Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression

The aim of the present study was to examine the effect of the selective 5-HT7 receptor antagonist SB 269970 (0.25-20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1-20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT7 receptor antagonists may play a role in the therapy of both anxiety and depression.     

The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats

While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.     

The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors

The effect of lesion of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 × 10 mg/kg), and the influence of the benzodiazepine receptor antagonist flumazenil (10 mg/kg) on the anticonflict action of N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), a selective 5-HT₆ receptor antagonist, were investigated in the Vogel conflict drinking test in rats. In addition, the interaction between SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) was evaluated in that test. All the compounds tested were administered intraperitoneally. The anticonflict activity produced by SB-399885 (3 mg/kg) was not modified in p-CA-pretreated rats, but it was totally blocked by flumazenil. Combined administration of non-active doses of SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) produced a pronounced anticonflict effect in rats. The present results suggest that the anticonflict activity of SB-399885 is not conditioned by the integrity of 5-HT neurons, and that benzodiazepine receptors are indirectly involved in its effect, possibly due to a functional interaction between 5-HT₆ receptors and the γ-aminobutyric acid (GABA)/benzodiazepine system.     

The 5-HT6 serotonin receptor antagonist SB-271046 attenuates the development and expression of nicotine-induced locomotor sensitisation in Wistar rats

5-HT₆ receptors are almost exclusively expressed in the central nervous system, particularly in areas relevant for addictive behaviour. Based on this, together with other data, this receptor may be a viable target for the control of drug abuse.The present study tested the ability of the 5-HT₆ receptor antagonist SB-271046 to attenuate the development and expression of nicotine-induced behavioural sensitisation.Rats were habituated to the test apparatus prior to experimentation (day 0) and locomotor activity recorded. On days 1 and 5, animals were placed in locomotor test apparatus and after 30 min injected with SB-271046 (1, 3, and 6 mg/kg, intraperitoneally IP) or vehicle. Thirty minutes later, nicotine (0.4 mg/kg, subcutaneously SC) or saline were administered and activity recorded for 60 min. On days 2, 3 and 4 treatments were performed in the home cage. After 17 days of withdrawal (day 23), a challenge test was performed with nicotine (0.4 mg/kg SC) or saline. In a separate experiment of similar design the effects of SB-271046 (1, 3, and 6 mg/kg IP) was tested for its ability to reduce the expression of behavioural sensitisation (day 23).SB-271046 dose dependently reduced the development and expression of nicotine sensitisation vs respective controls.In conclusion, the 5-HT₆ receptor antagonist SB-271046 reduced both the development and expression of nicotine sensitisation, suggesting that the 5-HT₆ receptor may be a viable target for the control of nicotine abuse. Further studies are warranted to substantiate this conclusion and further understand the role of 5-HT₆ receptors in addiction.     

Blockade of human atrial 5-HT4 receptors by SB 207710, a selective and high affinity 5-HT4 receptor antagonist

The mode of antagonism of 5-hydroxytryptamine-induced positive inotropic effects by the highly selective 5-HT₄ receptor antagonist SB 207710 (1-butyl4-piperidinyl) methyl 8-amino-7-iodo-1,4-benzodioxan-5-carboxylate was investigated on isolated preparations of human right atrial appendage. SB 207 710 caused concentration-dependent (0.1–10 nmol/l) surmountable antagonism of the effects of 5-hydroxytryptamine with a pK_B (mol/l) of 10.1. Due to its high selectivity and affinity, SB 207710 could be a powerful tool for the comparison of human atrial 5-HT₄ receptors with 5-HT₄ receptors of other organs of man and other species.     

Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

Summary Three chemical classes of serotonin 5-HT₄ receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT₄ receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3–5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded K_i values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT₃ receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (K_i, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID₅₀, 231 vs 0.5 g/kg, i.v.). No significant binding (K_i>10 mol/l) of DAU 6285 to serotonergic 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, and 5-HT₂ receptors as well as to adrenergic ₁, ₂, dopaminergic D₁, D₂ or muscarinic M₁–M₃ receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT₄ receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT₃ receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT₄ receptors. Send offprint requests to A. Dumuis at the above address     

Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression

The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.     

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Aim:

To investigate the antidepressant-like effects of a novel 5-HT₃ receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods:

5-HT₃ receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5–2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5–2 mg·kg⁻¹·d⁻¹, po) or a positive drug fluoxetine (10 mg·kg⁻¹·d⁻¹, po) in the last 2 weeks, followed by behavioral and biochemical assessments.

Results:

The 5-HT₃ receptor antagonism of 6z (pA₂=7.4) in guinea pig ileum was more potent than that of a standard 5-HT₃ receptor antagonist ondansetron (pA₂=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group.

Conclusion:

6z is a novel 5-HT₃ receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.     

5-HT1B receptor-mediated contractions in human temporal artery: evidence from selective antagonists and 5-HT receptor mRNA expression

1. In the human temporal artery both 5-HT_1-like and 5-HT_2A receptors mediate the contractile effects of 5-hydroxytryptamine (5-HT) and we have suggested that the 5-HT_1-like receptors resemble more closely recombinant 5-HT_1B than 5-HT_1D receptors. To investigate further which subtype is involved, we investigated the blockade of 5-HT-induced contractions by the 5-HT_1B-selective antagonist SB-224289 (2,3,6,7-tetrahydro-1′-methyl-5-{2-methyl-4′[(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] carbonyl} furo[2,3-f]indole-3-spiro-4′-piperidine oxalate) and the 5-HT_1D-selective antagonist BRL-15572 (1-phenyl-3[4-3-chlorophenyl piperazin-1-yl] phenylpropan-2-ol). We also used RT-PCR to search for the mRNA of 5-HT_1B, 5-HT_1D and other 5-HT receptors.
2. The contractile effects of 5-HT in temporal artery rings were partially antagonized by SB-224289 (20, 200 nM) (apparent K_B=1 nM) and ketanserin (1 μM) but not by BRL-15572 (500 nM).
3. Sumatriptan evoked contractions (EC₅₀, 170 nM) that were resistant to blockade by BRL-15572 (500 nM) but antagonized by SB-224289 (20, 200 nM).
4. The potency of 5-HT (EC₅₀) was estimated to be 94 nM for the ketanserin-sensitive receptor and 34 nM for the SB-224289-sensitive receptor. The fraction of maximal 5-HT response mediated through SB-224289-sensitive receptors was 0.20–0.67, the remainder being mediated through ketanserin-sensitive receptors.
5. We detected arterial receptor mRNA for the following receptors (incidence): 5-HT_1B (8/8), 5-HT_1D (2/8), 5-HT_1F (0/4), 5-HT_2A (0/8), 5-HT_2B (0/8), 5-HT_2C (0/8), 5-HT₄ (4/8) and 5-HT₇ (4/8).
6. We conclude that the ketanserin-resistant fraction of the 5-HT effects and the effects of sumatriptan are mediated by 5-HT_1B receptors. The lack of antagonism by BRL-15572 rules out 5-HT_1D receptors as mediators of the contractile effects of 5-HT and sumatriptan.

     

Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719

1. The functional profile of the long form of the human cloned 5-HT₇ receptor (designated h5-HT_7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT_7(a) receptor.
2. The receptor binding profile, determined by competition with [³H]-5-CT, was consistent with that previously reported for the h5-HT_7(a) receptor. The selective 5-HT₇ receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide) displayed high affinity (pK_i 7.5) for the receptor.
3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT>5-HT>8-OH-DPAT) was the same in functional and binding studies.
4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA₂ of 7.2±0.2 and slope not significantly different from 1, consistent with competitive antagonism.
5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT₇ receptor-mediated and to reflect inverse agonism.
6. It is concluded that in this expression system, the h5-HT_7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.

     

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.     

The effects of a 5-HT1 receptor ligand isapirone (TVX Q 7821) on 5-HT synthesis and the behavioural effects of 5-HT agonists in mice and rats

The effects of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-1,2-benzoisothiazol-3(2H)one-1,1-dioxide hydrochloride (isapirone, TVX Q 7821), a putative 5-HT₁ receptor antagonist, has been studied on various models of 5-HT receptor sub-type function. In mice TVX Q 7821 produced a dose-dependent inhibition of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) with an ED₅₀ of 5.3 mg/kg suggesting that TVX Q 7821 was an antagonist of the presynaptic (possibly somato-dendritic) 5-HT_1A receptor. TVX Q 7821 did not alter the locomotor response to the suggested 5-HT_1B agonist RU 24969. The rate of mouse brain 5-HT synthesis was accelerated by TVX Q 7821 (10 mg/kg). 5-HT₂ receptor-mediated head twitch behaviour induced by precursor loading with 5-HTP was unaffected by TVX Q 7821 (10 mg/kg) pretreatment 75 min earlier, but the head-twitch induced by the agonist 5-methoxy-N,N-dimethyltryptamine was enhanced by prior treatment with TVX Q 7821.In rats the hypothermia induced by 8-OH-DPAT was partially antagonised by TVX Q 7821 while the behavioural serotonin syndrome induced by 8-OH-DPAT (a possible post-synaptic 5-HT_1B-mediated effect) was unaffected by TVX Q 7821 as was the locomotion induced by RU 24969.The data suggest that TVX Q 7821 is a good presynaptic 5-HT_1A antagonist in mice, as indicated by the 8-OH-DPAT-induced hypothermia and 5-HT synthesis rate studies. It did not antagonise 5-HT_1B-mediated behaviour in mice or rats and appeared to have an antagonist action at pre- but not post-synaptic 5-HT_1A receptors in rats. Offprint requests to: G.M. Goodwin     

Effect of SB 200646A,a 5-HT2C/5-HT2B receptor antagonist,in two conflict models of anxiety

SB 200646A is the first selective 5-HT_2C/5-HT_2B receptor antagonist and has previously been observed to have anxiolytic-like properties in the rat social interaction test. In the present study the effects of the compound in two conflict models of anxiety, the rat Geller-Seifter and marmoset conflict test, were examined. In the rat Geller-Seifter test, suppressed responding was increased by all doses of SB 200646A between 5 and 40 mg/kg PO when given 1 h pretest. Unsuppressed responding was slightly increased only at 10 mg/kg PO. Suppressed responding was also increased by the benzodiazepine anxiolytic, chlordiazepoxide, at 1, 2.5 and 5 mg/kg PO 1 h pretest. Unsuppressed responding was modestly increased by chlordiazepoxide only at 5 mg/kg PO. In the marmoset conflict test marmosets were trained to lever press for a palatable food reward. Lever pressing was subsequently suppressed by air puffs. In this procedure suppressed responding was increased by both the benzodiazepine anxiolytic diazepam at 2 and 5 mg/kg PO and SB 200646A after 10 and 20 mg/kg PO. Both treatments caused small increases in unsuppressed responding at 2 and 20 mg/kg PO respectively. Taken together with the previous effects of SB 200646A in the rat social interaction test, this is compelling evidence that 5-HT_2C/2B receptor antagonists may possess anxiolytic properties.     

Effects of treatment with a 5-HT4 receptor antagonist in heart failure

BACKGROUND AND PURPOSE: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats. EXPERIMENTAL APPROACH: Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. KEY RESULTS: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl). CONCLUSIONS AND IMPLICATIONS: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.     

5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism

5-HT(6) receptors are expressed in brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. This study examined the effects of acute systemic administration of two selective 5-HT(6) receptor antagonists Ro 04-6790 and SB-271046 (10 mg kg(-1) i.p.) on acquisition, consolidation, and retrieval in the novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial, following inter-trial delays of up to 3 h. 5-HT(6) receptor antagonist administration 20 min prior to or immediately after the familiarisation trial, but not 20 min prior to the choice trial reversed the deficit in object discrimination produced by a 4 h inter-trial interval. The nootropic effects of the 5-HT(6) receptor antagonists in this task thus appear to involve enhanced consolidation. Pre-treatment with the non-competitive NMDA receptor antagonist MK-801 (0.05 mg kg(-1) i.p.) prevented the effect of Ro 04-6790 on delay-induced deficits in object discrimination. This suggests that the 5-HT(6) receptor antagonist-induced enhancement of consolidation involves increased central glutamatergic neurotransmission.     

Enhancement of the anti-immobility action of antidepressants by a selective 5-HT7 receptor antagonist in the forced swimming test in mice

Using the forced swimming test in mice, we examined the effect of the following antidepressants: citalopram, imipramine, desipramine and moclobemide (which are characterized by different mechanisms of action), administered in combination with the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB 269970). All those drugs were given in doses which did not shorten the immobility time of mice. Citalopram (1.25 mg/kg), imipramine (10 mg/kg), desipramine (5 mg/kg) or moclobemide (10 mg/kg) administered jointly with SB 269970 (5 mg/kg), produced a significant antidepressant-like effect. None of the compounds studied, given alone or in combination, increased the spontaneous locomotor activity of mice. The obtained results indicate that blockade of 5-HT7 receptors may facilitate the anti-immobility effect of antidepressants in mice.     

Potentiation of 5-HT3 receptor function by the activation of coexistent 5-HT2 receptors in trigeminal ganglion neurons of rats

5-HT receptor subtypes are widely expressed in primary sensory neurons, yet so far little is known about the interaction among them. This study aimed to investigate whether the activation of 5-HT2 and 5-HT1 receptors could modulate 5-HT3 receptor mediated current in rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The majority of TG neurons examined responded to 5-HT (10(-7)-10(-3) M) with a fast activating and rapid desensitizing inward current (77.2%, 71/92). This 5-HT activated current (I(5-HT)) was blocked by ICS 205-930 and mimicked by 2-methyl-5-HT, indicating that it was mediated by 5-HT3 receptor. With alpha-methyl-5-HT applied prior to 5-HT application, I(5-HT) was potentiated in a concentration-dependent manner, with the maximal modulatory effect at 10(-9) M of alpha-methyl-5-HT. The concentration-response curve for I(5-HT) pretreated with alpha-methyl-5-HT shifts upwards compared with that for I(5-HT) without alpha-methyl-5-HT pretreatment, the maximal I(5-HT) value having increased by (60.3 +/- 5.7)% of its control while the EC50 values of the two curves being very close, i.e. (2.0 +/- 0.3) x 10(-5) M vs (1.7 +/- 0.2) x 10(-5) M, respectively. The alpha-methyl-5-HT potentiation of I(5-HT) was removed by intracellular dialysis of either GDP-beta-S, a non-hydrolyzable GDP analog, or GF109203X, a selective PKC inhibitor, almost completely. Preapplication of R-(+)-UH-301, a selective agonist of 5-HT(1A) receptor, had no modulatory effect on I(5-HT). These results suggest that in the membrane of TG neurons, the activation of 5-HT2 receptors can exert an enhancing effect on the function of coexistent 5-HT3 receptors while that of 5-HT(1A) receptors cannot.     

5-HT6 receptor antagonists enhance retention of a water maze task in the rat

RATIONALE: 5-HT(6) receptors are predominantly located in the brain and may be involved in cognitive processes. The aim of this study was to assess the effects of two potent and selective 5-HT(6) receptor antagonists, SB-271046-A and SB-357134-A, on learning and memory in the rat. METHODS: Spatial learning and memory was assessed by testing the effects of SB-271046-A and SB-357134-A on acquisition and retention of a water maze task. RESULTS: In the water maze, administration of SB-271046-A or SB-357134-A (3 or 10 mg/kg) had no effect on learning per se. At 10 mg/kg, however, both compounds produced a significant improvement in retention of a previously learned platform position when tested 7 days after training. By contrast, the acetylcholinesterase inhibitor, Aricept (donepezil, 0.1, 0.3 mg/kg PO) had no effect in this task. CONCLUSIONS: This study demonstrates that systemic administration of SB-271046-A and SB-357134-A produces improvements in retention of a water maze task in the rat. These data indicate that 5-HT(6) receptor antagonism may be involved in cognitive function.     

mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes

The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist. As previously reported, mCPP (3 mg/kg) induced hyperactivity in 5-HT2C KO mice. A combination of the 5-HT1B receptor agonist CP-94,253 (20 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg) induced marked hyperactivity in WT but not in 5-HT2C KO mice, nor in mice treated with the selective 5-HT2C receptor antagonist, SB 242084 (1.5 mg/kg). Neither CP-94,253 nor 8-OH-DPAT had any intrinsic effect on locomotion in WTs. mCPP-induced hyperactivity was attenuated in 5-HT2C KO mice by the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg), and the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg) and M100907 (0.01 mg/kg) but not by the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg). The 5-HT(2A/2B/2C) receptor agonist, Ro 60-0175 (3 mg/kg), induced a modest increase in locomotor activity in WT mice pre-treated with SB 242084. However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity. Thus, joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion in WT mice but this response is dependent on a functional 5-HT2C receptor population and hence is absent in 5-HT2C KO mice. By contrast, mCPP-induced hyperactivity depends on the inactivation of a separate 5-HT2C receptor population and is mediated by 5-HT2A and 5-HT1B receptor activation.