clozapine and umespirone

Blockade of glutamatergic transmission in the striatum (using the NMDA-antagonist DL-2-amino-5-phosphonovaleric acid AP-5) was recently shown to induce stereotyped sniffing in rats. Comparable stereotyped behaviour is well known to be elicited by stimulation of dopamine activity, which since long was the basis for experimental models to check for possible antipsychotic activity of new compounds. However, whereas dopamine-induced stereotypies are antagonized only by classical neuroleptics, stereotypies induced by blockade of glutamatergic transmission are antagonized by classical as well as by atypical antipsychotics. Umespirone, a novel psychotropic which has been reported to exhibit behavioural effects predictive for antipsychotic as well as anxiolytic potential was evaluated for antagonistic effects against AP-5-induced behaviour. The profile of umespirone was compared with the profile of a non-benzodiazepine anxiolytic buspirone as well as with previously published data of neuroleptics. Umespirone like clozapine specifically antagonized AP-5-induced sniffing, i.e. did not impair spontaneous sniffing but reversed AP-5-induced excessive sniffing. In contrast, buspirone impaired spontaneous and AP-5-induced sniffing to about the same extend. These results are in accordance with the glutamate hypothesis of schizophrenia and again give evidence that umespirone should have antipsychotic potential and a very low liability to exhibit unspecific sedative action.

Topics: 2-Amino-5-phosphonovalerate; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Buspirone; Clozapine; Male; Molecular Structure; Odorants; Rats; Rats, Inbred Strains; Stereotyped Behavior; Structure-Activity Relationship

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.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Buspirone; Callithrix; Clozapine; Diazepam; Dopamine; Female; Interpersonal Relations; Limbic System; Male; Mice; Rats; Rats, Inbred Strains; Receptors, Drug; Substance Withdrawal Syndrome; Tetrahydronaphthalenes

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Avoidance Learning; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Buspirone; Chlorpromazine; Clozapine; Diazepam; Male; Mice; Rats; Rats, Inbred Strains; Time Factors

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Avoidance Learning; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Buspirone; Chlorpromazine; Clozapine; Conflict, Psychological; Diazepam; Rats; Rats, Inbred Strains; Receptors, Serotonin