Age dependence of 5-methoxytryptamine-induced hindlimb scratching in rats

The influence of age on hindlimb scratching induced in rats by the serotonin agonist, 5-methoxytryptamine (5-MeOT), was studied. The 5-MeOT-induced scratching was strongest in 30-day-old rats and least in 90-day-old rats. Sex hormones do not play a role in these differences since treatment of young male rats with testosterone propionate did not change the scratching response. The same age dependence was found for female rats as for males.     

5-HT1C receptors in the serotonergic control of periaqueductal gray induced aversion in rats

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT_1C activity while RU 24969 differs with a high 5-HT_1A activity. Proaversive effects were found with the mixed 5-HT_1C/5-HT₂ antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT_1C/5-HT₂ antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT₂ antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT_1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT_1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT_1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT_1C receptors appear to play a predominant function.     

Beta-adrenoceptor blockade in rats enhances the ambulation induced by 5-HT1A receptor agonists

The mixed beta-adrenoceptor and 5-HT1A receptor antagonists, (-)-pindolol and propranolol, enhance rather than inhibit the hyperlocomotion induced in rats by the 5-HT1A receptor agonist, 8-OH-DPAT. The mechanism of this effect was now investigated. The rats were pretreated with the beta-adrenoceptor antagonist or saline and with the agonist 45 min later. Ambulation was quantified as the number of quadrants entered during a 15 min observation period. (-)-Pindolol, alprenolol, betaxolol, ICI 118,551 and a combination of betaxolol and ICI 118,551 (all at 1 mg/kg) significantly enhanced the locomotion induced by 8-OH-DPAT (0.24 mg/kg). Timolol (1 and 10 mg/kg) given 45 min before 8-OH-DPAT was inactive; however, given at 10 mg/kg 15 min prior to 8-OH-DPAT, the compound enhanced locomotion. (-)-Pindolol (1 mg/kg) also enhanced the locomotion induced by the putative selective 5-HT1A receptor partial agonists, flesinoxan and ipsapirone, but not that induced by 5-OH-DPAT, a DA2 receptor agonist. These results suggest that beta 1- or beta 2-adrenoceptor antagonism can enhance the locomotion induced by 5-HT1A receptor agonists. In the case of mixed 5-HT1A and beta-adrenoceptor antagonists, the beta-adrenoceptor-mediated effect may mask the inhibition of locomotion expected from 5-HT1A receptor antagonism.     

Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs

The effect of drug acting on 5-HT1A, 5-HT2 and 5-HT3 receptors were studied against cisplatin and apomorphine induced emesis in dogs. Buspirone, 5-HT1A receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency. Mianserin, 5-HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency. Buspirone prevented the apomorphine induced emesis while mianserin had no effect. The antiemetic activity of buspirone may be attributable to its agonistic activity at 5-HT1A receptor and antagonistic activity at dopamine receptors. These findings further confirm the involvement of 5-HT1A and 5-HT2 receptor in cytotoxic drug induced emesis, though the species difference in their antiemetic action can not be ruled out.     

Evidence for the involvement of the 5-HT1A receptor in CCK induced satiety in rats

The present study was designed to examine possible interactions between exogenous CCK and the 5-HT_1A receptor subtype mediated serotonergic effects on feeding in rats. The somatodendritic 5-HT_1A receptor agonist 8-OH-DPAT (0.32 mg/kg sc) evoked feeding in freely feeding rats. This effect was attenuated by treatment with CCK-8 (1, 5 and 25 g/kg ip). In food deprived rats, CCK-8 (40 g/kg ip) significantly reduced the size of a test meal. Treatment with the 5-HT_1A receptor antagonist WAY-100135 (10 mg/kg ip) antagonized this anorectic effect of CCK-8. WAY-100135 on its own did not affect food intake. These results suggest the involvement of the 5-HT_1A receptor subtype in mediating 5-HT-CCK interactions in the control of food intake in rats.     

5-HT1A receptor activity disrupts spontaneous alternation behavior in rats

Agonists selective for three different serotonin (5-HT) receptor subtypes were tested for the ability to disrupt spontaneous alternation behavior (SAB) in the CD strain of rats. Rats were scored for alternation or repetition in their choice of arms of a T-maze equally baited with chocolate milk. Compared with vehicle controls, the 5-HT(1A) agonist 8-hydroxy-dipropylaminotetraline (8-OH-DPAT; 2 mg/kg) significantly (P<.0001) increased repetitive choices (disrupted SAB). In contrast, intraperitoneal injections with the 5-HT(2) agonist R-(-)-dimethoxyiodophenylaminoethane (DOI; 1 mg/kg) or the 5-HT(3) agonist N-methyl quipazine (NMQ; 3 mg/kg) had no significant effect on SAB in CD rats. Onset of vicarious trial and error (VTE) behavior prolonged the time required for each rat to select an arm of the T-maze when injected with either 8-OH-DPAT (P<.0001) or buspirone (1-2 mg/kg), a 5-HT(1A) partial agonist. The disruption of SAB and the induction of VTE behavior were reversible with behavioral scores returning to preinjection levels within 48 h after injections. The disruption of SAB by 8-OH-DPAT was also seen with the Long-Evans rat strain. The results extend the use of the SAB model and point to a specific role of 5-HT(1A) receptors in the induction of repetitive behavioral patterns.     

The 5-HT1A receptor full agonist, 8-OH-DPAT inhibits ACTH-induced 5-HT2A receptor hyperfunction in rats: involvement of 5-HT1A receptors in the DOI-induced wet-dog shakes in ACTH-treated rats

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.     

Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists,antagonists or antidepressants

The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT_1A receptor mediated lower lip retraction (LLR), 5-HT_1C receptor mediated penile erections (PE) or 5-HT₂ receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT_1A and 5-HT₂ receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT_1C receptor mediated behaviour remained unchanged. The ED₅₀ for the 5-HT_1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1mg/kg/day) pretreated rats. The number of 5-HT₂ receptor mediated (±)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT_1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED₅₀ for 8-OH-DPAT induced LLR (ED₅₀ values were 0.06 and 0.14 mg/kg, respectively, in placebo — and tranylcypromine — pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT_1C and 5-HT₂ receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT_1A and 5-HT₂ but not 5-HT_1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT_1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed.     

The functional change in the 5-HT1A receptor induced by stress and the role of the 5-HT1A receptor in neuroprotection]

Mice exposed to various stresses, especially restrained-stress, revealed the anxiogenic effect detected by the light-dark test. Under this condition, a remarkable decrease in [35S]GTPgammaS binding to membranes from the prefrontal cortex, amygdala and hypothalamus of restrained-stress mice stimulated by the selective 5-HT1A receptor agonist 5-carboxamidotriptamine (5-CT) was clearly observed, whereas a significant increase in [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist was clearly observed in the dorsal raphe nuclei (DRN) of restrained-stress mice. The immunohistochemical study showed a drastic reduction in phosphorylated-CREB-like immunoreactivity in the DRN of restrained-stress mice. Furthermore, we found a drastic reduction in myelin-associated glycoprotein (MAG)-like immunoreactivity (MAG-IR) in the DRN, amygdala and hypothalamus, indicating the direct suppression of synaptic transmission in these regions. It has been accepted that GSK3beta in the Wnt signal pathway plays an important role in various neuronal functions including apoptosis, clustering of synapsin I and early growth and axonal remodeling. In the present study, the increase in protein levels of GSK3beta and phosphorylated-GSK3beta to cytosol fractions of the amygdala was noted in restrained-stress mice. Taken together, these results suggest that restrained stress may directly affect the 5-HT1A receptor-regulated synaptic transmission in the brain, leading to the expression of the anxiogenic effect in mice. It is well known that various stresses induce intracellular oxidative stress. The present study was then undertaken to investigate the effect of the stimulation of 5-HT1A receptors on oxidative stress. Treatment with H2O2 caused the activation of caspase-3-positive cells and the reduction in levels of MAG-IR in the limbic neuron/glia cocultures as compared to medium alone. The stimulation of 5-HT1A receptor by 5-CT produced a dramatic protection against H2O2-triggered activation of caspase-3 and reduction in levels of MAG-IR. These results suggest that 5-HT1A receptors were involved in the modulation of anxiety and the understanding of molecular mechanisms of 5-HT1A receptor-related cascades may pave the way for new therapeutic strategies for affective disorders.     

5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms

Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. In this paper, studies focusing on anxiety using 5-HT1A receptor knockout (1AKO) and 5-HT1B receptor knockout (1BKO) mice are reviewed. 1AKO mice on different genetic background strains have initially been described as more anxious. In 1AKO mice on the 129/Sv background strain, the initial findings could not always be replicated, although under certain conditions, mild anxiety-like responses were observed in these 1AKO mice. In 1BKO mice, some indications of reduced anxiety have been found, but these observations may be confounded partly with increased motor impulsivity of these mutants. To study whether the putative effects of the null mutations on anxiety were reflected in the autonomic nervous system, basal heart rate and body temperature of 1AKO and 1BKO mice were measured, as well as their autonomic responses to novel cage exposure and to reversal of the light-dark rhythm. 1AKO mice did not differ from wild-type mice in any parameter, neither under non-stress conditions, nor following novel cage exposure. In 1BKO mice, basal heart rate was reduced and body temperature was increased. 1BKO mice showed exaggerated autonomic responses to novel cage stress. Adaptation to the reversal of the light-dark cycle was comparable in the three genotypes. The stress-induced hyperthermia procedure showed no differential responses of the three genotypes to the stressor. Pharmacological responses to various psychotropic drugs in the stress-induced hyperthermia test were also comparable in 1AKO, 1BKO and wild-type mice. The present data illustrate the complexity of studying the behavioural and physiological consequences of deletion of genes coding for important receptors in the CNS.     

Ligand-5-HT1A receptor interaction

In the present paper the general structure and pharmacophore of some 5-HT1A receptor ligands are described. For several compounds (approximately 15) the intrinsic activity in lower lip retraction (postsynaptic, rat) and hypothermia (presynaptic, mice) tests was determined. For the identified functional presynaptic agonists and antagonists the influence on the brain serotonin level was examined. No direct correlation between the functional intrinsic activity and the influence on the level was observed. Molecular modelling revealed the possibility of the existence of different binding sites for different examined compounds.     

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.     

5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4–5] décane-7,9 dione), is a high affinity full 5-HT_1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10^–8 M affinity for D₂ dopamine (DA) receptors, 100 fold lower than for 5-HT_1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 µg/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT_1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT_1A receptor antagonist tertatolol (2–5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT_1A agonist property opposes to that of D₂ dopamine receptor stimulation with regard to yawning and penile erections.     

Ejaculatory response induced by a 5-HT2 receptor agonist m-CPP in rats: differential roles of 5-HT2 receptor subtypes

It has been reported that systemic administration of m-CPP (1-[3-chlorophenyl] piperazine hydrochloride), a 5-HT(2) receptor agonist, produces a 5-HT(2C) receptor-mediated penile erections and self-grooming in rats. In the present study, we examined the ability of m-CPP to induce ejaculation in rats and determined which 5-HT(2) receptor subtypes may be involved in the m-CPP-induced ejaculation. The ejaculatory response was assessed by weighing the seminal materials accumulated over 30 min. In Experiment 1, systemic administration of m-CPP (0.1-3.0 mg/kg, i.p.) produced a dose-dependent increase in both the incidence of ejaculation and the weight of the seminal materials. The inverted U-shaped dose-response effects of m-CPP on penile erection and genital grooming were also observed, with maximum effects at 0.6 mg/kg. Pretreatment with SB242084 (0.1 and 0.3 mg/kg, i.p.), a selective 5-HT(2C) receptor antagonist, dose-dependently attenuated the ejaculatory response induced by m-CPP (3.0 mg/kg). The proejaculatory effect of m-CPP was also attenuated by ketanserin (0.3 and 1.0 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, whereas SB204741 (0.1 and 0.3 mg/kg, i.p.), a selective 5-HT(2B) receptor antagonist, significantly potentiated the m-CPP-induced ejaculatory response. Penile erection and genital grooming induced by m-CPP (0.3 mg/kg, i.p.) was only blocked by SB242084. In Experiment 2 (termed as corset test), in rats fitted with a corset at the thoracic level to prevent the loss of seminal materials by genital grooming, the proejaculatory effect of m-CPP was more efficiently detected than in the non-fitted animals: the ED(50) value for inducing ejaculation was reduced to less than 50% of the ED(50) in non-fitted animals. In this test, the proejaculatory effect of m-CPP (0.6 mg/kg, i.p.) was completely blocked by SB242084 (0.3 mg/kg, i.p.), whereas ketanserin (0.3 mg/kg, i.p.) or SB204741 (0.3 mg/kg, i.p.) did not affect the m-CPP -induced ejaculation. From these observations, it is suggested that the 5-HT(2) receptor agonist m-CPP at low doses (0.3-1.0 mg/kg) possesses the proejaculatory as well as proerectile effects in rats that are primarily associated with the activation of 5-HT(2C) receptors, and that the activation of 5-HT2B receptors may produce an inhibitory effect on ejaculation induced by a high dose (3.0 mg/kg) of m-CPP. Furthermore, the results of the present study also indicate that the corset test employed in this study may be useful for detecting the proejaculatory effect of the compounds.     

The evidence for the involvement of the 5-HT1A receptor in 5-HT syndrome induced in mice by tryptamine

The involvement of the 5-HT1A receptor in the 5-HT syndrome (head weaving and hindlimb abduction) induced in DBA mice by tryptamine was investigated. Methysergide, (-)propranolol and spiperone suppressed both the head weaving and hindlimb abduction induced by tryptamine. However, ketanserin and ICS 205-930 did not affect them. Haloperidol induced small decreases in the head weaving, but had no effect on the hindlimb abduction. These results indicate that the 5-HT syndrome induced by tryptamine in mice is mediated by the 5-HT1A receptor. Therefore, 5-HT syndrome may also be associated with the 5-HT1A receptor in mice, as it is in rats.     

Ligand induced conformational states of the 5-HT(1A) receptor

It has been shown that G-protein coupled receptors have seven transmembrane alpha-helices, but the structural changes occurring in a G-protein coupled receptor as a response on agonist stimulus and the molecular events leading to blockade of the signal transduction by antagonists are not well understood. In the present study, the AMBER 5.0 force field was used for comparative molecular dynamics simulations of a 5-HT(1A) receptor model in the absence of ligand, in complex with a 5-HT(1A) receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-8-OH-DPAT], in complex with a selective 5-HT(1A) receptor antagonist (S)-N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl ]-2-phenylpropanamide [(S)-WAY100135], and in complex with the partial agonist, buspirone. In the simulations, the agonist induced larger conformational changes into transmembrane helix 3 and 6 than into the other helices, while the main conformational differences between the agonist bound receptor and the antagonist bound receptor were in transmembrane helix 5 and 6. During the simulations, all the three ligands constrained the helical movements compared to those observed in the receptor without any ligand.     

Selective reduction by serotonergic agents of hypertonic saline consumption in rats: evidence for possible 5-HT1C receptor mediation

Previously, it has been shown that, in small doses, putative 5-HT_1A receptor agonists selectively increase ingestion of hypertonic saline without affecting either water or isotonic saline intake. Evidence was obtained in the present series of experiments for selective reduction in hypertonic saline following the administration of a variety of serotonergic directly- and indirectly-acting agonists. Water, isotonic saline (0.9%), or hypertonic saline (1.8%) were made available to separate groups of water-deprived rats. The results indicated some selectivity with the 5-HT-uptake inhibitor and releaser d-fenfluramine and the 5-HT uptake inhibitor fluoxetine, and with the 5-HT agonists mCPP [1-3-chlorophenyl)piperazine] and MK 212 [6-chloro-2-(1-piperazinyl)pyrazine]. In each case, hypertonic intake was significantly suppressed. Distinct from these compounds were TFMPP [1-(3-(trifluoromethyl)phenyl)piperazine], RU 24969 [5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)1H-indole], and quipazine. This second group either reduced fluid intake indiscriminately or reduced water and isotonic saline drinking. Selective reduction in the intake of hypertonic saline did not occur. Finally, peripheral-administration of 5-HT or the 5-HT_1B agonist CGS 12066B [7-trifluoro-methyl-4(4-methyl-1-piperazinyl-pyrolo) (1,2-a) 12 maleate], had no significant effect on fluid intake in any fluid condition. The results are discussed in terms of a possible serotonergic mechanism which may underlie inhibition of hypertonic salt drinking, and which involves mediation through a subtype of the 5-HT₁ receptor.     

Antihypertensive effect of 5-HT1A agonist buspirone and 5-HT2B antagonists in experimentally induced hypertension in rats

We investigated the antihypertensive effect of 5-HT1A agonist (buspirone) and 5-HT2B antagonists (SB204741 and SB200646) in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats. Experiments were divided into two sets: in the first set, sham-operated control and DOCA-treated hypertensive rats received buspirone (1 mg/kg/day p.o. for 4 weeks) and in the second set, in vivo and in vitro studies were carried out. In the case of in vivo studies, sham-operated control and DOCA-treated hypertensive rats received SB204741 or SB200646 (1 mg/kg/week i.v. for 4 weeks). Blood pressure was measured weekly by tail-cuff method. After completion of the treatment schedule, blood pressure and vascular reactivity to various agonists like 5-HT, noradrenaline and adrenaline were recorded. Chronic administration of buspirone, SB204741 and SB200646 produced a significant reduction in blood pressure and vascular reactivity to agonists in DOCA-salt hypertensive rats, implying an antihypertensive effect. However, chronic administration of the same drugs in sham control rats did not alter blood pressure and vascular reactivity to various agonists. For in vitro studies a similar treatment schedule was followed as in vivo studies and a cumulative concentration response curve of 5-HT was recorded on isolated thoracic aorta. Treatment with 5-HT2B antagonists shifted the concentration response curve of 5-HT to the right on isolated aorta. We conclude that 5-HT1A agonist and 5-HT2B antagonists possess an antihypertensive effect.     

Characterization of mechanisms involved in presynaptic inhibition of sympathetic pressor effects induced by some 5-HT1 receptor antagonists

1. In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT1A and 5-HT1D receptor subtypes. At the time, we observed that some 5-HT1 receptors antagonists - WAY 100,635 and NAN-190 (both 5-HT1A receptor antagonists), methiothepin (a 5-HT1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT1,2 receptor antagonist) - reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2. The inhibition induced by WAY 100,635 (1000 microg kg-1, i.v.) was blocked after i.v. treatment with idazoxan, an alpha2-adrenoceptor antagonist (300 and 1000 microg kg-1) and was not modified after i.v. treatment with propranolol, a beta-adrenoceptor antagonist (1000 microg kg-1) and sulpiride, a D2 receptor antagonist (1000 microg kg-1). The inhibition induced by spiperone (500 microg kg-1 i.v.) was significantly blocked by sulpiride (1000 microg kg-1) and was not modified by idazoxan or propranolol. 3. Sulpiride (1000 microg kg-1) partially blocked the inhibition induced by methiothepin (50 microg kg-1 i.v.). Only pretreatment with idazoxan (300 microg kg-1) modified the inhibition induced by NAN-190 (100 microg kg-1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4. All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5. The above results suggest that the inhibitory effects of these 5-HT1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT1 receptor antagonist studied.     

5-HT_(2B)受体阻断剂对心肌肥厚大鼠心肌5-HT含量及5-HT_(2B)受体表达的影响

目的观察5-HT2B受体阻断剂对去甲肾上腺素(norepinephrine,NE)诱导的心肌肥厚大鼠心肌中5-羟色胺(5-hydrotriptamine,5-HT)含量及5-HT2B受体表达的影响。方法雄性SD大鼠24只,随机分为3组,8只/组,分别为对照组、肥厚组、实验组。采用腹腔注射NE(1.5 mg/kg,2次/d,28 d)的方法建立心肌肥厚模型,自第15天起实验组腹腔注射SB204741(5-HT2B受体阻断剂;2 mg/kg,2次/d),连续注射14 d。对照组腹腔注射相同体积的生理盐水(2次/d,28 d)。检测各组左心室重量与体重之比(LVW/BW)、心肌组织中5-HT的含量及5-HT2B受体的表达情况。结果在NE诱导心肌肥厚过程中,应用SB204741干预可显著减轻心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。结论应用5-HT2B受体阻断剂可减轻NE诱导心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。