Anxiolytic profile of ropinirole in the rat, mouse and common marmoset.

RATIONALE: Some features of Parkinson's disease are exacerbated by stress and anxiety and it is important to understand the effects of dopamine receptor agonists on measures of anxiety. The aim of this study was to assess the effects of the dopamine D2/D3 receptor agonist ropinirole in models of anxiety and depression in the rat, mouse and marmoset. RESULTS: In the rat elevated plus-maze test, ropinirole (0.01-1 mg/kg, i.p.) produced an inverted-U dose-response curve in the percentage time spent in the open arms. Compared with vehicle, ropinirole (0.1 mg/kg) had a significant anxiolytic-like effect, which was similar to that observed with 1.5 mg/kg diazepam. This effect was found at doses that did not affect motor behaviour or induce stereotypy. In the mouse black and white box test of anxiety, ropinirole (0.1-10 mg/kg, i.p.) increased both the rearing time and number of line crosses in the white section. This effect reached statistical significance for both measures at a dose of 0.1 mg/kg and suggests an anxiolytic-like action of the compound. By contrast, the dopamine agonist bromocriptine (0.1-10 mg/kg, i.p.) did not produce significant changes in these behaviours. In the marmoset human threat test, ropinirole (0.01-10 microg/kg, s.c.) reduced the number of postures at all doses tested and this reached statistical significance at 10 microg/kg. Ropinirole did not compromise the effect of amitriptyline in the Porsolt test of depression and in itself produced antidepressant-like effects. CONCLUSIONS: These data demonstrate that systemic administration of ropinirole produces anxiolytic-like effects in three separate models in the mouse, rat and marmoset. This may predict an action of ropinirole in man that would provide a superior profile of action over other presently available anti-parkinsonian agents.

Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset.

The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment induced by the muscarinic receptor antagonist, scopolamine. For this purpose, marmosets were trained in an object discrimination task utilizing the Wisconsin General Test Apparatus. Administration of scopolamine (0.01-0.04 mg/kg, SC) caused a dose-dependent impairment in the acquisition of the object discrimination task in that marmosets required more trials to reach criterion, made more errors, and took longer to choose the objects. Administration of arecoline (0.06-0.1 mg/kg, SC) or 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one,HCl.2H2O (ondansetron) (0.1-1 micrograms/kg, SC) prevented the scopolamine-induced impairment in task acquisition in that the performance of marmosets was indistinguishable from that of saline-treated animals and was significantly better than that following scopolamine/saline. From these studies, we conclude that ondansetron prevents impairment in the cognitive performance of marmosets induced by administration of scopolamine.

The effects of umespirone as a potential anxiolytic and antipsychotic agent.

Umespirone was compared to buspirone, diazepam and clozapine as a potential anxiolytic and antipsychotic agent. In the mouse black and white test box, umespirone was considerably more potent than diazepam or buspirone to reduce aversive responding, tolerance to its effects was not observed and sedation was absent, a chronic treatment and withdrawal was not associated with an anxiogenic profile, and umespirone prevented the behavioural consequences of withdrawal from diazepam. Umespirone also had an anxiolytic profile of action in the tests of rat social interaction and in the marmoset exposed to a human threat. Both umespirone and clozapine reduced the hyperactivity induced by the infusion of dopamine into the nucleus accumbens of rat. In radioligand binding assays umespirone demonstrated nanomolar affinity for the alpha 1-adrenoceptor and the 5-HT1A and dopamine D2 receptors. It is concluded that umespirone may present as a novel psychotropic agent with anxiolytic and antipsychotic potential.

The effect of ondansetron on cognitive performance in the marmoset.

The 5-HT3 receptor antagonist, ondansetron, was administered to marmosets to determine its effect on their performance in a Wisconsin General Test Apparatus using an object discrimination reversal learning task. Briefly, this comprised a test situation in which marmosets were required to select a food rewarded object to reach criterion in performance (this was termed the initial discrimination task); the rewarded object was then changed (in the same test session) and the marmoset was required to abandon its recently learned strategy to gain reward by selection of the second object (this was termed the reversal task). At doses of 1-10 ng/kg SC b.i.d. ondansetron improved performance in both the initial discrimination and reversal tasks. This was indicated as a reduction in the number of trials required to reach criterion, a reduction in choice latency time and a reduction in the number of errors made in each test session. Higher doses of ondansetron impaired performance as measured by several criteria. The major conclusion of this study is, therefore, that ondansetron at low doses is able to improve the performance of marmosets in a cognitive task. This would support the concept that a 5-HT3 receptor antagonist can act as a cognitive enhancer.

Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist.

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.

Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset.

The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates.

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.

Zacopride: anxiolytic profile in rodent and primate models of anxiety.

Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug's action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.