Comparison of the effects of clozapine, haloperidol, chlorpromazine and d-amphetamine on performance on a time-constrained progressive ratio schedule and on locomotor behaviour in the rat

Abstract

Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on "reinforcer efficacy". It has been proposed that the effects of neuroleptic drugs on operant behaviour are mediated by a reduction of "reinforcer efficacy". We examined the effects of two "conventional" neuroleptics (haloperidol and chlorpromazine) and an "atypical" neuroleptic (clozapine) on progressive ratio schedule performance; d-amphetamine was used as a comparison compound. In experiment 1, rats responded for a sucrose reinforcer on a time-constrained progressive ratio schedule (75-min sessions). After 66 preliminary training sessions, the rats received single doses (IP) of haloperidol (0.05, 0.1 mg kg(-1)). chlorpromazine (2, 4 mg kg(-1)), clozapine (0.5, 1, 2, 4, 8 mg kg(-1)), and d-amphetamine (0.2, 0.4, 0.8 mg kg(-1)), and the corresponding vehicle solutions. The highest ratio completed was reduced by haloperidol and chlorpromazine, and increased by clozapine. All three neuroleptics reduced the peak response rate, at least at the highest doses administered. Response rates on the lower and intermediate ratios could be described by a three-parameter equation proposed to account for fixed ratio schedule performance. Haloperidol reduced, and clozapine dose-dependently increased the "motivational" parameter (a); d-amphetamine reduced it at low doses and increased it at high doses. The three neuroleptics increased the "response time" parameter (delta). Un-reinforced locomotor behaviour, measured in experiment 2, was not significantly altered by haloperidol, chlorpromazine or clozapine, but was increased by d-amphetamine. These results are consistent with a reduction of reinforcer efficacy produced by haloperidol and an increase produced by clozapine; clozapine's effect is unlikely to reflect a general increase in locomotion. All three neuroleptics induced some degree of motor debilitation. The quantitative analysis of progressive ratio schedule performance may provide a useful adjunct to existing methods for separating effects of drugs on motivational and motor processes.

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

“…We found that clozapine administration resulted in a horizontal leftward shift of the response functions relative to saline administration in PI trials (trials without gap). These data are consistent with an effect of clozapine on the clock stage of the internal stopwatch (MacDonald and Meck, 2005) or with an increase in reinforcer efficacy, as assessed by performance in progressive ratio schedules (Cilia et al, 2001;Mobini et al, 2000). Although the latter interpretation can not be ruled out, the fact that clozapine was shown to produce a leftward shift proportional to the timed criterion in a tri-peak procedure (MacDonald and Meck, 2005), strongly suggests that clozapine increases the speed of the internal stopwatch.…”

“…Because interval timing is dependent upon DA-glutamate interactions in corticostriatal circuits Matell et al, 2003;Meck, 1996Meck, , 2005Meck, , 2006aMeck, , 2006b), these findings suggest that clozapine may affect timing and time perception directly by changes in the mechanisms of an internal stopwatch (MacDonald and Meck, 2005) or by affecting motivational systems (Cilia et al, 2001;Mobini et al, 2000). The present experiment examined the effect of i.p.…”

Progressive ratio performance following challenge with antipsychotics, amphetamine, or NMDA antagonists in adult rats treated perinatally with phencyclidine

“…In humans with schizophrenia, amphetamine selectively improved negative symptoms (Kirrane et al 2000). Results of tests with amphetamine in previous progressive ratio studies using food reinforcement have been inconsistent: amphetamine decreased breakpoints (Schulze and Paule 1990;Caul and Brindle 2001), increased breakpoints (Poncelet et al 1983), or produced biphasic effects (Mayorga et al 2000;Mobini et al 2000). Given that procedures used in these studies (e.g.…”

Chronic Pubertal, but not Adult Chronic Cannabinoid Treatment Impairs Sensorimotor Gating, Recognition Memory, and the Performance in a Progressive Ratio Task in Adult Rats

“…After leverresponse training was completed, one PR session (for 30 min) was conducted on the subsequent day. The PR schedule was changed every second minute according to the following exponential progression: 1, 2, 4, 6, 9, 12, 15,y, derived from the formula 5.e 0.2n À5, where n is the position in the sequence of ratios (Mobini et al, 2000). The so-called 'break point', the conventional index of performance on a PR schedule of reinforcement (Reilly, 1999), was defined as the first PR sequence where lever-presses decreased p50% relative to the previous sequence without increasing X100% in the following sequence.…”