A new generation of proven or potential
antipsychotics, including
aripiprazole,
bifeprunox,
SSR181507 and
SLV313, exhibit agonist actions at
serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo
antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as
haloperidol,
olanzapine and
risperidone. All the drugs dose-dependently reduced
apomorphine-induced climbing or sniffing and, with the exception of
ziprasidone, produced complete suppression of these responses. In the bar
catalepsy test, when administered alone,
haloperidol,
olanzapine and
risperidone produced marked
catalepsy, whereas, at doses up to 40 mg/kg,
aripiprazole,
SLV313,
SSR181507, and
sarizotan produced little or no
catalepsy. The latter compounds, therefore, displayed a large separation between doses with '
antipsychotic-like' and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of
SSR181507 and
sarizotan were unmasked, and the
catalepsy induced by
bifeprunox was enhanced. In the case of
aripiprazole and
SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of
catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that
5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel
antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.