The selective 5-HT3 receptor antagonist,WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT₃ receptor antagonist, WAY 100289, on spatial learning and memory in the water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source of cholinergic projections to cortex and hippocampus. The representative cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline (1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before lesioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards improvement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY100289 improved performance at all three doses, though ameliorative effects of nicotine and arecoline were more marked also in lesioned rats. These results show that WAY100289 improved spatial learning in animals impaired after lesions to cholinergic projection nuclei, which may reflect an interaction with cholinergic transmission to enhance cognitive function. However, in the present study, WAY100289 appeared to be less effective than direct cholinergic agonists.     

Ondansetron improves cognitive performance in the Morris water maze spatial navigation task

In the present studies we investigated the actions of ondansetron, a prototypic 5-hydroxytryptamine₃ (5-HT₃) receptor antagonist, on performance in a complex spatial navigation/memory task in rats. Specifically, we compared the activity of ondansetron to that of the cholinesterase inhibitor physostigmine in attenuating two distinct cognitive deficits in the Morris water maze. In the first model, rats treated with the muscarinic receptor antagonist atropine (30 mg/kg) had significantly longer latencies to find the submerged platform across two days of testing. Physostigmine (0.03, 0.1 and 0.3 mg/kg) and ondansetron (0.03–1 mg/kg) significantly reduced the latencies to find the submerged platform in atropine-treated animals, suggesting an increase in cognitive performance. There was little evidence of a dose-response relationship for either compound, and a loss of efficacy for ondansetron was seen at 3 mg/kg. In the second model, pre-screened, aged (23 months), cognition-impaired and nonimpaired rats were tested. Ondansetron (0.1 mg/kg), but not physostigmine (0.1 mg/kg), decreased the latencies to find the submerged platform in the aged-impaired rats, while neither compound improved performance of aged-nonimpaired rats. These data suggest that ondansetron may have cognition enhancing properties in animal models of aging and cholinergic hypofunction.     

Spontaneous exploration of a 6-arm radial tunnel maze by basal forebrain lesioned rats: effects of the benzodiazepine receptor antagonist β-carboline ZK 93 426

Nine days following ibotenic acid induced basal forebrain lesions or a sham-operation, rats were allowed to explore an automated six-arm radial tunnel maze. From each session, several measures of locomotor and exploratory activity were registered. Lesioned and sham-operated animals were treated with either the benzodiazepine receptor antagonist -carboline ZK 93 426 (5 mg/kg; IP) or vehicle (Cremofor EL 10% in saline; IP; n=10 for each group). Treatment was carried out 30 min before each session during acquisition (seven sessions) and reversals of the maze configuration (seven session). Eight days following the 14th session, the animals were retested without any further drug treatment. The main results suggest that the lesion resulted in locomotor hyperactivity, an increase in the number of blind arm entries, and of choice stereotypy. Treatment with ZK 93 426 attenuated the lesion-induced alterations of locomotor and exploratory activities. During the retest, the lesioned, previously vehicle-treated rats revisited arms which they had already explored during this session more frequently than the lesioned, previously ZK-treated rats; the latter group did not differ from the sham-lesioned controls. It is concluded that basal forebrain lesioned animals explored the tunnel maze less efficiently than sham-lesioned controls and that the lesioned animals benefited from the treatment with ZK 93 426. Although the specificity of the lesion in terms of destruction of cholinergic neurons remains unsettled, and although the psychological significances of the behavioral measures obtained from the tunnel maze are not yet fully understood, these results suggest that antagonists or partial inverse agonists at the benzodiazepine receptor may be able to normalize basal forebrain lesion-induced behavioral alterations.     

Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats

Rationale Cholinergic receptor blockade produces memory deficits in animal models. These deficits can be prevented by 5-HT₃ receptor antagonists, such as ondansetron, which increases acetylcholine release. We investigated the effects on cognitive performance of combined treatments of ondansetron with either flumazenil, a GABA_A receptor benzodiazepine site antagonist, or tacrine, a cholinesterase inhibitor, which are also able to prevent scopolamine-induced cognitive impairment.Methods Spatial learning and memory was assessed by studying the effects of single and combined treatments on acquisition and retention of the Morris water maze task in rats.Results Scopolamine (0.6 mg/kg) induced significant learning and retention deficits. Both ondansetron (0.1 g/kg) and tacrine (3 mg/kg) partially prevented the scopolamine-induced learning deficit. A full reversal was only found after the combined treatment of ondansetron with flumazenil (10 mg/kg) and also after tacrine in combination with ondansetron. Likewise, scopolamine-induced retention deficit was fully counteracted by the combined treatment of ondansetron with either flumazenil or tacrine, and only partially by any of the single treatments tested.Conclusions The scopolamine-induced impairment of learning and retention in the water maze is fully prevented by ondansetron when given in combination with either flumazenil or tacrine, suggesting that both combined treatments result in a potentiated cholinergic function and may constitute the basis of a new therapy for cognitive disorders.     

Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety

Four non-selective 5-HT_2C/5-HT_2A receptor antagonists, mianserin (2–8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5–1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT_2A receptor antagonists ketanserin (0.2–1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT_1A, 5-HT_1B and-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT_1D receptor partial agonist and ₂ adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H₁ receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT_2C/5-HT_2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT_2C/5-HT_2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT_2C receptor, although the possibility of 5-HT_2B receptor mediation is discussed.     

An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function

As the 5-hydroxytryptamine₆ (5-HT₆) receptor is almost exclusively expressed in the CNS, particularly in areas associated with learning and memory, many studies have examined its role in cognitive function in the rodent, as reviewed herein. Most studies, in healthy adult rats, report that 5-HT₆ receptor antagonists enhance retention of spatial learning in the Morris water maze, improve consolidation in autoshaping tasks and reverse natural forgetting in object recognition. Antagonists appear to facilitate both cholinergic and glutamatergic neurotransmission, reversing scopolamine- and NMDA receptor antagonist-induced memory impairments. Recent reports show that the 5-HT₆ receptor antagonist, PRX-07034, restores the impairment of novel object recognition produced in rats reared in social isolation, a neurodevelopmental model producing behavioural changes similar to several core symptoms seen in schizophrenia. The 5-HT₆ receptor antagonist, Ro 04-6790, modestly improved reversal learning in isolation reared but not group-housed controls in the water maze. Ro 04-6790 also improved novel object discrimination both in adult rats that received chronic intermittent phencyclidine and drug-naïve 18-month-old rats. However, more information on their effect in animal models of schizophrenia and Alzheimer's disease is required. Several selective high-affinity 5-HT₆ receptor agonists developed recently also improve object discrimination and extra-dimensional set-shifting behaviour. Thus both 5-HT₆ receptor agonist and antagonist compounds show promise as pro-cognitive agents in pre-clinical studies but the explanation for their paradoxical analogous effect is currently unclear, and is discussed in this article.     

The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models

VA21B7 (3-[2-(4-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential 5-HT₃ receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT₃ receptors as compared to other receptors studied, it was not a potent 5-HT₃ receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable anxiolytic-like effect was found at doses of 2–500 µg/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT₃ receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT_1A agent buspirone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25–0.5 mg/kg IP or 2–4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2–4 mg/kg. At variance with other studies, 5-HT₃ receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic action in the light/dark test was not flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2–4 mg/kg reduced the memory deficits induced in rats by scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an anxiolytic in humans.     

5-HT3 receptor antagonists do not modify cocaine place conditioning or the rise in extracellular dopamine in the nucleus accumbens of rats

Three 5-HT₃ receptor antagonists, MDL 72222, tropisetron, and ondansetron were studied for their ability to modify the conditioned place preference (CPP) induced by 10 mg/kg IP cocaine in rats. MDL 72222 (0.03–3 mg/kg SC) and tropisetron (0.01–0.1 mg/kg SC) administered, respectively, 30 min and 1 h before each conditioning session, did not affect the acquisition of cocaine CPP. Ondansetron (0.01–0.1 mg/kg SC) administered 30 min before each conditioning session or just before testing likewise had no effect. At 0.1 mg/kg SC ondansetron did not modify the increase of extracellular dopamine caused by 10 mg/kg cocaine in the nucleus accumbens. The results suggest that 5-HT₃ receptor antagonists have no effect on the rewarding properties of cocaine or on the behaviour elicited by the stimuli previously associated with the drug's action.     

Anticataleptic properties of α<Subscript>2</Subscript> adrenergic antagonists in the crossed leg position and bar tests: differential mediation by 5-HT<Subscript>1A</Subscript> receptor activation

Rationale Recent studies suggest that ₂ adrenoceptor blockade may improve the antipsychotic-like effects of neuroleptics and attenuate dopamine D₂ receptor antagonist-induced catalepsy. However, several ₂ adrenergic antagonists also display serotonin 5-HT_1A receptor agonist activity, which may contribute to anticataleptic actions.Objectives In this study, we examined a series of ₂ adrenergic antagonists to determine the role of activity at serotonin 5-HT_1A receptors in their anticataleptic effects.Methods Catalepsy in rats induced by the antipsychotic haloperidol (2.5 mg/kg, SC) was measured using the cross-legged position (CLP) and bar tests. The compounds examined in this study, in decreasing rank order of ₂ adrenergic versus 5-HT_1A receptor selectivity, were atipamezole, methoxy-idazoxan (RX821002), efaroxan, idazoxan, and yohimbine. Antagonism studies were conducted using the selective 5-HT_1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide dihydrochloride (WAY100635).Results Idazoxan, efaroxan, and yohimbine significantly attenuated the cataleptic effects of haloperidol (2.5 mg/kg, SC) in the CLP test and the actions of their highest doses were significantly blocked by pre-treatment with WAY100635 (0.63 mg/kg, SC). In contrast to the other compounds, methoxy-idazoxan was ineffective in the CLP test. Atipamezole exhibited anticataleptic effects in the bar and CLP tests which were not blocked by WAY100635. Similarly, the anticataleptic effects of methoxy-idazoxan and idazoxan in the bar test were not blocked by WAY100635.Conclusions Serotonin 5-HT_1A receptors play a prominent role in anticataleptic effects of certain ₂ adrenergic antagonists in the CLP test, whereas ₂-adrenergic mechanisms are likely to be primarily responsible for the anticataleptic effects of these ligands in the bar test.     

Influence of 5-HT3 receptor antagonists and the indirect 5-HT agonist,dexfenfluramine, on heroin self-administration in rats

The purpose of the present study was to examine the effects of the 5-HT₃ antagonists ondansetron and MDL72222, and the 5-HT releaser and reuptake inhibitor dexfenfluramine, on intravenous heroin self-administration by Wistar rats. Using separate squads of animals, two separate schedules of heroin reinforcement were used; a relatively low dose (0.03 mg/kg per infusion) made available under a FR5 schedule for 1 h each day, and a moderate heroin dose (0.1 mg/kg per infusion) available under a FR1 schedule for 2 h each day. Following the acquisition of stable levels of responding across days, both naloxone pretreatment (0.25 mg/kg SC) and halving the heroin infusion dose produced increases in operant responding for heroin at each concentration. Neither ondansetron (0.01–1 mg/kg SC) nor MDL72222 (0.1–3 mg/kg SC) pretreatment influenced heroin self-administration. Chronic treatment (5 day) of ondansetron (0.01–0.1 mg/kg) was similarly ineffective. However, dexfenfluramine (0.5–2.5 mg/kg IP) consistently reduced heroin self-administration at doses producing only modest decreases in food responding. These findings are in contrast to place conditioning studies, which show that 5-HT₃ antagonists but not indirect 5-HT agonists block a morphine-induced place preference. Reasons for such discrepancies remain to be determined.     

The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test

 We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT_1A, 5-HT_1B/1D, 5-HT_2A, 5-HT₃ or 5-HT₄ receptors. The SSRIs, paroxetine (ED₅₀ in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (>30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT_1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT_1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT_2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT₃ receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT₄ receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT_2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT_1A receptor agonist, 8-OH-DPAT [(±)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT_2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/ kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT_1A and 5-HT_2A receptors produces a decrease of USV, we postulate that only 5-HT_2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety. Received: 19 May 1997 / Final version: 21 July 1997     

Effect of 5-HT3 receptor antagonists on the discriminative stimulus properties of morphine in rats

5-HT₃ receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously reported to block a morphine (1.5 mg/kg)-induced conditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine discriminative stimulus using a two-choice, food reinforced, operant paradigm. In an attempt to provide consistency with previous place conditioning studies, a morphine training dose of 1.5 mg/kg was used in addition to a higher 3 mg/kg dose which was studied in separate animals. Stimulus control of behaviour was attained at both morphine training doses, the characteristics of each being consistent with an effect at the mu opioid receptor. Ondansetron (0.001–1 mg/kg), MDL72222 (0.1–3 mg/kg), and ICS205-930 (0.001–1 mg/kg) all failed to consistently antagonise the morphine cue at both training doses, although a mild attenuation was seen in the 1.5 mg/kg group following pretreatment with an intermediate dose of ondansetron and ICS205-930 (both 0.01 mg/kg). The present results therefore suggest hat 5-HT₃ antagonists do not block a morphine discriminative state, at least in rats.     

Effects of acute selective 5-HT1, 5-HT2, 5-HT3 receptor andα 2 adrenoceptor blockade on naloxone-induced antinociception

Several studies have demonstrated a paradoxical form of antinociception induced by the repeated administration of opioid antagonists accompanied by exposure to a painful stimulus. The underlying mechanism of this naloxone-induced antinociception (NIA) is still unknown, but the results of several studies suggest that it is a non-opioid response. This study was designed to investigate serotonergic and noradrenergic involvement in NIA. Rats were treated daily with systemic injections of 5 mg/kg naloxone, followed by a 45-s hot plate test of nociception (temperature=51.5 ± 0.5°C). After rats reached plateau levels of NIA, they received a test trial in which they were treated with various doses of different selective 5-HT or ₂ adrenoceptor antagonists in addition to naloxone before the hot plate test. Rats treated with 0.16, 0.32 and 0.63 mg/kg pirenperone or 2.5 mg/kg ritanserin showed significant reductions in paw lick latency with respect to rats treated with vehicle. In addition, high doses of yohimbine (7.5–10 mg/kg) also effectively reversed NIA. In contrast, NIA was not affected by acute blockade of 5-HT₁ or 5-HT₃ receptors by methiothepin or MDL 72222, respectively, or by the ₂ adrenoceptor blocker idazoxan. None of the 5-HT or ₂ adrenoceptor antagonists had any effect on the paw lick latencies of saline-treated rats. A possible role of 5-HT₂ receptors in the antinociception induced by opioid receptor blockade is discussed.     

5-Hydroxytryptamine potentiates neurogenic contractions of rat isolated urinary bladder through both 5-HT(7) and 5-HT(2C) receptors

Serotonin (5-HT) enhances the neurogenic contractile response induced by electrical field stimulation (EFS) in the rat isolated urinary bladder. The aim of this study was to functionally characterize the receptors involved in this effect by using a range of 5-HT receptor subtype selective agonists and antagonists. 5-HT produced a concentration-dependent potentiation of contractile responses to EFS with a pEC₅₀ value of 6.86 ± 0.24. SB-269970 (0.01, 0.1 and 1 μM), a selective 5-HT₇ receptor antagonist, caused a concentration-dependent rightward shift of the 5-HT-induced response. The pA₂ value was 8.16 with a slope of 0.46 ± 0.08. Neither ketanserine nor SB-204741, 5-HT_2A and 5-HT_2B receptors antagonists, respectively, affected the concentration–response curve to 5-HT. However, 5-HT response was antagonized by the selective 5-HT_2C receptor antagonist SB-242084 (0.1 and 1 μM). In the presence of 1 μM of both antagonists SB-269970 and SB-242084, 5-HT response was almost fully inhibited. 5-CT, a 5-HT₇ receptor agonist, induced a biphasic concentration-dependent potentiation of neurogenic contractions. SB-269970 concentration-dependently antagonized the first phase of 5-CT response with a pA₂ value of 8.77 and a slope not significantly different from unity (0.91 ± 0.11) that suggests a competitive antagonism. WAY-161503, a 5-HT_2C receptor agonist (0.01–10 μM), induced a concentration-dependent potentiation of contractile response to EFS while DOI (a selective 5-HT_2A agonist) had no effect. SB-242084 (0.1 and 1 μM) antagonized the effect of WAY-161503 in a concentration-dependent manner. The current results demonstrate that 5-HT potentiates neurogenic contractions of rat isolated detrusor muscle through both 5-HT₇ and 5-HT_2c receptors.     

Pretreatment with serotonin 5-HT<Subscript>3</Subscript> receptor antagonists produces no observable blockade of long-term motor sensitization to cocaine in rats

Abstract Rationale. Serotonin 5-HT₃ receptor antagonists are proposed to serve as potential anti-addictive and anti-psychotic therapies. Objective. The present study re-examined the hypothesis that the activation of 5-HT₃ receptors is required for the development of long-term motor sensitization to repeated cocaine (COC). Methods. Rats were pretreated with vehicle (VEH) or one of three 5-HT₃ receptor antagonists, MDL 72222, Y-25130 or ondansetron, 30 min prior to seven daily COC or saline (SAL) injections. Three weeks later, animals were challenged with COC in a test for sensitization. For comparison, the effects of pretreatment with the dopamine (DA) receptor antagonist fluphenazine and a combination of fluphenazine and Y-25130 were assessed. Results. Pretreatment with ondansetron, Y-25130, fluphenazine and their combination significantly attenuated COC-induced behaviors during repeated treatment but not on the test for sensitization. MDL 72222 pretreatment enhanced motor sensitization on the test day. In repeated SAL rats, pretreatment with ondansetron, Y-25130 and fluphenazine+Y-25130 enhanced COC-induced rearing on the test for sensitization. Conclusions. These data indicate the effects of 5-HT₃ receptor antagonists on both acute COC-induced motor behavior and COC-induced motor sensitization are compound-selective. As none of the 5-HT₃ receptor antagonists attenuated the magnitude of the sensitized motor response to COC in the long term, these data also indicate that like DA receptor activation, 5-HT₃ receptor activation is necessary for the full expression of acute COC-induced motor hyperactivity, but it is not required for the development of long-term motor sensitization. Electronic Publication     

Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats

This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal—so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT₃ antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at deses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT₃ antagonist ondansetron (0.01–0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT₃ antagonists may have relatively limited utility in treating some signs of BZ dependence.     

Profile of action of 5-HT3 receptor antagonists,ondansetron and WAY 100289, in the elevated plus-maze test of anxiety of mice

The effects of ondansetron (0.001–0.1 mg/kg) and the novel 5-HT₃ receptor antagonist, WAY 100289 (0.01–10.0 mg/kg), on anxiety were examined in male mice using an ethological version of the elevated plus-maze paradigm. This procedure involves scoring specific aspects of defensive behaviour in addition to the more usual spatiotemporal measures. Results show that, at the doses tested, neither compound produced a behavioural profile consistent with anxiety reduction. Indeed, the lowest dose of ondansetron (0.001 mg/kg) produced some behavioural trends more typically associated with mild anxiety enhancement. Data are discussed in relation to the enigmatic effects of 5-HT₃ receptor antagonists in animal models of anxiety. It is suggested that the large within- and between-test variability observed with these compounds may indicate an action on mechanisms other than anxiety.     

Spatial memory alterations by activation of septal 5HT1A receptors: no implication of cholinergic septohippocampal neurons

Introduction

In rats, activation of medial septum (MS) 5-HT_1A receptors with the 5-HT_1A/5-HT₇ receptor agonist 8-OH-DPAT disrupts encoding and consolidation, but not retrieval of a spatial memory in the water maze task. These findings might be explained by an action of 8-OH-DPAT on 5-HT_1A receptors located on cholinergic neurons which the drug could transiently hyperpolarise. If so, selective damage of these neurons should mimic the effects of 8-OH-DPAT, or, at least, synergistically interfere with them.

Methods

To test this hypothesis, rats were subjected to intraseptal infusions of 8-OH-DPAT (or phosphate-buffered saline) during acquisition of a water maze task before and/or after 192 IgG-saporin-induced MS cholinergic lesion (vs. sham-operated).

Results

We confirmed that only pre-acquisition intraseptal 8-OH-DPAT infusions prevented learning and subsequent drug-free retrieval of the platform location in intact rats and found that (1) the cholinergic lesion did not prevent recall of the platform location, and (2) the impairing effects of 8-OH-DPAT were similar in sham-operated and lesioned rats, whether na?ve or not, to the task before lesion surgery.

Conclusions

An action of 8-OH-DPAT on only MS cholinergic neurons is not sufficient to account for the drug-induced memory impairments. A concomitant 8-OH-DPAT-induced hyperpolarisation of cholinergic and/or GABAergic and/or glutamatergic neurons (intact rats), or of only GABAergic and/or glutamatergic ones after cholinergic lesion, might be necessary to obliterate task acquisition, confirming that, in the MS, (1) the three neuronal populations could cooperate to process hippocampal-dependent information, and (2) non-cholinergic septohippocampal neurons might be more important than cholinergic ones in serotonin-induced modulation of hippocampus-dependent memory processing.     

Effects of 5-HT3 agonists on reproductive behaviors in rats

Activity at 5-HT₁ and 5-HT₂ receptor sites influences sexual behavior in male and female rats. 5-HT₃ antagonists reportedly have no effect on copulatory activity in rats of either sex although they influence a variety of other behaviors. The effects of 5-HT₃ agonists on sexual behavior are unknown. The following experiments were undertaken to assess the influence of the 5-HT₃ agonists 1-phenylbiguanide (PBG) and 2-methyl-serotonin (2-Me-5-HT) on sexual behavior, when administered intracerebroventricularly. Consistent with earlier reports indicating that 5-HT₁ and 5-HT₂ receptor activity influences reproductive activity in a sex-dependent manner, PBG was found to facilitate male, but not female, rat sexual behavior. 2-Me-5-HT, however, failed to modify either female or male rat sexual activity. Evidence that PBG, but not 2-Me-5-HT, induces carrier-mediated dopamine release suggests that the effect of PBG in male rats is due to dopaminergic mediation. Overall, the present data indicate that 5-HT₃ receptor activation has only slight effects on rat sexual behavior.     

Inhibition by 5-HT3 receptor antagonists of release of cholecystokinin-like immunoreactivity from the frontal cortex of freely moving rats

Summary Effects of the 5-HT₃ receptor antagonists, ondansetron and tropisetron, on the release of cholecystokipin-like immunoreactivity (CCK-LI) in rat frontal cortex were investigated in conscious, unrestrained rats using intracerebral microdialysis. The release of CCK-LI was augmented by perfusion with 100 g/ml veratrine and was fully Ca²⁺-dependent and tetrodotoxin-sensitive. Ondansetron and tropisetron, each at 0.1–1 mol/l, decreased concentration-dependently the veratrine-evoked efflux of CCK-LI. The reduction of CCK-LI output was approximately 30%u when the antagonists were infused at 0.1 mol/l.The data suggest that 5-HT₃ receptor antagonists prevent the release of CCK evoked by endogenous 5-hydroxytryptamine. These drugs may thus represent a novel therapeutic approach in disease states, like anxiety, in which an inappropriately high release of brain CCK or 5-hydroxytryptamine seems to be involved.Correspondence to M. Raiteri at the above address