Does clozapine affect the discriminative stimulus effects of food deprivation in rats trained to discriminate between 2 and 22 hours food deprivation?

Abstract

In humans, weight gain is a side effect of several atypical antipsychotics. Previous research with rodents indicates clozapine may increase food consumption for the first 2‐4 hours after injection (Antelman et al. 1977; Benvenga & Leander 1997; Lee & Clifton 2002) as well as increase motivation to acquire food under a progressive ratio schedule (Abela et al. 2020; Loh et al. 1992; Mobini et al. 2000). In other studies, however, clozapine has been shown to reduce response rates in lever pressing operant procedures (Ford et al., 1997; Kaempf & Porter, 1997; Varvel et al., 2002; Wiley et al., 1994; Abela 2020) and decrease food intake in rodents (Baptista et al., 1993). The current study investigated if clozapine would affect the discriminative stimulus effects of food deprivation. Male, Sprague‐Dawley rats (n = 11) were trained to discriminate 22 hrs of food deprivation from 2 hrs of food deprivation in a two‐lever, operant choice task. Rats were trained to respond on the right lever after 2 hrs of food deprivation to earn a 45 mg food pellet under an FR 15 schedule. Left lever presses were punished with 8 seconds of darkness. Under 22 hr deprivation conditions, the contingencies were reversed (left lever presses were reinforced with food delivery and right lever presses resulted in 8 seconds of darkness). Training sessions lasted until subjects earned 10 reinforcers or 15 minutes elapsed. Acquisition of discrimination was defined as 80% or greater condition appropriate responding both before the first reinforcer was earned and for the entire session for 8 out of 10 consecutive days. After acquiring the discrimination, subjects were food deprived for 2 or 22 hrs and administered clozapine (1.0 ‐ 5.6 mg/kg, s.c.). or vehicle (30% DMSO; 1.0 ml/kg, s.c.). During test sessions, responses toward either lever were reinforced under the FR 15. The session lasted until subjects earned 5 reinforcers or 5 minutes elapsed, whichever occurred first. The discriminative stimulus effects of food deprivation and response rates were assessed every 15 min for the succeeding 2 hrs. After test sessions, each subjects’ food intake was recorded for 1 hour. Clozapine had no effect on the discriminative stimulus effects of 2 hr deprivation, however, clozapine (1.0 ‐ 5.6 mg/kg) significantly decreased response rates. After 22 hrs food deprivation, clozapine (1.0 ‐ 5.6 mg/kg) significantly decreased % 22 hr deprivation‐appropriate responding. Response rates were significantly increased by 1.0 mg/kg clozapine, whereas response rates were decreased by 5.6 mg/kg clozapine compared to rates of responding following 30% DMSO. Clozapine (3.2 ‐ 5.6 mg/kg) decreased food intake in rats under both food deprivation conditions. These data provide further support for the notion that clozapine decreases feeding‐related behaviors in rats.