Evaluation of the potential of antipsychotic agents to induce catalepsy in rats: assessment of a new, commercially available, semi-automated instrument

Abstract

Haloperidol induced catalepsy was determined using the classic bar test and a new MED Associates Catalepsy Test Chamber instrument. The dose that produced an adverse effect in 50% of rats (AED50) for haloperidol was calculated using the instrument data as 0.29 mg/kg. Hand scoring of the video recordings gave AED50 values of 0.30 and 0.31 mg/kg, both well within the 95% CL of the instrument data. Clozapine was also evaluated and catalepsy was not detected up to 40 mg/kg. No significant difference was found between the instrument and hand scoring data. The instrument was useful for testing haloperidol and clozapine, relieving much of the tedium and variability experienced without its use. It was especially valuable at measuring shorter time periods, where the researcher cannot react as quickly. Finally, olanzapine was also evaluated. However, clenched forepaws and hind paws prevented the use of the instrument alone at higher doses. A backup stopwatch was used for the bar test in these cases. Some of the advantages and limitations are discussed. Results are also compared to the crossed-legs position (CLP) test for all three antipsychotics. While haloperidol gave similar results at all concentrations tested, clozapine deviated significantly at the highest dose (40 mg/kg) displaying catalepsy in the CLP test but not in the bar test. Olanzapine displayed catalepsy in rats significantly different from vehicle at 40 mg/kg in both the bar and CLP tests. However, the CLP test may be more suited to compounds with gripping problems which prevent the consistent grasping of the bar. Overall, the instrument was found to be a useful aid in conducting the bar test for catalepsy. The CLP test was found to complement the bar test under certain conditions and could provide additional data that might be missed by the bar test for compounds producing grasping problems.

Keywords: Atypical antipsychotics; Bar test for catalepsy; Catalepsy instrument; Crossed-leg position (CLP) test; Extrapyramidal side effect (EPS); Typical antipsychotics.

Figure 1

Med Associates Catalepsy Test Chamber system. Four white test chambers with bars are shown in the foreground. Computer used for data collection and associated hardware (center blue module on left only) are shown in the background. Other units are for other test systems.

Figure 2 A-F

Meantime in seconds in the bar test measured using the instrument (Inst) (graphs A, C, E), instrument plus stopwatch (SW + Inst) (graph E, solid line), or in the CLP test measured with a stopwatch (graphs B, D, and F). Graph A, haloperidol bar instrument, AED₅₀ = 0.29 mg/kg. Graph B, haloperidol CLP, AED₅₀ = 0.38 mg/kg. Graph C, clozapine bar instrument, no significant catalepsy. Graph D, clozapine CLP, significant catalepsy at 40 mg/kg. Graph E, olanzapine stopwatch + instrument (SW + Inst.), significant catalepsy at 40 mg/kg. Graph E, Inst. only, gripping problems prevented accurate detection of time on the bar. Dashed line shown only to illustrate problem. Graph F, olanzapine CLP, significant catalepsy at 40 mg/kg. n=7 rats/dose. Compared to vehicle, **, ***, and **** indicate p < 0.01, 0.001, and 0.0001 respectively.

Figure 3 A-D

Comparison of time in seconds measured by the instrument (filled circles, squares, and triangle) to hand scoring of video playback (open circles, squares, and triangle). No significant difference between the instrument and either researcher #1 (graphs A and B) or #2 (graphs C and D) at any dose, t-test, p > 0.05. (n=7 rats/dose).

Figure 4 A-B

Correlation between data obtained using the instrument and data obtained from researcher observations of video recordings for haloperidol using the bar test. The times (seconds) for 35 data pairs for graphs A and B, were evaluated. Correlation coefficients r = 0.9985 (graph A) and r = 0.9975 (graph B) were found, with a 2-tailed probability p < 0.0001 for all graphs (A, B).