Ritanserin Research Articles

Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition

The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D1 receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D2 receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT2A/C receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT2A/C receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D2 receptors and that dopamine D2 receptors participate in attention processes.

A serotonin receptor antagonist induces oocyte maturation in both frogs and mice: Evidence that the same G protein‐coupled receptor is responsible for maintaining meiosis arrest in both species

Accumulating evidence has indicated that vertebrate oocytes are arrested at late prophase (G2 arrest) by a G protein coupled receptor (GpCR) that activates adenylyl cyclases. However, the identity of this GpCR or its regulation in G2 oocytes is unknown. We demonstrated that ritanserin (RIT), a potent antagonist of serotonin receptors 5-HT2R and 5-HT7R, released G2 arrest in denuded frog oocytes, as well as in follicle-enclosed mouse oocytes. In contrast to RIT, several other serotonin receptor antagonists (mesulergine, methiothepine, and risperidone) had no effect on oocyte maturation. The unique ability of RIT, among serotonergic antagonists, to induce GVBD did not match the antagonist profile of any known serotonin receptors including Xenopus 5-HT7R, the only known G(s)-coupled serotonin receptor cloned so far in this species. Unexpectedly, injection of x5-HT7R mRNA in frog oocytes resulted in hormone-independent frog oocyte maturation. The addition of exogenous serotonin abolished x5-HT7R-induced oocyte maturation. Furthermore, the combination of x5-HT7R and exogenous serotonin potently inhibited progesterone-induced oocyte maturation. These results provide the first evidence that a G-protein coupled receptor related to 5-HT7R may play a pivotal role in maintaining G2 arrest in vertebrate oocytes.

The effect of fluoxetine on thermal hyperalgesia in STZ-induced diabetic mice: possible involvement of 5-HT1/2 receptors

Diabetic neuropathic pain, an important micro vascular complication in diabetes mellitus, has been recognized as one of the most difficult types of pain to treat. Lack of understanding of etiology involved, inadequate relief, development of tolerance and potential toxicity of classical anti-nociceptive agents warrants the investigation of newer agents to relieve this pain. The aim of the present study was to explore the anti-nociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (STZ, 200 mg/kg). After 4 weeks of a single intraperitoneal injection of STZ, diabetic mice were subjected to tail-immersion and hot plate assay. Diabetic mice exhibited a significant hyperalgesia as compared to control mice. When diabetic mice were injected with fluoxetine (10 and 20, but not 5 mg/kg, i.p.) produced anti-nociceptive effect in both tail immersion and hot plate assays. The %MPE produced by fluoxetine (20 mg/kg/i.p) was significantly less in diabetic mice as compared with that in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT1A/1B receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT2A/2C receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/kg, i.p., a selective 5-HT3 receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT1 and 5-HT2 receptors, but not through 5-HT3 receptors in chronic pain associated with STZ-induced diabetic neuropathic pain. Furthermore, the potentiation of anti-nociceptive effect of fluoxetine by pindolol indicates the usefulness of combination of an antidepressant and a 5-HT1A/1B receptor antagonist in therapy of human diabetic neuropathic pain.

L‐thyroxine affects involvement of H1, 5‐HT2, prostaglandin receptors and the endothelial NO system in allergic vascular response in guinea pigs

AbstractDysfunction of the vascular system is involved in anaphylactic shock from antigen challenge. Chronic L‐thyroxine (Thy) administration induces cardiac remodeling and multiple ion channelopathies which contribute to exacerbated cardiac arrhythmias and a change in vascular responses. We measured the changes in the allergic vascular response in a Thy model. The allergic vascular response developed rapidly by exposure to antigen with two components, a peak observed at 4 min and a declining second phase. In the Thy group, the peak was reduced and the tone in the second phase increased. The H1 receptor blocker diphenhydramine (DPH) reduced the peak tension in both control and Thy groups, but increased the second phase in control and decreased the second phase in the Thy group. No effect of the H2 blocker (famotidine) was observed. The 5‐HT2 receptor antagonist ritanserin (RTS), the COX inhibitor indomethacin (IDM), and the lipoxygenase inhibitor caffeic acid (CFA) were more effective inhibitors in the Thy groups relative to the control group. Nitro‐L‐arginine (NLA), which is an NO synthase (NOS) inhibitor, enhanced peak tension in control, but not in the Thy group. The peak tension in the control group was also increased following hemoglobin (HB), which inactivates the NO pathway, by methylene blue (MTB), which suppresses cGMP formation, and by saponins, which destroy the endothelium. However, the same procedures were without effect in the Thy group. L‐Arginine, an NO donor, produced a larger reduction of peak of tension in the Thy group relative to the control group. In conclusion, suppression of allergic vascular responses by DPH, RTS, CFA, and IDM was enhanced in the Thy model and the enhancement of these responses by NLA, HB, and MTB was abolished in this group. Drug Dev. Res. 58:125–130, 2003. © 2003 Wiley‐Liss, Inc.

Anxiolytic effect of ting-chih-wan in mouse behavior models of anxiety.

The anxiolytic effect of the alcoholic extract of ting-chih-wan (TCWa) was studied using the black and white test (BWT) and the elevated plus-maze (EPM). We further demonstrated the anxiolytic mechanism of TCWa by combining with diazepam (DIZ), serotonin (5-HT) agonists or antagonists, and measuring the levels of monoamines and its metabolites in the brain stem and cortex. In the BWT, TCWa (0.1-1.0 g/kg, p.o.) increased the time spent in the white chamber and total change between the two chambers, and decreased the time spent in the black chamber. TCWa (0.1-0.5 g/kg, p.o.) increased the arm entries and the time spent on the open arms, and decreased the arm entries and the time spent on the closed arms in the EPM. On the other hand, TCWa (1.0 g/kg, p.o.) decreased horizontal activity and prolonged pentobarbital-induced sleeping times. TCWa (0.1, 0.5 g/kg) decreased the levels of norepinephrine (NE), dopamine (DA), 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) and increased the levels of vanillylmandelic acid (VMA) and homovanillic acid (HVA) in the brain stem. TCWa (0.1 and 0.5 g/kg) decreased the levels of NE, DA and increased the levels of VMA and HVA in the cortex. TCWa also attenuated the anxiogenic effect of 5-hydroxytryptophan (5-HTP) and enhanced the anxiolytic effect of 9p-chlorophenylalanine (PCPA), buspirone (BUS) and ritanserin (RIT) in the EPM. From these results, TCWa at 0.1 and 0.5 g/kg possessed an anxiolytic effect T heanxiolytic mechanisms of TCWa might be due to decreased catecholaminergic activity caused by the increase in the turnover rate of catecholamines in the brain and decreased concentrations of 5-HT in the brain stemvia activating somatodendritic 5-HT1A autoreceptors and inhibiting postsynaptic 5-HT receptors.

Behavioral and Neuroendocrine Assessment of Ritanserin Exposure in the Developing Chicken: Lack of Toxicity at Effective Doses

The 5-HT 2 antagonist ritanserin (RIT) is undergoing Phase III clinical trials for the treatment of substance abuse disorders. RIT has also shown preclinical therapeutic potential for attenuating or blocking lethal and/or toxic effects of exposure to cocaine or the selective 5-HT 2 agonist dimethoxyiodophenyl-aminopropane (DOI) in the developing chicken. To assess the potential toxicity (“side effects”) of RIT itself during development, we exposed chicken embryos to 0, 0.1, 0.3, 0.9, or 2.7 mg RIT/kg egg by injecting the drug into eggs with 14-day-old embryos (E14). Voltage generated by spontaneous embryonic activity (motility) was measured on E15 to assess short-term effects of RIT; none were observed. There was no overall effect of these RIT doses on hatchability, though sample sizes were small ( n = 13–15 per group). One to 2 weeks after hatching, chicks’ acquisition of a detour learning response was tested. There were no observable effects of any RIT dose on detour learning. To assess potential effects of RIT on responsiveness to stress, some chicks were exposed to isolation stress approximately 3 weeks after hatching and killed 15 min later. Blood was assayed for serum corticosterone. There was no effect of any embryonic RIT dose on corticosterone concentrations in nonstressed subjects. Although corticosterone was elevated in all stressed groups, the group exposed to the highest embryonic RIT dose (2.7 mg/kg egg) showed a stress-induced elevation greater than other groups. Thus, except for the highest RIT dose (six to seven times greater than a therapeutically effective dose used in earlier work), embryonic RIT exposure on E14 had no effect on embryonic behavior, hatchability, posthatch learned behavior, and basal serum corticosterone concentrations. At a supraefficacious dose it appears to have modified the responsiveness of the neuroendocrine axis to mild stress.

Relationships Between Midembryonic 5-HT 2 Agonist and/or Antagonist Exposure and Detour Learning by Chickens

The importance of serotonin (5-HT) as both a transmitter and a regulatory signal during development of many species is well established. The availability of 5-HT receptor subtype agonists and antagonists will enable pharmacological dissection of the importance of one or more of the 5-HT receptors for their involvement in the mediation of developmental insults by drugs that are less selective but include actions upon serotonergic function. Such insults include exposure to cocaine or opiate withdrawal, both of which are blocked or attenuated by 5-HT 2 antagonists. The 5-HT 2 receptor agonist dimethoxyiodophenylaminopropane (DOI), like cocaine, causes vasoconstriction during embryogenesis, herniated umbilici in hatchlings, and altered detour learning by young chickens after injection into eggs at late stages of embryogenesis. The 5-HT 2 antagonist ritanserin (RIT) blocks or significantly attenuates these effects. This study describes an effect of DOI on posthatch detour learning when injected earlier during embryogenesis (i.e., on embryonic day 12, E12) which is opposite its effect when injected later (i.e., on E15). Both effects are blocked by an inactive dose of RIT (0.3 mg/kg egg) and by a higher dose of RIT (0.9 mg/kg egg), which itself retards posthatch detour learning following E12 injection. Thus, excessive stimulation or blockade of 5-HT 2 receptors around midembryogenesis can cause a similar behavioral teratogenic outcome. The data are discussed in relation to the likelihood that potential use of 5-HT 2 antagonists for treating pregnant women and their fetuses who are not at risk is nil.

Study on the suitability of a rat model for tardive dyskinesia and the preventive effects of various drugs

1. 1. Male Sprague-Dawley rats (weighing 260–300 g) were administered 1.5 mg/kg of haloperidol (HPD) intraperitoneally once daily for 28 days to produce an animal model for tardive dyskinesia (TD). The daily administration of HPD significantly increased the frequency of involuntary orofacial movements (chewing movements, tongue protrusions and buccal tremors). 2. 2. Its suitability as a model for TD was assessed in terms of the therapeutic effects of 6 drugs [trihexyphenodyl hydrochloride(THP), clonazepam(CZP), sodium valproate(VPA), α-tocopherol (Vit E), ritanserin(RS) and propranolol hydrochloride(PPL)]. These drugs were also used concomitantly with HPD to study their preventive effect. 3. 3. As for the therapeutic effects of the drugs, both the single and the 14-day daily administrations of CZP as well as of VPA significantly suppressed the chewing movements. The results were mostly consistent with the effect of each drug on human TD, indicating this would be an excellent model for TD in terms of the drug responsiveness. 4. 4. The concomitant administration of RS from the start of HPD administration significantly suppressed the appearance of chewing movements. The concomitant administration of Vit E for 42 days also suppressed chewing movements and buccal tremors. On the other hand, the concomitant administration of THP tended to aggravate these involuntary movements. 5. 5. The fact that the therapeutic and preventive effects of the drugs on this model differed suggested that the development and recovery of the movements might also differ, at least in part.

Partial inhibition of reverse tolerance by a high dose of ritanserin or low dose of haloperidol in methamphetamine-sensitized rat.

To clarify the implication of antagonism of serotonin (5-HT)2 receptors in the treatment of schizophrenia, the effects of ritanserin (RIT) on the development of reverse tolerance in rats repeatedly administered methamphetamine (MAP) were investigated and compared with those of low doses of haloperidol (HPD). RIT administered at a dose of 2 mg/kg and low doses of HPD (0.05, 0.1 mg/kg) shared partial inhibition of the development of reverse tolerance in MAP-sensitized rats; the drugs inhibited sniffing but not head moving and had no effect on locomotion or rearing. A combination of low doses of HPD and RIT resulted in the inhibition of head moving. These results suggested that strong antagonism for 5-HT2 receptors would be useful to some extent to treat MAP-induced psychosis and schizophrenia as well as weak antagonism of dopamine D2 receptors, and that a combination of these two actions would produce better results in these psychoses than that obtained from D2 antagonism alone. In the presence of 0.05 mg/kg of HPD, RIT caused increased locomotion and rearing, whereas it decreased them in the presence of 0.1 mg/kg of HPD. This result suggested that the interactions between 5-HT and dopamine (DA) neurons are complex, and that 5-HT2 antagonism may inhibit or disinhibit DA neurons depending on the level of D2 blockade.

Ritanserin blocks DOI-altered embryonic motility and posthatch learning in the developing chicken

Developing chicken embryos exposed to cocaine show altered motility, hatchability, and posthatch detour learning. Pretreating such subjects with the serotonin 2 (5-HT 2) antagonist ritanserin (RIT) can block the motility suppression and reduced hatchability, indicating 5-HT 2 receptor involvement in these cocaine effects. To study behavioral consequences of more selective 5-HT 2 receptor stimulation and its blockade during development and to compare such exposure with that of cocaine, we injected eggs with 15-day-old chicken embryos with the 5-HT 2 agonist dimethoxyiodophenylaminopropane (DOI, 1.0 mg/kg egg) and 1 h later, with RIT (0.3 and 0.9 mg/ kg egg). Motility was recorded 2.5 or 24 h after DOI. This DOI dose suppressed motility 2.5 h but not 24 h after administration. Both RIT doses blocked DOI's motility suppression. No treatment affected hatchability. Subjects were tested on posthatch days 6–9 for detour learning acquisition. DOI “enhanced” learning (i.e., reduced latency), a cocaine-like effect observed in prior work, which was also blocked by both RIT doses. Thus, some consequences of DOI exposure late during embryonic development resemble cocaine's and are blocked by RIT, suggesting a therapeutic role for RIT-like drugs against cocaine's potential developmental toxicity.

Excessive stimulation of Serotonin 2 (5-HT 2) receptors during late development of chicken embryos causes decreased embryonic motility, interferes with hatching, and induces herniated umbilici

The existence and functional significance of 5-HT 2 receptors in chicken embryos was studied by injecting the selective agonist dimethoxyiodophenylaminopropane (DOI), alone or in conjunction with the selective 5-HT 2 antagonist ritanserin (RIT), into domestic chicken eggs with embryos of varying ages. DOI caused dose-dependent reductions in hatchability and herniated umbilici in hatchlings. These effects were observed after injection early, mid, or late during embryonic development, with evidence of the toxic effects of DOI being greater in older embryos, probably due to 5-HT 2 receptor activation late in development, even after injecting DOI as early as on day 3 of embryogenesis. This is based upon the fact that embryos in eggs injected with DOI early continued to develop apparently normally, failing to hatch, often after pipping their shells. Additionally, those that hatched often did so with herniated umbilici, as did late-exposed embryos, indicating that DOI's effects upon this organ were most likely mediated during the prehatching period (i.e., days 18–20). The agonist's selectivity was confirmed by the capacity of RIT to dose dependently block both of these toxic effects of DOI. Reduced embryonic motility monitored on day 19, after injection of DOI on the evening of day 18, suggests that excessive activation of 5-HT 2 receptors late during development of this species interferes with some normal embryonic behaviors and physiological changes neccessary for inducing and/or maintaining the hatching process.

Effects of ritanserin, a specific serotonin-S2 receptor antagonist, on the release of anterior pituitary hormones during insulin-induced hypoglycemia in normal humans

The role of serotonin in the insulin hypoglycemia (IH) stimulated secretion of prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH) and cortisol (F) was studied in a group of 12 normal subjects during the control period after placebo and a consecutive six-day treatment with 20 mg ritanserin (RIT) per day. RIT failed to affect the baseline levels of all the four hormones as well as the PRL response to IH (p > 0.5). The serum GH response to IH was moderately diminished after RIT, the reduction of integrated trapezoidal area under hormone curves (nAUC) being 50.7% +/- 6.9% (p < 0.005). Furthermore, RIT was found to slightly decrease the plasma ACTH response to IH, the reduction of nAUC being 36.3% +/- 2.6% (p < 0.005). Decrease in the corresponding plasma F response to IH was accompanied by 29.1% +/- 2.4% reduction of nAUC (p < 0.005). According to our results, serotonin-S2 receptors appeared to be moderately involved in IH-induced release of GH, but slightly in that of ACTH, leaving unaffected that of PRL.

Effects of ritanserin, a novel serotonin-s2 receptor antagonist, on the secretion of pituitary hormones in normal humans

The availability of a new potent and selective serotonin-S2 antagonist, ritanserin (RIT), encouraged us to further investigate the effect of serotonin on the basal secretion of anterior pituitary hormones in normal humans. Administered in a single 30-mg dose to group 1 consisting of 10 normal women, RIT failed to affect the baseline LH, FSH, GH or TSH levels. In group 2 consisting of 20 normal subjects (ten males and ten females), the same dose of RIT decreased in parallel both ACTH and cortisol levels but only at 180 min. Group 3 consisting of 8 normal men was studied on three separate occasions seven days apart: each subject received graded doses of 10 mg, 20 mg and 30 mg RIT. The mean baseline PRL concentration at 180 min as well as the net integrated area under the hormone curve (nAUC) decreased only after the highest dose, while the baseline cortisol concentrations at 180 min as well as the corresponding nAUC values displayed a clear dose-dependent response. The findings indicated the serotonin-S2 receptors to be only partially involved in the basal secretion of ACTH in normal humans.

The effect of acute pharmacological manipulation of central serotonin neurotransmission on osmoregulated secretion of arginine vasopressin in the rat.

To explore the hypothesis that serotonin (5-HT) is important in osmoregulated arginine vasopressin (AVP) secretion, we administered (i.p.) fluoxetine (FL) a 5-HT reuptake inhibitor (10 mg/kg body weight), ritanserin (RIT), an antagonist at the 5-HT2 and 5-HT1c receptor subtypes (1 mg/kg body weight), 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2 receptor agonist (1 mg/kg body weight) or vehicle to rats 30 min before they were given an osmotic challenge. Rats received distilled water, normotonic saline (150 mmol NaCl/l) or hypertonic saline (500 mmol NaCl/l) (20 mg/kg i.p.) and were killed 30 min later. The osmotic stimulus alone produced significant (P < 0.001) effects on plasma osmolality and plasma sodium but FL, RIT and DOI did not have any significant effect on this stimulus. FL had no significant effect on the osmotic threshold of AVP release but significantly (P < 0.001) increased basal AVP secretion from 1.6 +/- 1.0 to 3.1 +/- 1.3 (S.E.M.) pmol AVP/l and significantly (P < 0.001) increased the AVP response to changes in plasma osmolality: vehicle-treated, 0.7 +/- 0.4; FL-treated, 1.7 +/- 0.2 pmol AVP/l per mOsm per kg. Neither RIT nor DOI had any significant effect on basal or stimulated AVP secretion. In a second study, RIT was administered 60 min i.p. prior to FL i.p. (doses as above), which was followed 30 min later by a hypertonic stimulus i.p. and rats were killed 30 min after hypertonic saline treatment. RIT had no significant effect on the AVP response to plasma osmolality and did not significantly alter the FL-augmented AVP response, suggesting that neither the 5-HT2 nor the 5-HT1c receptors are involved in the response of AVP to FL. We conclude that FL modulates osmoregulated AVP secretion but that the mechanism of this is unknown and is apparently not through the 5-HT2 or 5-HT1c receptor subtypes.

Effect of ritanserin, specific 5HT–2 antagonist, on PRL secretion in normal subjects and in different hyperprolactinaemic conditions

The availability of a new specific anti 5HT-2 compound, ritanserin (RTS), led us to further investigate the role of serotonin in controlling PRL secretion. The drug was administered to normoprolactinaemic subjects and to patients with differing hyperprolactinaemic conditions. While RTS failed to modify PRL levels in normoprolactinaemic subjects and in patients with PRL-secreting pituitary adenomas, a marked decrease in the hormone was obtained in patients with functional and puerperal hyperprolactinaemia. The lack of effect of RTS in PRL-secreting pituitary adenomas suggests that the reported suppression of PRL by other antiserotoninergic drugs, such as metergoline, is probably due to their concomitant dopaminergic activity.

Ritanserin in the treatment of neuroleptic-induced akathesia

Ritanserin in the treatment of neuroleptic-induced akathesia