The predictive validity of catalepsy as a rodent model for detecting the extrapyramidal side effects (EPS) of antipsychotic drugs was recently questioned when the novel antipsychotic savoxepine produced little catalepsy in rodents while producing significant EPS in schizophrenic patients. Because catalepsy is viewed as an important model for predicting EPS, we decided to re-evaluate the effects of savoxepine. Savoxepine, clozapine, haloperidol, olanzapine, ORG 5222, raclopride, and risperidone were examined in two tests for catalepsy (grid and bar tests) in male Sprague-Dawley rats. The ability to antagonize amphetamine-induced hypermotility was also examined, since this measure is believed to predict clinical efficacy. With the exception of clozapine, all drugs produced dose-dependent catalepsy in both tests. For each drug, the minimum effective dose for producing catalepsy was greater than or equal to the ED50 for antagonizing amphetamine-induced hyperactivity (defined as the dose producing a 50% reduction in hyperactivity). Clozapine resulted in the widest separation of effective doses in the catalepsy and activity models. Raclopride produced the next largest separation while the remaining drugs resulted in only a one- or two-fold dose separation between the two behavioral tests. The results with haloperidol and clozapine are consistent with the clinical effects of these drugs (severe versus mild EPS). The ratios of effective doses in catalepsy and activity for the remaining novel drugs are also consistent with preliminary clinical findings indicating some EPS with each of these compounds. Thus, catalepsy remains a suitable rodent model for detecting compounds with EPS liability in humans.

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperiodol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D2 receptor affinity. In the present study, the role of the D1 receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D1 receptor antagonist SCH 23390 were examined and compared to the effects of the D2 receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D1 antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D2 antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D1 or D2 receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Because amphetamine-induced place conditioning is believed to be mediated by dopamine (DA) receptors within the nucleus accurnbens, this behavioral model may be useful for detecting drugs with antipsychotic efficacy. To test the selectivity and specificity of the model, the present study examined whether amphetamine-induced place conditioning is reversible in rats pretreated with the classical antipsychotic haloperidol, the atypical antipsychotic clozapine, and the novel antipsychotics raclopride and risperidone. The non-antipsychotic drugs baclofen and prazosin were also tested. Male Sprdgue-Dawley rats received d-amphetamine (5.4 pmolikg ip) paired with one side of d two-compartment box and saline paired with the other side. During these pairings, locomotor activity was measured On the test day, the amount of time drug-free rats spent in each compartment was determined Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre-to postconditioning, indicating a place preference. Pretreatment with the highest dose of either haloperidol (0 026, 0.13, 0 26 p+mol/kg 5c), clozdpine (3, 15, 30, 60 pmolikg sc), raclopride (0 1 , 0.2, 1 0 pmol/kg), or risperidone (0 12, 0 24, 1 2 pmolikg sc) prior to amphetamine significantly blocked the establishment of place conditioning. Treatment with the antipsychotic alone did not support place conditioning (preference or aversion) On conditioning days, hdloperidol, clorapine, raclopride, and risperidone significantly decreased amphetamine-induced locomotor activity Pretreatment with either baclofen or prazosin failed to disrupt amphetarnine-induced place conditioning despite significant decreases in locomotor activity on the conditioning days These data provide preliminary cupport for amphetarnine place conditioning as a rodent model for detecting drugs with antipsychotic efficacy o 1995 Wllcy-Lls inc