binding of [3H]5‐HT to various hippocampal membrane preparations (from developing rats, from subcellular fractions of adult tissues, and from adult rats after the selective degeneration of serotoninergic innervation in the forebrain) indicated that the amplitudes of the Ca2+‐induced increase and of the GTP‐induced decrease were generally correlated. This conclusion did not apply to striatal membranes of kainic acid‐treated rats because [3H]5‐HT binding sites persisting after the intrastriatal injection of kainic acid (i.e., half of the total number in striatal membranes from control rats) were markedly less affected by GTP but at least as responsive as control membranes to the Ca2+‐induced increase. These data are compatible with the hypothesis of a possible coupling of some–but not all–[3H]5‐HT binding sites to adenylate cyclase in the rat brain.

On the prolactin-inhibiting effect of neurotensin. The role of dopamine.

Neurotensin (NT) when injected in a dose of 5 micrograms into the third cerebral ventricle of conscious, unrestrained male rats, outfitted with chronic third ventricle and jugular cannulae, decreased the resting prolactin (PRL) levels. NT (5 micrograms) also markedly inhibited the PRL-releasing effect of activation of central serotonin receptors by 5-hydroxytryptophan (5HTP, 15 mg/kg) in animals pretreated with fluoxetine (4 mg/kg). however, interruption of dopamine (DA) neurotransmission by either alpha-methyl-p-tyrosine (alpha MT, 250 mg/kg) or spiroperidol (0.3 mg/kg) led to a blockade of the PRL-inhibiting effect of NT. Treatment of animal with alpha MT prior to the injection of fluoxetine and 5HTP also blocked the PRL-inhibiting effect of NT. These results suggest that the central dopaminergic system mediates the PRL-inhibitory effect of NT.

Pharmacological evidence of supersensitivity of central serotonergic receptors involved in the control of prolactin secretion

m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, induced dose-related increases in plasma prolactin levels in the rat. This effect was significantly prevented by pretreatment with metergoline, a serotonin receptor blocker. Long-term degeneration of hypothalamic serotonin nerve endings induced by intraventricular injection of 5,7-dihydroxytryptamine, significantly enhanced the PRL-releasing action of m-CPP, as revealed by the shift to the left in the dose-response curve that relates the dose of m-CPP to plasma PRL levels. Thus the evidence suggests the possible development of supersensitivity of central serotonin receptors involved in the control of prolactin release.

Role of bulbar serotonergic neurotransmission in the initiation of swallowing in the rat

In rats anaesthetized with urethane and subjected to pharyngolaryngeal deafferentation, activation of central serotonin receptors was shown to evoke repetitive swallowing. Dose-response relationships were examined for the deglutitory effects of l-tryptophan, l-5-hydroxytryptophan ( l-5-HTP), quipazine (QPZ), chloro-piperazinyl-pyrazine (CPP), 5-methoxydimethyltryptamine (5-MeODMT) and tryptamine. Agonists could be grouped according to their efficacy in increasing either repetitive swallowing rate or buccopharyngeal deglutitory pressure. With respect to the former, the efficacy increased in the following order: 5-MeODMT, l-tryptophan < tryptamine, l-5-HTP < QPZ < CPP; with respect to the latter, it decreased in the order: 5-MeODMT, QPZ > l-5-HTP, l-tryptophan > tryptamine, CPP. The stimulatory effects on the swallowing rate were inhibited by methysergide, metergoline and d-lysergic acid diethylamide (LSD). The persistence of these effects after decerebration and their elicitation, upon close-arterial and topical drug administration to the fourth ventricle, implicate the rhombencephalon as the major locus of action. Serotonin agonists enhanced reflex deglutition elicited by electrical stimulation of the superior laryngeal nerve or the solitary tract. Antagonists blocked the facilitation of reflex swallowing at the same dose levels at which they abolished agonist-evoked swallowing; however, they failed to diminish maximal reflex responses. The data support the hypothesis that the neural substrate of serotonergically-evoked, “automatic” swallowing is organized within the rhombencephalon and operates to set a facilitatory bias for deglutitory internuncial neurones as well as effector motoneurones.

Hypersensitivity to central serotonin receptor activation in scrapie-infected hamsters and the effect of serotonergic drugs on scrapie symptoms

Low doses of the serotonin agonist, quizapine, and the serotonin precursor, l-5-hydroxytryptophan methyl ester, produce small but significant reductions in scrapie-induced ataxia and action jerks in hamsters. Higher doses of both drugs elicit a behavioral syndrome specific for central serotonin receptor activation. Scrapie-infected hamsters show a dramatic hypersensitivity to both drugs compared to control animals. This suggests that scrapie infection in hamsters causes a disturbance in the serotonergic pathway of the brain stem.

Two distinct central serotonin receptors with different physiological functions.

Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the "serotonin behavioral syndrome," indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.

On the mode of the prolactin release-inhibiting action of the serotonin receptor blockers metergoline, methysergide, and cyproheptadine.

Using animals with large electrolytic lesions of the median eminence-mediobasal hypothalamus, we confirmed earlier findings that metergoline (ME) and methysergide (MS) inhibit PRL secretion through activation of the dopamine receptors of the pituitary lactotrophs and established, in a quantitative manner, that their dopaminergic potencies are comparable to the potency of the dopamine receptor agonist, piribedil, with ED50 in the order of 0.35 to 0.22 mg/kg. Cyproheptadine (CYP), acting by an unknown mechanism, had only a weak inhibiting effect (ED50 greater than 20.0 mg/kg) in these experimental conditions. In the second part of the study, the PRL-inhibiting actions of ME, MS, CYP, and piribedil, respectively, were tested against the PRL release-stimulating effect of activation of the central serotonergic system that was induced by administration of a large dose of L-5-hydroxytryptophan (5HTP; 100 mg/kg), a small dose of 5HTP (15 mg/kg) in rats pretreated with fluoxetine, or by the serotonin receptor agonist quipazine (10.0 mg/kg, ip). The inhibiting potencies of ME (ED50 0.019, 0.014, and 0.048 mg/kg, respectively) against these three stimuli were much larger than in the lesioned animals or than the corresponding potencies of piribedil (ED50 2.2, 0.24, and 0.41 mg/kg, respectively). It is assumed that in these experimental conditions ME inhibited PRL release by blockade of the central serotonin receptors in addition to its dopaminergic effect and that at low doses (0.1 mg/kg or less) the entire inhibiting effect of ME was probably due to its antiserotonergic activity. With MS, which is a weaker serotonin receptor blocker than ME (ED50 0.178, 0.075, and 0.55 mg/kg, respectively, for the three serotonergic stimuli of PRL release), the antiserotonergic component in its PRL-inhibiting effect was evident but less clearly separable from the dopaminergic component in experiments with 5HTP and with fluoxetine plus 5HTP, whereas in experiments with quipazine the entire action could be accounted for by its dopaminergic activity. CYP was the least potent among the three blockers (ED50 0.6, 0.4, and 1.37 mg/kg, respectively, for the three serotonergic stimuli of PRL release), but appropriate tests indicated that it acted only as a serotonin receptor blocker and not by virtue of its antihistaminic, anticholinergic properties or by a direct action on the pituitary lactotrophs. SQ 10,631, another serotonin receptor blocker that was also tested, had no PRL-inhibiting activity. Because of the dual nature of the PRL-inhibiting mechanism of ME and MS and the low effectiveness of CYP, combined possibly with other actions, the serotonin receptor blockers have limited value in studies concerning the role of the central serotonergic system in the regulation of PRL secretion.

Transitional states of central serotonin receptors in Parkinson's disease.

Crude membrane preparations from the frontal cortex of controls and parkinsonian patients were used to demonstrate affinity changes of the specific 3H-5-hydroxytryptamine (5-HT) binding sites. Two such sites were notable in controls, a finding consistent with earlier observations. In Parkinson's disease, both high- and low-affinity sites are significantly decreased. Additional experiments either with prolonged incubation times or pre-incubation with N-ethylmaleimide change the two affinities to a single high-affinity or low-affinity constant. The concept of transitional states of 5-HT receptors is discussed and seems to have important implications in the treatment of parkinsonism.

Hyper- and hyposensitivity of central serotonin receptors: [ 3H]serotonin binding and functional studies in the rat

The effect of repeated treatment with d-fenfluramine, a serotonin releaser, or methergoline, a serotonin antagonist, on [ 3H]5-HT binding was studied in various rat brain areas. In animals with the same pretreatments, the anorectic activity of m-chlorophenylpiperazine, a serotonin agonist, was investigated. A 14-day treatment with d-fenfluramine caused a significant decrease in the number of [ 3H]5-HT binding sites (B max) in the diencephalon. A reduction of binding sites was found in the cortex too when d-fenfluramine was administered for 28 days. Methergoline caused no changes of [ 3H]5-HT binding in any brain area exmined when given for 14 days but 28-day treatment led to a significant increase in the striatum, hippocampus and cortex. d-Fenfluramine and methergoline caused, respectively, a decrease and increase in the effect of m-chlorophenylpiperazine on food intake. The data show that central 5-HT receptor numbers and sensitivity may change after repeated treatments with drugs acting on brain serotonin.

Pharmacological profile of a model for central serotonin receptor activation

The head shake response in rats after systemic administration of the serotonin (5HT) precursor 5-hydroxytryptophan (5HTP) was pharmacologically characterized and shown to be a useful animal model to quantify brain 5HT receptor activation. The behavior occurred in a dose-dependent manner after injection of 5HTP and the 5HT agonist quipazine. Head shakes were also observed after injection of L-tryptophan, 5-methoxydimethyltryptamine and fenfluramine. The 5HT antagonists cyproheptadine and metergoline were potent blockers of the response. Xylamidine, a peripheral 5HT antagonist, had no effect on head shaking. Inhibition of 5HT uptake with fluoxetine potentiated the head shake response after 5HTP. Manipulation of central cholinergic or GABAergic mechanisms did not alter 5HTP-induced shakes. Alpha-noradrenergic receptor blockade had no significant effect on head shakes. However, desmethylimipramine was equipotent with methysergide as an antagonist of the behavior. Beta-noradrenergic receptor blockade had no specific effect on 5HTP head shakes. Concomitant dopamine receptor activation with SK&F 38393 did not affect head shakes but the neuroleptics chlorpromazine and pimozide reduced the number of head shakes after 5HTP. The H 1 receptor antagonist pyrilamine had no effect on head shakes. It is concluded that 5HTP-induced head shakes in rats is a quantitative model of brain 5HT receptor activation which is particularly sensitive to 5HT antagonists.

Modification by levo-propranolol of tremors induced by harmine in mice.

It has been recently reported that the levo isomer of propranolol possesses anti-serotonin properties in animals. Since harmine-induced behavioural changes in mice are reported to be mediated through central serotonergic receptors, an attempt was made to test whether 1-propranolol would also modify harmine-induced responses by virtue of its anti-serotonergic or anti-adrenergic property. The results indicated that l- and dl-propranolol inhibited central serotonin receptor mediated responses to harmine in mice, a finding that is analogous to other recent observations.

Nature of the central serotonin receptors mediating hypotension.

The stimulation of central serotonin receptors leading to a decrease in blood pressure is well documented, but the nature of these receptors is not well known. It was therefore decided to characterize such receptors by assessing the modifications in blood pressure and heart rate after the intracerebroventricular administration of several drugs to anesthetized cats. Serotonin produced a dose-related decrease in blood pressure and heart rate, while parachloroamphetamine produced a slowly developing increase in blood pressure, and quipazine did not affect any of the parameters measured. The hypotension produced by serotonin was not modified by pretreatment with methysergide, was partially antagonized by quipazine, and was completely blocked by tolazoline. The present findings suggest that the central serotonin receptors which modulate blood pressure are different not only from peripheral receptors, but also from other receptors of this type.

On the Role of the Central Serotoninergic System in the Regulation of the Secretion of Thyrotropin and Prolactin- Thyrotropin-Inhibiting and Prolactin-Releasing Effects of 5-Hydroxytryptamine and Quipazine in the Male Rat*

Injection of 5-hydroxytryptamine (5-HT) into the third ventricle of unanesthetized, unrestrained rats induced a dose-related decrease of serum TSH and an increase of serum PRL. Quipazine, a 5-HT receptor stimulant, elicited similar hormonal changes when administered intraventricularly or systemically. The effects of quipazine were augmented in animals depleted of central 5-HT stores, presumably as a consequence of supersensitivity of central serotonin receptors, but they were abolished in rats with electrolytic lesions of the median eminence. Quipazine did not influence the stimulation of TSH secretion evoked by exogenous TRH. Methysergide, a 5-HT receptor blocker, had different effects on responses elicited by 5- HT or quipazine; while preventing TSH and PRL changes induced by intraventricular 5-HT and the rise of serum PRL by quipazine, it did not antagonize the effects of quipazine on TSH secretion. On the other hand, cyproheptadine, also a 5-HT receptor blocker, abolished the inhibitory effects of qui...

The central action of pizotifen.

The central action of the potential antidepressant drug pizotifen (Sandomigran) was studied in mice, rats and rabbits. Pizotifen in doses up to 10 mg/kg i.p. was ineffective in classic tests for antidepressant activity. It neither antagonized the effects of reserpine in rats (hypothermia, ptosis) nor potentiated the effects of amphetamine (in mice and rats), nialamide or L-dopa (in mice) on locomotor activity. However, its antidepressant activitiy was found in the 'despair test' in rats. On the other hand, pizotifen inhibited the head twitch reaction induced by L-5-hydroxytryptophan in mice (ED50 = 0.009 mg/kg, i.p.) and by 5-methoxytryptamine (+ tranylcypromine) in rats (ED50 = 0.45 mg/kg, i.p.). It also antagonized tryptamine-induced clonic convulsions of fore-paws in rats (ED50 = 0.35 mg/kg, i.p.), and in doses of 5--10 mg/kg s.c. inhibited hyperthermia produced by LSD in rabbits. Finally, pizotifen (0.1--0.3 mg/kg, i.v.) inhibited or abolished LSD- or quipazine-induced stimulation of the hind limb flexor reflex of spinal rats; the above effect was not due to noradrenolytic action of the drug. These results suggest that pizotifen strongly blocks the central postsynaptic serotonin receptors.

Lisuride and LSD: dopaminergic and serotonergic interactions in the "serotonin syndrome".

A characteristic behavioral syndrome has been associated with stimulation of central serotonin receptors in rats. This behavior can be produced by inhibition of monoamine oxidase and administration of 5-hydroxytryptophan as well as by direct acting serotonergic agonists. LSD and the novel ergot derivative lisuirde produced this syndrome in rats. These drugs possess both serotonergic and dopaminergic properties. Since changes in dopaminergic function have also been reported to affect the so-called serotonin syndrome, it was not clear how the two ergot drugs acted to produce this syndrome. The syndrome produced by pargyline and 5-hydroxytryptophan methyl ester was blocked by haloperidol, methysergide, parachlorophenylalanine, and alpha-methylparatyrosine; these treatments failed to block the effects of lisuride. Metoclopramide did not block the syndrome produced by either lisuride or pargyline plus 5-hydroxytryptophan methyl ester. Methysergide partially blocked the behavioral effects of LSD; pretreatment with either haloperidol or metoclopramide potentiated and prolonged the behavioral effects of LSD. The results suggest that dopaminergic modulation of the serotonin syndrome occurs before the serotonin receptor involved in this behavior. Also, the differences between LSD and lisuride may be relevant to their different psychopharmacological properties.