Zalospirone

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.

The olfactory bulbectomized (OB) rat has been proposed as an animal model of depression. The following behavioural changes have been observed following bilateral olfactory bulbectomy: hyperactivity in an enclosed arena, such as the open-field; enhanced nocturnal hyperactivity in a 24-hr home cage activity monitor; deficits in memory, as shown by passive avoidance behaviour and in the Morris maze and the 8-arm radial maze; increased open arm entries in the elevated plus-maze; and changes in food motivated and conditioned taste aversion behaviour. Alterations in the noradrenergic, serotonergic, cholinergic, gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmitter systems are also associated with olfactory bulbectomy. The variety of immune changes following olfactory bulbectomy includes reduced neutrophil phagocytosis, lymphocyte mitogenesis, lymphocyte number and negative acute phase proteins, increased leucocyte adhesiveness/aggregation, monocyte phagocytosis, neutrophil number and positive acute phase proteins. An enhanced nocturnal secretion of corticosterone is observed in OB rats, which is normally suppressed by dexamethasone. The most commonly employed behavioural indicator of antidepressant activity is attenuation of the OB-related hyperactivity in the open-field. However, many of the other behavioural, neurotransmitter and immune changes have been shown to be attenuated by chronic (but not acute) antidepressant treatment. Tricyclic antidepressants (amitriptyline, desipramine), atypical agents (mianserin), selective serotonin reuptake inhibitors (paroxetine, sertraline, fluvoxamine), reversible inhibitors of monoamine oxidase A (moclobemide), as well as putative antidepressants such as 5-hydroxytryptamine1A agonists (zalospirone, ipsapirone), noncompetitive N-methyl-D-aspartate antagonists (MK-801) and triazolobenzodiazepines (alprazolam, adinazolam), have demonstrated antidepressant-like activity in this model. As many of the changes exhibited by the OB rat are qualitatively similar to those observed in depressed patients, it may be concluded that the OB rat is a model of depression and not just a means whereby putative antidepressants may be tested.