Abstract
The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT₂) and histamine (H₁) 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 schedule 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 Δ⁹-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 H₁ receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H₁ and 5-HT₂ 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.
Highlights
It is generally agreed that „conventional‟ antipsychotic drugs, including the phenothiazines and butyrophenones, are less effective in combating the negative symptoms of schizophrenia than they are in suppressing positive psychotic symptoms
Operant behaviour maintained by food or psychostimulant self-administration is suppressed by conventional antipsychotics, and it has been proposed that this effect is caused by a reduction of the incentive value of primary reinforcers (Wise 1982, 2006)
Less is known about the effects of atypical antipsychotics on motivation and reinforcement processes; there is evidence that these drugs enhance food intake in rodents (Hartfield et al 2003) as they do in humans (Meltzer et al 2003), and that they may increase the incentive value of food in operant behaviour paradigms (Mobini et al 2000; Cilia et al 2001; Zhang et al 2005a, 2005b; see below)
Summary
It is generally agreed that „conventional‟ antipsychotic drugs, including the phenothiazines and butyrophenones, are less effective in combating the negative symptoms of schizophrenia (anhedonia, avolition, flattened affect) than they are in suppressing positive psychotic symptoms (hallucinations, delusions). There is evidence that conventional antipsychotics may have an adverse effect on motivation in man, as they are known to do in animals (Wise 1982, 2006; King and Waddington 2004). Operant behaviour maintained by food or psychostimulant self-administration is suppressed by conventional antipsychotics, and it has been proposed that this effect is caused by a reduction of the incentive value of primary reinforcers (Wise 1982, 2006). Less is known about the effects of atypical antipsychotics on motivation and reinforcement processes; there is evidence that these drugs enhance food intake in rodents (Hartfield et al 2003) as they do in humans (Meltzer et al 2003), and that they may increase the incentive value of food in operant behaviour paradigms (Mobini et al 2000; Cilia et al 2001; Zhang et al 2005a, 2005b; see below)
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