Antipsychotic-induced suppression of locomotion in juvenile, adolescent and adult rats

Abstract

Schizophrenia is a serious psychiatric disorder that is most frequently treated with the administration of antipsychotics. Although onset of schizophrenia typically occurs in late adolescence, the majority of preclinical research on the behavioral effects of antipsychotics and their mechanism(s) of action has been conducted on adult male animals. In this study, the acute effects of haloperidol (0.03-0.3 mg/kg, i.p.) and clozapine (1-10 mg/kg, i.p.) on locomotor activity were examined in juvenile [postnatal day 22 (PN22)], adolescent (PN40), and adult (>PN70) rats of both sexes. Subsequently, in order to determine whether tolerance to the activity suppressive effects of these drugs would occur in adolescents, PN40 rats were dosed and assessed for an additional nine days. While all groups exhibited some degree of suppression following acute administration of both drugs, juvenile rats were considerably more sensitive to this effect. With sub-chronic administration during late adolescent development (PN40-PN49), tolerance failed to develop. These results emphasize the importance of age in pharmacological characterization of antipsychotics and suggest that pre-adolescents may have enhanced sensitivity to the motor effects of these drugs. Further, they suggest that, similar to adults, older adolescents may not develop tolerance to the activity suppression induced by these two antipsychotics.

Figure 1

Left panels show acute effects of haloperidol on spontaneous activity in female (panel A) and male (panel B) rats aged PN22, PN40 and adult. Right panels show acute effects of clozapine on spontaneous activity in female (panel C) and male (panel D) rats aged PN22, PN40 and adult. Baseline activity after vehicle (saline) injection is shown at the left of each panel and is the same for each drug. Each value represents the mean (± S.E.M.) of data from 6–10 rats, except for the vehicle condition, n=10–16 rats. # indicates significant main effect (P<0.05) for age as compared to adult. $ indicates significant main effect (P<0.05) for dose as compared to vehicle. * and + indicate significant age X dose interaction and that value is different from vehicle for that age (*) or from the adult group at the dose (+), respectively.

Figure 2

Effects of repeated injections of saline on spontaneous activity (total number of photocell beam breaks) in female and male rats aged PN40–PN49 are shown in panels A and D, respectively. The middle set of panels show effects of haloperidol on spontaneous activity during the same time period in female (panel B) and male (panel E) rats. Values are expressed separately for each sex as a percentage of saline control for haloperidol for the day (as shown in panels A and D for females and males, respectively). Panels C and F show effects of clozapine on spontaneous activity in female and male rats, respectively. Values are expressed separately for each sex as a percentage of saline control for clozapine for the day (as shown in panels A and D for females and males, respectively). Each value represents the mean (± S.E.M.) of data from 4–7 rats. ANOVA indicated a significant main effect (P<0.05) for day for saline controls, with means for all days different from PN40. $ in the symbol legend indicates significant main effect (P<0.05) for the dose compared to saline.