Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857)

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).     

Effect of chronic treatment with 5-hydroxytryptophan on cortical serotonin receptors in the rat

L-5-Hydroxytryptophan (5-HTP) is a clinically useful antimyoclonic drug that is thought to act at serotonin (5-HT) receptors after decarboxylation to 5-HT. However, the chronic effects of 5-HTP on central 5-HT receptors and the activity of 5-HTP at 5-HT receptor subtypes have not been previously reported. In rats treated 28 but not 7 consecutive days with high doses of 5-HTP (50-200 mg/kg), cortical 5-HT2 (-20%) and 5-HT1 (-11%) sites were downregulated without altered receptor affinity, but only the changes in 5-HT2 sites were significant. In naive frontal cortex in vitro, however, 5-HTP and 5-HT were more active at 5-HT1 sites, and 5-HTP was inactive at 5-HT2 sites. The differential effects of high-dose 5-HTP on 5-HT receptors suggest that 5-HT2 receptor downregulation may be relevant either to the antimyoclonic effect of chronic 5-HTP therapy in posthypoxic myoclonus or to development of tolerance.     

L-5HTP treatment and serum 5-HT level after L-5-HTP loading on depressed patients.

Based on 5-HT hypothesis, L-5-HTP (150 or 300 mg/day) was given orally to 18 depressed patients. The global estimates were 2 very much improved; 8 much improved; 3 minimally improved, and 5 unchanged. The action of L-5-HTP was usually rapid. The elevation of the serum 5-HT level 1 week after L-5-HTP administration was relatively lower in the 5-HTP nonresponder group, compared with the responders. The chronological change of the serum 5-HT level in depressed patients after an oral loading dose of 3 mg/kg of L-5-HTP showed a gradual and slight elevation, compared with manic and normal groups. It seemed that the therapeutic effect of L-5-HTP on responders was related to lower 5-HT level in the brain for their pathogenesis, and that there was a metabolic disturbance of L-5-HTP into 5-HT in some depressed patients.     

Evidence that the 5-HT1A autoreceptor is an important pharmacological target for the modulation of cocaine behavioral stimulant effects

The psychostimulant effects of cocaine critically depend on the serotonergic (5-HT) system, of which the 5-HT1A receptor is an essential component. We recently showed divergent contributions of various pre- and postsynaptic 5-HT1A receptor populations to the behavioral effects of cocaine. Here, we further investigate the role of 5-HT1A autoreceptors in the acute and chronic stimulant effects of cocaine using 5-HT1A receptor ligands in autoreceptor preferring doses. In experiment 1, four groups of rats (N = 10) received either saline or the 5-HT1A agonist, 8-OHDPAT (0.05 mg/kg) 20 min prior to a saline or cocaine (10 mg/kg) injection on 9 consecutive days. In experiment 2, six groups (N = 10) were given either saline, the 5-HT1A antagonist, WAY 100635 (0.05 mg/kg) or 8-OHDPAT (0.05 mg/kg) plus WAY 100635 (0.05 mg/kg) 20 min before a saline or cocaine (10.0 mg/kg) treatment on 9 consecutive days. Initially, both the 8-OHDPAT and WAY 100635 pretreatments completely blocked the locomotor stimulant effects of cocaine whereas the combined 8-OHDPAT plus WAY 100635 pretreatment had no effect. In saline treated groups, neither the WAY 100635 nor the 8-OHDPAT plus WAY 100635 pretreatment influenced spontaneous activity levels, whereas the 8-OHDPAT alone severely reduced spontaneous activity. These effects persisted over the course of the 9 test sessions. A different pattern of results was obtained for the cocaine treatment groups. With repeated treatments, the WAY 100635 treatment always blocked the locomotor activation effect of cocaine, whereas the effects of 8-OHDPAT were transformed from an inhibition to an enhancement of cocaine locomotor stimulation. The combined 8-OHDPAT plus WAY 100635 pretreatment did not affect the stimulant effect of cocaine. These findings demonstrate that low dose autoreceptor preferring treatments with a 5-HT1A agonist and antagonist can strongly modify the behavioral stimulant effects of cocaine and suggest that the 5-HT1A autoreceptor may be an important pharmacological target for the development of treatments for cocaine addiction.     

5-hydroxytryptamine in the central nervous system and sexual receptivity of female rhesus monkeys.

The role of 5-hydroxytryptamine (5-HT) in the control of sexual receptivity in female rhesus monkeys has been studied in 24 adult females paired with 6 adult males. p-Chlorophenylalanine (PCPA, 75 mg/kg or 100 mg/kg, every fourth day), a selective inhibitor of 5-HT, was found to reverse unreceptivity induced by adrenalectomy in ovariectomised, oestrogen-treated females. PCPA-treated females presented more frequently and initiated more sexual behaviour, or else they refused fewer of the male's attempts to mount. These effects were in turn reversed by 5-hydroxytryptophan (5-HTP, 20 mg/kg every second day), when this was given to PCPA-treated animals. In addition, 5-HTP given alone to ovariectomised oestrogen-treated females reduced their receptivity. Parallel biochemical experiments showed that PCPA in the doses used lowered the levels of 5-HT in the brain as measured by the levels of 5-hydroxyindole-3-acetic acid (5-HIAA) in the CSF, and that these were restored by 5-HTP. Both oestradiol benzoate (15 mug/day for 10 days) and testosterone propionate (250 mug/day or 400 mug/day for 10 days) lowered the turn-over rates of 5-HT in the brain (as measured by the probenecid test) in ovariectomised female monkeys. These effects of oestradiol on turnover were antagonised by progesterone (15 mg/day for 10 days, given with oestradiol). A substance other than an adrenal androgen has thus been found to reverse the effects of adrenalectomy on sexual receptivity in female monkeys. It is therefore possible that androgens regulate receptivity in female monkeys by modifying the activity of 5-HT-containing neural systems.     

Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat

The present study re-evaluated an existing notion that serotonin (5-hydroxytryptamine; 5-HT) could not cross the brain to the circulating blood via the blood-brain barrier (BBB). To elevate brain 5-HT alone, 5-hydroxytryptophan (5-HTP; 30-75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5-HT after 5-HTP administration). A microdialysis method and HPLC system were used to determine the brain 5-HT levels in samples collected from the frontal cortex. Blood 5-HT levels were determined from whole blood, not platelet-poor plasma, collected from the central vein. We found that blood 5-HT levels showed a significant augmentation whenever brain 5-HT levels were significantly elevated after the administration of 5-HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5-HT levels remained augmented. These results indicate that augmented brain 5-HT can cross the BBB through the 5-HT transporter from the brain to the circulating blood.     

Estradiol and progesterone influencel-5-hydroxytryptophan-induced myoclonus in male guinea pigs: Sex differences in serotonin-steroid interactions

The effects of castration in males and sex differences in the effects of estradiol and progesterone on L-5-hydroxytryptophan (L-5-HTP)-induced myoclonus in guinea pigs were examined. Castration had no effect on L-5-HTP-induced myoclonus in males. There were sex differences in sensitivity to L-5-HTP. In the absence of steroids, L-5-HTP-induced myoclonus was higher in gonadectomized males than females. A low dose of estradiol benzoate (EB; 3.5 micrograms) given 46 h before L-5-HTP (100 mg/kg) enhanced myoclonus in gonadectomized females but not males. However, at a higher dose of EB (10 micrograms) and a lower dose of L-5-HTP (80 mg/kg), myoclonic responding was enhanced in males. These findings indicate that estradiol has a similar effect on L-5-HTP-induced myoclonus in males and females, but do not rule out the possibility of sex differences in sensitivity to L-5-HTP when both sexes are given estradiol priming. When L-5-HTP was given 6 h after 0.5 mg progesterone in estradiol-primed males, myoclonus was enhanced. Progesterone treatment reverses the facilitative effect of EB on L-5-HTP-induced myoclonus in females. Therefore, progesterone has opposite effects on L-5-HTP-induced myoclonus in males and females. These findings were discussed with respect to the interaction of steroids and 5-HT transmission in the regulation of steroid-dependent reproductive behavior.     

Parathion (O,O-dimethyl-O-p-nitrophenyl phosphorothioate) induces pineal melatonin synthesis at night

The effects of parathion on male rat pineal N-acetyltransferase (NAT) activity, hydroxyindole-O-methyltransferase (HIOMT) activity and pineal and serum melatonin levels at the end of light period (2000 h) and at night (2300 h and 0100 h) were studied. Additionally, pineal levels of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were estimated. Parathion was administered intragastrically at total doses (over 6 days) of either 6.5 or 13 mg/kg. Control rats received vehicle (corn oil) only. During the study, the rats were exposed to light:dark cycles of 14:10 with light off at 2100 h. Pineal NAT activity was increased at 0100 h following parathion administration at both doses, but HIOMT activity was unaffected. Pineal and serum melatonin levels were increased at night (2300 h and 0100 h) after the 13 mg/kg dose of parathion while the lower dose increased pineal melatonin only at 0100 h. Also, both doses decreased 5-HTP at 2000 h while the lower dose increased it at 2300; 5-HT was significantly decreased at 2300 h and 5-HIAA levels were lower but only significantly so for the 13 mg/kg dose at 2000 h. The results indicate that parathion has significant effects on pineal melatonin synthesis by mechanisms which remain unknown.     

Effects of chlorimipramine and protriptyline on the hyperactivity induced by 5-hydroxytryptophan after peripheral decarboxylase inhibition in mice

Summary DL-5-HTP in doses from 100 mg/kg is reported to increase the spontaneous motor activity in mice pretreated with L--hydrazino--methyl--(3, 4-dihydroxyphenyl)-propionic acid (MK-486), an inhibitor of peripheral aromatic aminoacid decarboxylase. Exogenously administered 5-HTP gives rise to accumulation of 5-HT in both central 5-HT-and catecholamine-neurons. The stimulant effect of DL-5-HTP may be mediated via increased activation of 5-HT receptors or, via displacement, increased activation of catecholamine receptors. In the present experiment pre-treatment with chlorimipramine, 25 mg/kg concomitant with MK-486 markedly potentiated the stimulant effect of DL-5-HTP on motor activity,i.e. the dose response curve was shifted to the left. DL-5-HTP, 75 mg/kg, induced in these animals a pronounced increase of the motor activity but had no significant effect on the brain concentrations of DA or NA. Pre-treatment with protriptyline-HCl, 25 mg/kg, concomitant with MK-486 did not potentiate the stimulant effect of DL-5-HTP. The results indicate that the DL-5-HTP induced motor activity is largely dependent on an increased activation of central 5-HT receptors.     

Functional meaning of tryptophan-induced increase of 5-HT metabolism as clarified by in vivo voltammetry

Differential pulse voltammetry with carbon fiber electrodes was used to study serotonin (5-HT) metabolism in freely moving rats. The electrodes implanted in the striatum recorded the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak after oral tryptophan (150 mg/kg). This 5-HT precursor did not modify the 5-HIAA peak in any rat tested, but it raised 5-HIAA levels determined in total tissue by a classical biochemical method (HPLC). The administration of 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.) induced an increase of 5-HIAA detectable both in the extracellular medium by voltammetry and in tissue samples. As previously shown, dorsal raphe electrical stimulation raises extracellular 5-HIAA in the striatum and this effect is enhanced by pretreatment with tryptophan. The results suggest that tryptophan in 'normal' conditions enhances 5-HT metabolism without affecting 5-HT release unless such release is stimulated. 5-HTP increases 5-HT metabolism and release.     

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.     

Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils

The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.     

Effect of 5-HTP and ketanserine on the aggressive reaction induced by food competition in dominant and submissive pigeons (Columba livia)

There is abundant literature about the effects of manipulation of 5-hydroxytryptamine (5-HT) systems on some killer behaviors as well as on social isolation and shock-induced aggression in rodents. In this work we have analyzed the effect of 5-HT manipulation on the aggressive behavior induced by food competition in undernourished pigeons. Adult males (n = 12) were caged individually and their body weight kept at 80-85% by a restricted diet. These were divided in pairs which were exposed daily to an aggressive interaction test (20 min) in a 1.5 x 1.5 x 2.0 m chamber bearing a central feeding device. Once consolidation of dominance was obtained in each pair, the dominant and the submissive members were injected subcutaneously, on alternating days, with 5-hydroxytryptophan (5-HTP) (7.5, 15 and 30 mg/kg), ketanserine (20 and 30 mg/kg) and a combination of ketanserine (20 mg/kg) and 5-HTP (7.5 mg/kg). Aggression was evaluated by scoring the frequency and time spent biting, wing beating, aggressive following and vocalizations, threatening and pushing the opponent in 20-min tests. The time spent running away was also scored. Intratest feeding was ascertained by weighing the subjects immediately before and after testing. The scores were compared with those obtained after saline injection on the preceding day (C-scores). 5-HTP (7.5 mg/kg) attenuated aggression without affecting feeding in dominant members, and decreased the time spent running away by submissives. Higher doses of 5-HTP decreased feeding but did not potentiate the anti-aggressive effects. The 5-HT2 antagonist, ketanserine did not affect aggression but decreased feeding at the dose of 30 mg/kg. Ketanserine injection clearly prevented the anti-aggressive effects of 5-HTP but caused a decrease of feeding. Results show that 5-HT stimulation in pigeons can preferentially block aggression in this particular experimental situation. It is suggested, in addition, that 5-HT2 receptors might be involved in such an effect.     

In vivo and in vitro studies on the effect of the serotoninergic system on luteinizing hormone and luteinizing hormone-releasing hormone secretion in prepubertal and peripubertal female rats

The present investigations were designed to assess the effect of the serotoninergic system on luteinizing hormone (LH) and LH-releasing hormone (LH-RH) secretion in female rats aged 14 and 30 days. The administration of 5-hydroxytryptophan (5-HTP; 75 mg/kg i.p.) increased hypothalamic serotonin (5-HT) concentrations in both age groups, and did not affect hypothalamic norepinephrine (NE) concentrations or release. Serum LH levels were raised by 5-HTP in 14-day-old, but not in 30-day-old rats. Basal and KCl- (28 mM) stimulated LH-RH release by incubated hypothalamic fragments was significantly enhanced when 5-HTP was injected previously to 14-day-old animals. In 30-day-old rats, 5-HTP treatment did not modify basal LH-RH release, and decreased the KCl-stimulated LH-RH output. Similarly, the addition of 5-HT (10(-7) M) to superfused hypothalamic fragments enhanced basal LH-RH release in 14-day-old rats and blocked the increment in LH-RH release evoked by KCl in 30-day-old rats. The present results show that in 14-day-old female rats, the serotoninergic system (activated in vivo by 5-HTP treatment, or in vitro by 5-HT addition) exerts a stimulatory effect on LH-RH, and thus, on LH release. On the contrary, in 30-day-old animals, stimulated LH-RH secretion was inhibited by 5-HT. Apparently, the hypothalamic NE system is not implicated in this response. The participation of this changing effect of 5-HT on LH-RH/LH release at the onset of puberty is postulated.     

Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats.

The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.     

Cocaine and serotonin: a role for the 5-HT(1A) receptor site in the mediation of cocaine stimulant effects.

Cocaine induced locomotor stimulant effects are generally attributed to cocaine effects on brain dopamine. In this report, we present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and the 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cycylhexanecarboxaminde maleate (WAY 100635) can enhance or block, respectively, the locomotor stimulant effects induced by cocaine. In two separate experiments, rats administered cocaine (10 mg/kg) exhibited a locomotor stimulant effect and decreased grooming behavior compared to saline treated rats. Pretreatment with the 5-HT(1A) agonist, 8-OHDPAT (0.2 mg/kg) enhanced and pretreatment with the 5-HT(1A) antagonist, WAY 100635 (0.4 mg/kg) eliminated the locomotor stimulant effect of cocaine. Neither the 8-OHDPAT nor WAY 100635 effects were attributable to effects on the behavioral baseline. The 8-OHDPAT and WAY 100635 had opposite effects on grooming behavior. 8-OHDPAT decreased and WAY 100635 increased grooming. Neither treatment, however, affected the grooming suppression induced by cocaine. Ex vivo biochemical measurements indicated that neither 8-OHDPAT or WAY 100635 affected brain dopamine metabolism or cocaine availability in brain. Both treatments affected 5-HT metabolism and altered the effect of cocaine on 5-HT metabolism. 8-OHDPAT increased and WAY 100635 decreased cocaine effects on 5-HT metabolism. Cocaine and 8-OHDPAT but not WAY 100635 increased corticosterone. Altogether, these findings indicate that the 5-HT(1A) receptor site may be an important target for the development of pharmacotherapies for the treatment of cocaine abuse.     

Measurement of 5-hydroxyindole compounds during L-5-HTP treatment in depressed patients.

L-5-hydroxytryptophan (L-5-HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for antidepressive effects of the agent. A relatively small dose, 150mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate emelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5-hydroxyindole compounds, 5-HTP, 5-HT and 5-HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5-HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5-HIAA. Excretion levels of these compounds in urine were not consistenly altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5-HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5-HT and 5-HIAA in urine, and lower plasma levels of 5-HT than responders. Administered L-5-HTP may not be fully utilized in the depressed patients who did not react to the agent.     

Estradiol and progesterone influence a serotonin mediated behavioral syndrome (myoclonus) in female guinea pigs: Comparison with steroid effects on reproductive behavior

L-5-hydroxytryptophan (L-5-HTP)-induced myoclonus was used as a behavioral index of central serotonergic activity. Estradiol benzoate (EB) and progesterone (P) influenced the induction of myoclonus by L-5-HTP. When L-5-HTP was injected 46 h after EB, myoclonus was enhanced. P blocked this effect on EB when 100 or 125 mg/kg L-5-HTP (but not 80 mg/kg) was given 6 h after P in EB-primed animals. When L-5-HTP was given 3 or 11-15 h after P in EB-primed animals, there was no inhibitory effect of P on myoclonus. In fact, at the lowest dose (80 mg/kg), L-5-HTP increased myoclonus when given 3 h after P in EB-primed animals. The inhibitory effects of P in EB-primed females on myoclonus were temporally correlated with the display of lordosis, suggesting that the neural progestin receptor mechanisms that have been proposed to mediate P effects on lordosis are also involved in the inhibitory effects of P on myoclonus.     

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat

Summary Copulatory behavior in the ovariectomized rat, the lordotic response (L. R.), was induced by estrogen followed by progesterone. L. R. is inhibited by lysergic acid diethylamide (LSD) (0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L. R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine₂ (5-HT₂) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L. R., and the doses required (0.05–0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT₂ receptors.     

Serotonin involvement in the blockade of bulbospinal inhibition of the spinal monosynaptic reflex.

Bulbospinal inhibition of the extensor quadriceps monosynaptic reflex (MSR) was antagonized by the serotonin precursor, 5-hydroxytryptophan (5-HTP, 75 mg/kg), in unanesthetized, mid-collicular, decerebrate cats. Fluoxetine HCl (Lilly 110140, 0.25 - 6 mg/kg), a specific serotonin neuronal uptake blocker, also blocked this inhibition as well as bulbospinal inhibition of the flexor posterior biceps-semi-tendinosus MSR. The serotonin antagonist, cyproheptadine HCl (5 mg/kg), partially reversed the above blocking actions of 5-HTP and fluoxetine and enhanced bulbospinal inhibition when administered alone in doses of 2.5-5 mg/kg. Imipramine HCl (0.125 - 4 mg/kg) was more potent in antagonizing bulbospinal inhibition of the dorsal root-ventral root MSR when administered intra-arterially to the spinal cord than when injected intra-arterially to the brain stem or intravenously, indicating that the spinal cord is the site of imipramine's action. These results support our earlier proposal that a 5-HT system antagonizes bulbospinal inhibition of the MSR. They also indicate that the 5-HT system is tonically active and exerts its blocking action in the spinal cord.