A clozapine-like effect of cyproheptadine on progressive ratio schedule performance

Abstract

Abstract. The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT 2 ) and histamine (H 1 ) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive-ratio schedules, as revealed by Killeen"s (1994) mathematical model of scheduled controlled behaviour. These drugs increase the values of a parameter that expresses the "incentive value" of the reinforcer (a) and a parameter that is inversely related to the "motor capacity" of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive-ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ 9 -tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5 mg kg -1 ) and clozapine (3.75, 7.5 mg kg -1 ) increased a and δ. Haloperidol (0.05, 0.1 mg kg -1 ) reduced a and increased δ.Chlordiazepoxide (3, 10 mg kg -1 ) increased a but reduced δ. THC (1, 3 mg kg -1 ) had no effect. Interpretation based on Killeen"s (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H 1 receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H 1 and 5-HT 2 receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide"s effect on a is consistent with its food intake-enhancing effect.

Quantitative analysis of performance on a progressive-ratio schedule: effects of reinforcer type, food deprivation and acute treatment with Δ9-tetrahydrocannabinol (THC)

“… Valencia-Torres et al (2014) found that diabetes induced by systemic treatment with streptozotocin was associated with a reduction of a , consistent with an antihedonic effect of this treatment ( Nefs et al, 2012 ). D 1 and D 2 dopamine receptor antagonists also reduce a , consistent with the purported antihedonic effect of these drugs ( Olarte-Sánchez et al, 2012 : data re-analysed by Bradshaw and Killeen, 2012; Olarte-Sánchez et al, 2013 ). Some drugs with known sedative properties, including clozapine and cyproheptadine, have been found to increase the response-time parameter δ ( Olarte-Sánchez et al, 2012 : data re-analysed by Bradshaw and Killeen, 2012 ).…”

“…It was injected intraperitoneally (2.5 ml kg −1 ; 25-gauge needle) 30 min before the start of the experimental session. The doses of THC were selected on the basis of previous experience of the effect of this drug on performance on the progressive-ratio schedule ( Olarte-Sánchez et al, 2012 ).…”

“…Moreover, in view of the known orexigenic effect of THC ( Abel, 1975; De Luca et al, 2012; Higgs et al, 2003; Williams et al, 1998; Williams and Kirkham, 2002a,b ), it was expected that this drug would induce an increase in the value of a . However, in apparent conflict with the latter prediction, Olarte-Sánchez et al (2012) recently reported that THC had no effect on the value of a for food-pellet reinforcers. The present experiment extended these findings by examining the effect of THC on performance on progressive-ratio schedules maintained by sucrose and corn oil reinforcers.…”

“…The present experiment extended these findings by examining the effect of THC on performance on progressive-ratio schedules maintained by sucrose and corn oil reinforcers. In addition, since Olarte-Sánchez et al (2012) analysed their data using an earlier model derived from MPR, designed to account for performance on fixed-ratio schedules ( Killeen, 1994 ), a re-analysis of their data was carried out using the new progressive-ratio model.…”

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

“…The breakpoint was defined as the last ratio completed before 5 min elapsed without any responding or, when this criterion was not met within the session, the highest completed ratio (Olarte-Sánchez et al , 2012). The mathematical model (Bradshaw and Killeen, 2012) used to analyse PR performance comprises three key equations.…”