Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.

As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.

Effect of 5-HT(2A) receptor antagonists on blood flow in the carotid vessels upon elevation of serotonin level.

We studied the ability of predominantly 5-HT2A receptor antagonists to prevent a serotonin-induced change of blood flow in the carotid vessels of rats with experimental serotonin-induced spasm. Ritanserin, ketanserin, and 5-HT2A receptor antagonist RU-476 reduced the effect of serotonin on the blood fl ow velocity in the internal carotid artery by 2.3, 1.7, and 2.6 times, respectively.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

Influence of Withania somnifera on obsessive compulsive disorder in mice.

OBJECTIVE: To study the influence of methanolic and aqueous extract of Withania somnifera (W. somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior. METHODS: Mice were divided in different groups (n = 6). Fluoxetine (5, 10, 15 mg/kg), (10, 25, 50, 100 mg/kg) and methanolic extract W. somnifera (MEWS) (10, 25, 50, 100 mg/kg) were administered i.p. 30 min. prior to the assessment of marble burying behavior and locomotor activity. The control group received vehicle of the extract. RESULTS: Administration of aqueous extracts W. somnifera (AEWS) and MEWS (50 mg/kg) successively decreased the marble burying behavior activity without affecting motor activity. This effect of AEWS and MEWS was comparable to standard fluoxetine, ritanserin and parachlorophenylalanine. CONCLUSIONS: W. somnifera extract is effective in treating obsessive compulsive disorder.

Influence of Withania somnifera on obsessive compulsive disorder in mice

OBJECTIVE@#To study the influence of methanolic and aqueous extract of Withania somnifera (W. somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior.@*METHODS@#Mice were divided in different groups (n = 6). Fluoxetine (5, 10, 15 mg/kg), (10, 25, 50, 100 mg/kg) and methanolic extract W. somnifera (MEWS) (10, 25, 50, 100 mg/kg) were administered i.p. 30 min. prior to the assessment of marble burying behavior and locomotor activity. The control group received vehicle of the extract.@*RESULTS@#Administration of aqueous extracts W. somnifera (AEWS) and MEWS (50 mg/kg) successively decreased the marble burying behavior activity without affecting motor activity. This effect of AEWS and MEWS was comparable to standard fluoxetine, ritanserin and parachlorophenylalanine.@*CONCLUSIONS@#W. somnifera extract is effective in treating obsessive compulsive disorder.

Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors.

RATIONALE: After reports of adverse effects with hormone replacement therapy, such as reproductive and breast cancer and coronary heart disease, much attention has been given to the development of new remedies to alleviate menopausal depression in women, but methods for their preclinical evaluation have not been clarified. We previously developed a procedure to predict the drug effect on the menopausal depressive-like state in female mice. OBJECTIVES: We attempted to identify psychoactive components from ginseng root, one of the earliest known materials for menopausal disorder, and to clarify the possible mechanism involved. METHODS: As an index of a depressive-like state, we used the prolongation of immobility time induced by an ovariectomy during the forced swimming test. Chronic treatment with the candidate substance began the day after ovariectomy and continued for 14 days. To examine whether the 5-HT(2A) receptor antagonist ritanserin antagonized the antidepressant-like effect of ginsenoside Rb(1), ritanserin was given as pretreatment 15 min before the daily administration of ginsenoside Rb(1) and the antagonistic effect was compared with ginsenoside Rb(1) alone. RESULTS: Ginsenoside Rb(1) and compound K were active ingredients that dose-dependently prevented the prolongation of immobility time induced by ovariectomy. Co-administration of ritanserin, a 5-HT(2A)-receptor antagonist, antagonized the effect of ginsenoside Rb(1). CONCLUSIONS: We suggest that ginsenoside Rb(1) and its metabolite, compound K, are antidepressant-like components of the ginseng root, and that 5-HT(2A) receptors may play an important role in mediating the antidepressant-like effect of ginsenoside Rb(1).

Role of growth hormone-releasing hormone in sleep and growth impairments induced by upper airway obstruction in rats.

Upper airway obstruction (UAO) can lead to abnormal growth hormone (GH) homeostasis and growth retardation but the mechanisms are unclear. We explored the effect of UAO on hypothalamic GH-releasing hormone (GHRH), which has a role in both sleep and GH regulation. The tracheae of 22-day-old rats were narrowed; UAO and sham-operated animals were sacrificed 16 days post-surgery. To stimulate slow-wave sleep (SWS) and GH secretion, rats were treated with ritanserin (5-HT(2) receptor antagonist). Sleep was measured with a telemetric system. Hypothalamic GHRH, hypothalamic GHRH receptor (GHRHR) and GH receptor, and orexin were analysed using ELISA, real-time PCR and Western blot. UAO decreased hypothalamic GHRH, GHRHR and GH receptor levels, while orexin mRNA increased (p<0.01). In UAO rats, the duration of wakefulness was elevated and the duration of SWS, paradoxical sleep and slow-wave activity was reduced (p<0.001). Ritanserin alleviated these effects, i.e. normalised hypothalamic GHRH content, decreased wake duration, increased duration and depth of SWS, and attenuated growth impairment (p<0.001). Here, we present evidence that growth retardation in UAO is associated with a reduction in hypothalamic GHRH content. Our findings show that abnormalities in the GHRH/GH axis underlie both growth retardation and SWS-disorder UAO.

Ameliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats.

The aim of the present study was intended to investigate the ameliorating effects of emodin on memory consolidation via cholinergic, serotonergic and GABAergic neuronal systems in rats. First, we evaluated the ameliorating effects of emodin on cycloheximide (CXM)-induced impairment of passive avoidance response in rats. Secondly, we clarified the role of cholinergic, serotonergic or GABAergic system on the ameliorating effect of emodin by using 5-HT1A receptor partial agonist, 5-HT2 receptor antagonist, GABAB agonist, GABAA antagonist and muscarinic receptor antagonist. Emodin protected the rat from CXM-induced memory consolidation impairment. The beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by 8-OH-DPAT (5-HT1A receptor partial agonist) and ritanserin (5-HT2 receptor antagonist), but reduced by scopolamine. These results suggested that the beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by serotonergic 5-HT1A-receptor partial agonist and 5-HT2 receptor antagonist but reduced by muscarinic receptor antagonist.

The ameliorating effect of the water layer of Fructus Schisandrae on cycloheximide-induced amnesia in rats: interaction with drugs acting at neurotransmitter receptors.

Our previous study indicated that the water layer present in Fructus Schisandra(FS(w)) at 10 and 25 mg kg(-1)significantly counteracted cycloheximide (CXM)-induced amnesia. Therefore, the mechanism of action of the ameliorating effect of FS(w)on CXM-induced amnesia in the passive avoidance task was investigated in rats. The ameliorating effect of FS(w)on CXM-induced amnesia was depressed by scopolamine. The serotonin releaser, p -chloroamphetamine significantly antagonized the ameliorating effect of FS(w)on CXM-induced amnesia. Furthermore, the ameliorating effect was also inhibited by the 5-HT(1A)receptor agonist 8-OH-DPAT, but potentiated by the 5-HT(2)receptor antagonist ritanserin. Finally, the GABA(A)receptor antagonist bicuculline blocked the ameliorating effect of FS(w). These results suggest that the beneficial effect of FS(w)on CXM-induced amnesia is amplified by treatment with serotonergic 5-HT(2)receptor antagonists, but reduced by serotonergic 5-HT(1A)receptor agonists as well as GABA(A)and cholinergic receptor antagonists.

The Role of 5-HT Receptors on the Acetylcholine Release from the Rat Striatum / 대한정신약물학회지

The aim of this study was to investigate the role of the 5-HT receptors in acetylcholine (ACh) release from the striatum. Slices from the rat striatum and synaptosomes were incubated with [3H]-choline and the release of the labelled products was evoked by electrical (3 Hz, 2 ms, 5 V/cm, rectangular pulses, 2 min) and potassium-stimulation (25 mM), respectively, and the influence of various serotonergic drugs on the evoked tritium outflows was investigated. Serotonin decreased the electrically-evoked ACh release in striatum in a concentration-dependent manner without the change of basal release. In hippocampal and entorhinal cortical slices, serotonin did not affect the evoked and basal release of ACh, but, at large dose (30 microM) decreased the evoked ACh release in hippocampus. 2,5-Dimethoxy-4-iodoamphetamine (DOI), a specific 5-HT 2A/2C agonist, decreased evoked ACh release in the striatum. CGS-12066A (5-HT 1B agonist), m-chlorophenyl-biguanide (5-HT 3 agonist) and 5-[(dimethyl -amino)methyl]-3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazole (5-HT 3 antagonist) did not affect the evoked and basal ACh release in all tissues. Ritanserin, a specific 5-HT 2A/2C antagonist, blocked the inhibitory effects of serotonin and DOI, whereas, ketanserin, an another type of specific 5-HT 2A/2C antagonist did not affect the inhibitory effects of serotonin and DOI. In striatal synaptosomal preparation, serotonin and DOI did not affect the K +-evoked ACh release. These findings suggest that ritanserin-sensitive 5-HT 2A/2C receptors located in the soma and/or axons of the striatal cholinergic neurons play a important role in ACh release.

alpha2-Adrenoceptor antagonists reverse the 5-HT2 receptor antagonist suppression of head-twitch behavior in mice.

The alpha2-adrenoceptor agonist clonidine, as well as 5-HT2 receptor antagonists, reportedly suppress 5-HT2 receptor-mediated head-twitch behavior. We investigated the effect of alpha2-adrenoceptor antagonists on the suppressive action of 5-HT2 receptor antagonists in mice pretreated with the noradrenaline toxin 6-hydroxydopamine (6-OHDA) or the 5-HT synthesis inhibitor p-chlorophenylalanine (p-CPA). In normal mice, idazoxan (0.08-0.2 mg/kg, IP) or yohimbine (0.2-2.0 mg/kg, IP), both alpha2-adrenoceptor antagonists, had no effect on the head-twitch response caused by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 16 mg/kg, IP), but idazoxan significantly enhanced the response at 0.5 mg/kg. On the other hand, these alpha2-adrenoceptor antagonists, at doses that had no effect on the basal number of head-twitches (idazoxan 0.2 mg/kg and yohimbine 0.5 mg/kg), significantly attenuated not only the suppressive effect of clonidine (0.01 mg/kg, IP) on head-twitch response but also that of the 5-HT2 receptor antagonist ritanserin (0.03 mg/kg, IP). Moreover, idazoxan (0.2 mg/kg) also significantly reversed the inhibition by 0.01 mg/kg (IP) ketanserin, a selective 5-HT2 receptor antagonist. Pretreatment with 6-OHDA plus nomifensine but not with p-CPA significantly attenuated the effect of idazoxan (0.2-0.5 mg/kg) on the ritanserin inhibition of the head-twitch response. Prazosin, an alpha1-adrenoceptor antagonist, dose-dependently suppressed the response, and the effect of prazosin (1.25 mg/kg) was significantly attenuated by 0.5 mg/kg idazoxan. These results indicate that endogenous noradrenaline is involved in the apparent antagonistic interaction between selective alpha2-adrenoceptor antagonists and 5-HT2 receptor antagonists in the head-twitch response, and suggest that noradrenaline stimulation of alpha1-adrenoceptors may be involved in this apparent antagonism.

[The effect of ritanserin on the formation and expression of an opiate abstinence syndrome]. / Vliianie ritanserina na formirovanie i ékspressiiu opiatnogo abstinentnogo sindroma.

The described dependence was formed in mice [correction of rats] by subcutaneous injections of morphine in doses growing from 10 to 100 mg/kg (8 days, twice a day). The effect of 5-HT2 receptor blocker ritanserine (1, 5, and 10 mg/kg) on expression of the abstinence syndrome (according to the behavioral and somato-autonomic parameters) 24 h after morphine discontinuation was studied. Ritanserine attenuated the manifestation of some abstinence parameters associated with activation of the serotonin system in formation of the dependence. The effect was less in expression of abstinence.

5-HT3-like receptors in the rat medial prefrontal cortex: further pharmacological characterization.

The aim of the study was to further characterize the pharmacological properties of 5-hydroxytryptamine (5-HT)3-like receptors in the rat medial prefrontal cortex (mPFC) using combinations of biochemical and electrophysiological approaches. Phenylbiguanide (PBG) and three chlorinated derivatives, ortho-chloro-PBG (oCPBG), meta-chloro-PBG (mCPBG) and para-chloro-PBG (pCPBG), dose-dependently stimulated phosphoionositide (PI) turnover in fronto-cingulate cortical slices. All three chloro-isomers of PBG were equipotent in stimulating PI turnover. SR 57227A ((4-amino)-(6-chloro-2-pyridyl) L-piperidine hydrochloride, a novel compound with high affinity and selectivity for peripheral and central 5-HT3 receptors) dose-dependently stimulated PI turnover in fronto-cingulate cortical slices. The rank order of potency of all the 5-HT3 receptor agonists tested in the PI assay as compared to 5-HT was: 5-HT > 2-Me-5-HT > SR57227A > PBG = mCPBG = oCPBG = mCPBG. 5-HT and 5-HT receptor agonists depressed the firing rate of both spontaneously active and glutamate-activated quiescent mPFC cells in a current (dose)-dependent fashion. The rank order of effectiveness of these compounds was: 5-HT > SR57227A = 2-Me-5-HT = mCPBG = oCPBG = pCPBG = PBG. Unlike its action on the 5-HT3 receptors in the periphery or cultured cell lines, D-tubocurarine chloride appears to be non-specific in blocking the depressant action of 2-Me-5-HT, gamma-aminobutyric acid and dopamine. Our results combined support the view that the pharmacological properties of 5-HT3-like receptors in the mPFC are not identical to those located in peripheral tissues and in cultured cell lines.

5-HT2A receptor antagonists inhibit potassium-stimulated gamma-aminobutyric acid release in rat frontal cortex.

Several drugs selective for the serotonin 5-HT2A receptor were tested for their effects on spontaneous and K(+)-evoked [3H] gamma-aminobutyric acid (GABA) release from slices of rat frontal cortex. Under K+ stimulation, the antagonists ketanserin, spiperone, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]- 4-piperidinemethanol (MDL 100,907) and ritanserin inhibited GABA release by 12-31%. Rats were treated with the serotonin-depleting agent para-chlorophenylalanine and with the serotonergic neurotoxin para-chloroamphetamine. In para-chlorophenylalanine-treated animals, stimulated GABA release in the presence of ketanserin remained depressed. In animals treated with both para-chlorophenylalanine and para-chloroamphetamine, ketanserin or the hallucinogenic agonist (2,5-dimethoxy-4-iodophenyl)-2-aminoethane (2C-I) each appeared to decrease stimulated GABA release but this was not significant. However, when ketanserin and 2C-I were both present in the superfusion buffer an additive inhibitory effect was observed, and GABA release was decreased 30%. These results suggest that serotonin facilitates GABA release in cortex via 5-HT2A receptors and that the functional response of this system is resistant to serotonin depletion.

Serotonin--one possible link between oxygen metabolism and the regulation of blood flow in the brain?

Hyperoxemia is known to alter tissue oxygenation, which in the brain results in a scattered and an uneven distribution of cerebrocortical tissue oxygen pressures (PtO2). This study examined the effect of ritanserin (a highly specific serotonin receptor antagonist, 5-HT2) on the PtO2 distribution during hyperoxemia. The measurements of brain oxygenation were performed on the motor cortex in anesthetized pigs with a multiwire Clark-type microelectrode. Ritanserin was administered (0.035 mg/kg i.v.) during hyperoxemia (inspired oxygen fraction = 0.70). In 4 of 5 animals, the disturbed oxygenation that was registered during hyperoxemia was normalized after the ritanserin injection. These results indicate that serotonin may be involved in the regulation of brain oxygenation during hyperoxemia, and they also suggest that serotonin may be a link in the coupling between the oxygen metabolism and the regulation of blood flow in the brain.

Modulation of rat neocortical high-voltage spindle activity by 5-HT1/5-HT2 receptor subtype specific drugs.

To investigate the role of serotonin (5-hydroxytryptamine; 5-HT) receptors in the modulation of rat thalamocortical oscillations, we studied the effects of 5-HT1/5-HT2 receptor subtype specific drugs on neocortical high-voltage spindle activity in adult male rats. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.03, 0.1, 0.3 and 1.0 mg/kg s.c.), had no effect on neocortical high-voltage spindle activity. Furthermore, a mixed 5-HT1/5-HT2 receptor antagonist, methysergide (1.0, 5.0 and 15.0 mg/kg i.p.), had no effect, whereas a non-specific mixed 5-HT1/5-HT2 receptor antagonist, methiothepin (0.2, 1.0 and 5.0 mg/kg i.p.), significantly increased neocortical high-voltage spindles. Of the 5-HT2 receptor antagonists, ritanserin (0.1, 1.0 and 5.0 mg/kg s.c.) had no effect, whereas ketanserin (1.0, 5.0 and 20.0 mg/kg s.c.) increased neocortical high-voltage spindles, but only at the highest dose used. A 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.5, 1.0 and 2.0 mg/kg s.c.), at the two highest doses significantly decreased neocortical high-voltage spindle activity, and this effect was blocked by the 5-HT2 receptor antagonists, ketanserin (1.0, 5.0 and 20.0 mg/kg s.c.) and ritanserin (1.0 and 5.0 mg/kg s.c.), as well as by methiothepin (0.2, 1.0 and 5.0 mg/kg i.p.) and methysergide (1.0, 5.0 and 15.0 mg/kg i.p.). Furthermore, unilateral intrathalamic infusions, but not intrahippocampal control infusions, of DOI (10 and 50 micrograms/1.0 microliters/rat) decreased neocortical high-voltage spindle activity and systemic administration of ketanserin (20.0 mg/kg s.c.) completely blocked this effect. The present results suggest that (1) the serotonergic system modulates rat thalamocortical oscillations as measured by neocortical high-voltage spindle activity, (2) activation of 5-HT2 receptors, possibly located in the thalamus, with a specific 5-HT2 receptor agonist, DOI, causes a reduction in rat neocortical high-voltage spindle activity.

Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response.

Intense auditory stimuli elicit an involuntary startle response that is attenuated when the startling stimulus (the pulse) is preceded immediately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gating and is significantly reduced in schizophrenic patients. Noncompetitive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and ((+)-D-aspartate 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (dizocilpine, or MK-801) have been found previously to disrupt PPI in animals. The present investigation assessed the ability of several antipsychotic drugs to reverse PCP-induced deficits in PPI in rats. Animals were pretreated with either the atypical antipsychotic clozapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg), the D2 dopamine antagonist raclopride (0, 0.1 or 0.5 mg/kg), the D1 dopamine antagonist SCH23390 (0, 0.01 or 0.05 mg/kg) or the 5-hydroxytryptamine2 antagonists ritanserin (0 or 2.0 mg/kg) or ketanserin (0 or 1.0 mg/kg) and then were given PCP (1.0 mg/kg). After drug administration, animals were tested in startle chambers. PCP repeatedly and robustly decreased PPI without affecting base-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this effect of PCP without altering PPI by itself. Raclopride, SCH23390, ritanserin and ketanserin were ineffective at reversing the PCP-induced deficit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disruption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appears that the ability of clozapine to reverse deficits in PPI produced by noncompetitive N-methyl-D-aspartate antagonists cannot be attributed to a sole antagonism of either D1 dopamine, D2 dopamine or 5-hydroxytryptamine2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of 5-hydroxytryptophan to inhibit and disinhibit mouse behaviour in the light/dark test.

The involvement of 5-HT receptors in behavioural responding to an aversive situation was investigated in the mouse light/dark test. The administration of 5-hydroxytryptophan (5-HTP) (12.5-50 mg/kg i.p.) increased brain 5-HT turnover and inhibited mouse behaviour in the light/dark test box. The 5-HT2C/5-HT2A receptor antagonists methysergide (1.0 and 5.0 mg/kg i.p.) and ritanserin (0.1-1.0 mg/kg i.p.) antagonised (methysergide) or reversed (ritanserin) the effects of 5-HTP to an increased exploration of the light compartment; a low dose of the 5-HT3 receptor antagonist ondansetron (0.01 mg/kg i.p.) had a similar effect. The disinhibitory effect of the 5-HTP/ritanserin interaction was antagonised by the 5-HT3/5-HT4 receptor antagonists SDZ205-557 (0.001-0.1 mg/kg) and a high dose of tropisetron (1.0 mg/kg i.p.) but not by ondansetron (1.0 mg/kg i.p.). At these doses tropisetron and ondansetron had no effect in their own right. Thus the dominant effect of 5-HTP in the mouse is to inhibit behaviour, a response mediated via 5-HT2C/5-HT2A and 5-HT3 receptors. A 5-HT4 receptor may effect an opposing disinhibitory potential as revealed by ritanserin.

Comparative study of the psychomotor and antistress effects of ritanserin, alprazolam and diazepam in healthy subjects: some trait anxiety-independent responses.

The new potential anxiolytic ritanserin was studied in a double-blind manner vs. alprazolam, diazepam and placebo in 23 healthy subjects. The subjects belonged either to a high anxiety level group or a low anxiety level group, in order to study the effect of the anxiety level on the pharmacodynamic responses. The assessments included cognitive function (memory tests), psychomotor performance [Critical Flicker Fusion (CFF), Choice Reaction Time (CRT)], subjective ratings of alertness and overnight sleep and stress paradigm. Ritanserin (10 mg), alprazolam (0.75 mg), diazepam (10 mg) and placebo were given as single oral doses following a latin square design. Groups were well contrasted on the Cattell anxiety scale and were not overlapping. On no psychometric variable have there been any interactions between the anxiety level and the drug factor. At baseline an anxiety-related difference between the two groups was observed: lower CFF value in the high anxiety group (-1.4 Hz). Both benzodiazepines impaired psychomotor assessment and memory function and increased sleepiness. Ritanserin decreased CFF values without significantly affecting CRT on which nevertheless a trend to impairment was observed. Memory tests, and subjective ratings of alertness were unaffected by ritanserin. A trend to an antistress effect was observed on electrodermogram after ritanserin. Both benzodiazepines decreased central nervous system arousal and memory while ritanserin was inactive except on CFF. Recent data support the hypothesis that 5-HT2 blockers decrease pupil diameter which is a well known covariate of flicker frequency.

[The effect of pharmacologic blockade of serotonin receptors (S2) on arterial pressure in rats with 2 forms of hereditary arterial hypertension]. / Vliianie farmakologicheskoi blokady serotoninovykh (S2) retseptorov na arterial'noe davlenie u krys s dvumia formami nasledstvennoi arterial'noi gipertenzii.

The influence of blockade of serotonin S2 receptors with ketanserin was studied in two strains of rats with inherited arterial hypertension: spontaneously hypertensive rats (SHR strain) and rats with inherited stress-induced arterial hypertension (ISIAH strain). It was found that peripheral injection of ketanserin produced a greater decrease of arterial blood pressure than i.c.v. administration. ISIAH rats were more sensitive to the hypotensive effect of ketanserin when compared to normotensive Wistar or SHR rats.