Time Course of the Antipsychotic Effect and the Underlying Behavioral Mechanisms

Abstract

Antipsychotic drugs work for patients only when given repeatedly. The overall temporal pattern of symptom improvement is not clear. Some recent data question the traditional 'delayed-onset' hypothesis and suggest that the onset of antipsychotic response may be relatively early, and the improvement may grow with repeated treatment. The present study systematically examined the time course of the antipsychotic effect and the underlying behavioral mechanisms using a conditioned avoidance response (CAR) model. Rats repeatedly treated with either typical (haloperidol) or atypical (olanzapine, risperidone) antipsychotics, but not anxiolytics (chlordiazepoxide), show an early-onset, progressive across-session decline in avoidance responding, which re-emerges when the treatment is stopped. This effect is dose-dependent, transferable between antipsychotics, and cannot be attributed to simple sedation or motor side effects. Furthermore, we found that the pattern of this drug-induced decline depends on the number of exposures to the conditioned stimulus in the presence of the drug, and is best understood as the result of drug-induced attenuation of the reinforcing effectiveness of the conditioned stimulus. We also found that repeated drug exposure can create a drug interoceptive state that allows the attenuated reinforcing property of the stimulus to be maintained over time. Together, these data provide preclinical support for the newly postulated 'early-onset' hypothesis, and suggest that the repeated antipsychotic CAR model may be useful for understanding the neurochemical and behavioral mechanisms underlying the clinical effects of antipsychotics in patients with schizophrenia.

Cognitive performance in neurokinin 3 receptor knockout mice

“…The effect of NK 3 knockout on active avoidance seen in the present study stands in contrast to the effects of currently known antipsychotics, which impair performance in the active avoidance task when given both acutely and chronically (Li et al 2007;Wadenberg and Hicks 1999). Indeed, deficits in active avoidance have been suggested as a screening method for detecting antipsychotic activity.…”

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…Based on measures of D2 receptor occupancy, Kapur et al (2003) concluded that in order to achieve D2 receptor occupancy in the rat that corresponds with D2 occupancy in patients following clinically effective doses (65-80% D2 occupancy), 0.04-0.08 mg per kg haloperidol needs to be administered. Defining a low dose in terms of lower, 50% D2 receptor occupancy, 0.025 mg per kg (Li et al, 2007a) was selected as a dose (see also Table 1 in Kapur et al, 2003). Haloperidol was administered for 10 days and given 30 min prior to the task onset, so that performance was assessed while plasma levels rose and before reaching the half-life point for haloperidol in rats (Cheng and Paalzow, 1992).…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…We recently developed a rat conditioned avoidance responding model based on a repeated treatment regimen and examined its validity in modeling the time course of antipsychotic effect (Li et al, 2007). We found that rats repeatedly treated with haloperidol, olanzapine, or risperidone exhibited a decrease in avoidance responding starting on the first day of treatment.…”

“…We included 10.0 mg/kg chlordiazepoxide as a pharmacological control. This dose of chlordiazepoxide is ineffective in disrupting avoidance responding (Li et al, 2004(Li et al, , 2007Mead et al, 2008), but it is effective in several aversively conditioned paradigms, such as Pavlovian fear conditioning and passive avoidance responding (Burghardt et al, 2004;Joordens et al, 1998;Klint, 1991;Mead et al, 2008).…”

“…The basic procedure was identical to that of Experiment 1. We chose olanzapine 1.0 mg/kg dose because this is a clinically relevant dose in terms of its ability to disrupt conditioned avoidance responding (Li et al, 2007), as well as to give rise to ~70% striatal D 2 occupancy (Kapur et al, 2003b). We included 10.0 mg/kg chlordiazepoxide as a pharmacological control.…”