M. Elizabeth Kelly

The actions of nicotine and cocaine in a mouse model of anxiety

The acute administration of nicotine (0.01-1.0 mg/kg IP) to the mouse increased the time spent and rearings and line crossings in the aversive brightly illuminated white area of a two compartment white/black test box, with a corresponding decrease in the black. This profile of change was maintained during twice daily administration (0.1 mg/kg IP) for 14 days. Eight to 96 hr following withdrawal of nicotine (14-day treatment), the behavioural profile was reversed to a preference for the black area: by 240 hr values had returned to control levels. In contrast to the effects of nicotine, an acute injection of cocaine (0.1-10 mg/kg IP) exacerbated the aversive response to the white area. However, similarly to nicotine, the administration of cocaine (1.0 mg/kg IP) twice daily for 14 days reduced the aversion to the white area and exacerbated the response following cocaine withdrawal. The effects of nicotine and cocaine to reduce and enhance responsiveness to the aversive properties of the white area are discussed in terms of an anxiolytic and anxiogenic response and the possibility of a serotonergic involvement.

Cognitive enhancing actions of PD123177 detected in a mouse habituation paradigm

The anxiolytic-like and cognitive enhancing potential of PD123177, a non-peptide with selectivity for the angiotensin II-2 receptor recognition site, was assessed in a mouse light/dark aversion test and habituation test, respectively. PD123177 (0.01 ng kg-1 to 1.0 mg kg-1 i.p.) failed to alter the behavioural repertoire of animals in the light/dark aversion test. In contrast, daily administration of PD123177 (10.0 ng kg-1 i.p. b.d.) enhanced the performance of mice in a habituation test. In addition, PD123177 overcame the cognitive impairment induced by the administration of scopolamine (0.25 mg kg-1 i.p.). Such findings indicate for the first time a functional role for the angiotension II-2 receptor and further implicate the angiotensin system in the modulation of cognitive processes.

The effects of ACE inhibitors captopril and SQ29,852 in rodent tests of cognition.

The ACE inhibitors captopril and SQ29,852 enhanced a habituation response to bright illumination in young adult and aged mice measured in a two-compartment light/dark test box. The treatments also antagonised a scopolamine-induced impairment and SQ29,852 was approximately 100 times more potent than captopril. In rats trained on a reinforced alternation paradigm in a T-maze, aged rats, as compared to young adults, showed a reduction in choice performance which was antagonised by SQ29,852. The impairment in choice performance in the T-maze induced by scopolamine in young adult rats was antagonised by SQ29,852 whilst captopril only delayed the onset of the scopolamine-induced impairment. SQ29,852 also antagonised scopolamine-impaired escape latency in a spatial learning/memory paradigm in a water-maze test. The effects of SQ29,852 in the rat were achieved within a somewhat restricted dose range. The ability of captopril and SQ29,852 to increase performance in the behavioural tests is discussed in terms of an antagonism of angiotensin converting enzyme to remove an inhibitory role of angiotensin II on central cholinergic function.

The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.

The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.

Anxiolytic-like action of DuP753, a non-peptide angiotensin II receptor antagonist.

The potential of DuP753, an angiotensin II receptor antagonist, to inhibit the suppressed behaviour of mice in a light/dark aversion test was investigated. The aversive response to the light compartment of the apparatus was reduced (increase in latency to move from the light to the dark compartment and decreases in rears, line crossings and percentage of time spent in the dark compartment) following treatment with DuP753 (0.1-1000 micrograms kg-1 p.o., 45 min before the test). These results further implicate the modulation of mental function by angiotensin II.

Withdrawal syndrome following subchronic treatment with anxiolytic agents

The acute administration of diazepam (0.1-2.5 mg/kg IP), sulpiride (0.5-20 mg/kg IP) and tiapride (0.5-40 mg/kg IP) to the mouse enhanced exploratory activity (rearings/line crossings) in the brightly illuminated white area of a two compartment white/black anxiety test box, with a corresponding decrease in the black, indicating an anxiolytic action. This profile of change was maintained during a twice daily administration for 7 days with diazepam (2.5 and 10 mg/kg), sulpiride (5 and 20 mg/kg) and tiapride (10 and 40 mg/kg). However, 8 and 48 hr following withdrawal of diazepam, the profile of exploratory behaviour was reversed to a preference for the black area: by 96 hr values for behaviour had returned to control levels. In contrast, an anxiolytic profile of action was maintained 8 and 48 hr following the withdrawal of sulpiride and tiapride, the values returning to control levels after 96 hr. It is concluded that a sub-chronic treatment with diazepam, sulpiride and tiapride induces an anxiolytic profile of action in the mouse model, that an anxiogenic profile follows the abrupt withdrawal of diazepam but that this is not recorded following the abrupt withdrawal of sulpiride and tiapride.

Profiles of interaction of R(+)/S(-)-zacopride and anxiolytic agents in a mouse model

The mouse black and white test box was used to measure changes in behaviour in an aversive situation where the administration of R(+)-zacopride (but not S(-)-zacopride) alone decreased aversive responding to the white area. A similar anxiolytic profile of action was observed using parachlorophenylalanine (PCPA), whose effects were antagonised by a co-treatment with R(+)-zacopride and reversed by S(-)-zacopride to an exacerbation of the aversive response. An anxiolytic profile of action was also observed using ondansetron, granisetron, chlordiazepoxide, diazepam, ritanserin, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), E4424 (2-[4-[4-(4-chloro-l-pyrazoyl)butyl]-l-piperazinyl]-pyrimidine), umepsirone, DuP753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)]-imidazole), SQ29,852 ((S)-1-[6-amino-2[hydroxy)(4-phenyl-butyl)phosphinyl]-oxy)-1- nexy]-2-proline), devazepide and guanfacine, and this was retained following co-treatment with PCPA. The anxiolytic profile of action of PCPA was also retained following co-treatment with renzapride which when administered alone failed to modify behaviour. However, the ability of chlordiazepoxide, diazepam, ondansetron and E4424 (but not devazepide, DuP753 or SQ29,852) to reduce aversive responding was inhibited by co-treatment with R(+) and/or S(-)-zacopride. It is concluded that the reduction in aversive responding caused by pharmacological manipulation at the benzodiazepine, 5-HT receptor subtypes 5-HT1A, 5-HT1C/5-HT2 and 5-HT3 (but not at the cholecystokin CCKA or angiotensin receptors or inhibition of angiotensin converting enzyme) can be inhibited by R(+) and S(-)-zacopride. The data is discussed in terms of zacopride having an agonist or partial agonist effect at the 5-HT3 receptor.

The production of asymmetry and circling behaviour following unilateral, intrastriatal administration of neuroleptic agents: A comparison of abilities to antagonise striatal function

The abilities of typical and atypical neuroleptic agents to antagonise at striatal dopamine receptors were determined in the rat. Neuroleptic agents were injected unilaterally into the striatum and asymmetric body posturing/circling behaviour (always ipsilateral to the side of neuroleptic injection) assessed (1) to neuroleptic challenge alone (vehicle injected into the contralateral striatum), (2) as that revealed after neuroleptic challenge by peripherally administered apomorphine or (3) by dopamine injection into the contralateral striatum. Unilateral intrastriatal fluphenazine (1-5 micrograms), cis- and trans-flupenthixol (1-20 micrograms), haloperidol (0.5-5 micrograms), thioridazine (5-10 micrograms), clozapine (1-5 micrograms), tiapride (1-5 micrograms), metoclopramide (1-10 micrograms), (+)-sulpiride (20 micrograms) and piperoxan (10 micrograms) each failed, alone, to cause any postural asymmetry/circling. However, ipsilateral asymmetry was induced by unilateral intrastriatal (-)-sulpiride (1-5 micrograms). In contrast, ipsilateral asymmetry developed when the intrastriatal injection of all neuroleptic agents (excepting (+)-sulpiride and trans-flupenthixol) was followed by peripheral challenge with apomorphine: effective neuroleptic doses were all in the range 0.5-10 micrograms, although (-)-sulpiride was effective at 0.001-0.1 microgram. Active circling was only recorded for (-)-sulpiride and tiapride. The striatal imbalance caused by (-)-sulpiride could be revealed by apomorphine for 24 h, although other intrastriatal neuroleptic responses persisted for 6-8 h. The abilities of all neuroleptic agents to cause striatal imbalance could also be revealed by injecting dopamine into the contralateral striatum (at a dose which alone did not cause any asymmetric motor responding). These intrastriatal injection approaches are forwarded as valuable techniques for determining striatal dopamine antagonist activity in the rodent.

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.