S 16924 antagonized locomotion provoked by
dizocilpine and
cocaine, reduced conditioned avoidance responses and blocked climbing elicited by
apomorphine, models predictive of control of the positive symptoms of
schizophrenia: its median inhibitory dose (ID)50 was 0.96 mg/kg, s.c. vs. 1.91 for
clozapine and 0.05 for
haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D1 agonist,
SKF 38393, and by the D2 agonist,
quinpirole, was blocked equipotently by
S 16924 (0.8 and 1. 7) and
clozapine (0.6 and 2.0), whereas
haloperidol preferentially blocked
quinpirole (0.02) vs.
SKF 38393 (1.8).
S 16924 more potently inhibited the head-twitches elicited by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by
phencyclidine than it inhibited the locomotion elicited by
amphetamine (ID50s = 0.15 and 0.02 vs. 2.4).
Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not
haloperidol (0. 07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by
S 16924 (ID50 = 0.17) and
clozapine (0. 05) but not by
haloperidol (>0.16).
S 16924 fully (100%) generalized [effective dose (ED)50 = 0.7] to a
clozapine DS and
clozapine (0.23) fully generalized to a
S 16924 DS whereas
haloperidol (>/=0.08) only partially generalized (</=50%) to their DS in each case. Power spectra analysis of electroencephalograms from frontal cortex showed that both
S 16924 (2.0) and
clozapine (5.0) reinforced frequencies in the 7 to 8 Hz range whereas
haloperidol (0.5) preferentially reinforced frequencies in the 10 to 14 Hz range. In a model of perturbation of cognitive-attentional function, significant latent inhibition was obtained with
S 16924 (0.08) and
clozapine (0.16), but not
haloperidol (0.0063 and 0.04): higher doses of
S 16924 (2.5),
clozapine (5.0) and
haloperidol (0.1) all blocked disruption of latent inhibition by
amphetamine (1.5).
Catalepsy was provoked by
haloperidol (0.04-0.63) but not by
S 16924 (>/=80.0) or
clozapine (>/=80.0). Further,
S 16924 (ID50 = 3.2) and
clozapine (5.5) inhibited induction of
catalepsy by
haloperidol. This action of
S 16924 was abolished by the
5-HT1A receptor antagonist,
WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of
clozapine. Further, although gnawing elicited by
methylphenidate was inhibited by
S 16924 (ID50 = 8.4),
clozapine (19.6) and
haloperidol (0.04), only the action of
S 16924 was blocked by
WAY 100,635 (0.16).
Haloperidol potently (0.01-0.16, approximately 24-fold) increased
prolactin levels whereas they were less markedly affected by
S 16924 (2.5-40.0, 4-fold) and
clozapine (10.0-40.0, 3-fold).
Clozapine displayed high affinity at cloned, human,
muscarinic (M1) and native,
histamine (H1) receptors (Kis = 4.6 and 5.4 nM, respectively), whereas
S 16924 (>1000 and 158) and
haloperidol (>1000 and 453) displayed low affinity. In conclusion,
S 16924 displays a profile of activity in diverse models of potential
antipsychotic and extrapyramidal properties similar to that of
clozapine and different to that of
haloperidol. In particular, reflecting its partial agonist actions at 5-HT1A receptors,
S 16924 inhibits rather than induces
catalepsy in rats. However, in contrast to
clozapine,
S 16924 displays only low affinity for
muscarinic and histaminic receptors.