Effect of reinforcer magnitude on performance maintained by progressive-ratio schedules.

This experiment examined the relationship between reinforcer magnitude and quantitative measures of performance on progressive-ratio schedules. Fifteen rats were trained under a progressive-ratio schedule in seven phases of the experiment in which the volume of a 0.6-M sucrose solution reinforcer was varied within the range 6-300 microl. Overall response rates in successive ratios conformed to a bitonic equation derived from Killeen's (1994) Mathematical Principles of Reinforcement. The "specific activation" parameter, a, which is presumed to reflect the incentive value of the reinforcer, was a monotonically increasing function of reinforcer volume; the "response time" parameter, delta, which defines the minimum response time, increased as a function of reinforcer volume; the "currency" parameter, beta, which is presumed to reflect the coupling of responses to the reinforcer, declined as a function of volume. Running response rate (response rate calculated after exclusion of the postreinforcement pause) decayed monotonically as a function of ratio size; the index of curvature of this function increased as a function of reinforcer volume. Postreinforcement pause increased as a function of ratio size. Estimates of a derived from overall response rates and postreinforcement pauses showed a modest positive correlation across conditions and between animals. Implications of the results for the quantification of reinforcer value and for the use of progressive-ratio schedules in behavioral neuroscience are discussed.

Effects of quipazine and m-chlorophenylbiguanide (m-CPBG) on temporal differentiation: evidence for the involvement of 5-HT2A but not 5-HT3 receptors in interval timing behaviour.

RATIONALE: Temporal differentiation refers to animals' ability to regulate their behaviour during an ongoing interval. Striatal dopaminergic mechanisms are purported to be involved in temporal differentiation, and recent evidence also implicates 5-hydroxytryptaminergic (5-HTergic) mechanisms, possibly mediated by 5-HT(2A) receptors. There is evidence that 5-HT(3) receptors contribute to the regulation of dopamine release in the basal ganglia; however, it is not known whether 5-HT(3) receptor stimulation can influence temporal differentiation. OBJECTIVE: We examined the effects of a selective 5-HT(3) receptor agonist m-CPBG, a mixed 5-HT(2A/3) receptor agonist quipazine, and selective 5-HT(3) and 5-HT(2A) receptor antagonists (MDL-72222 and ketanserin, respectively) on temporal differentiation in a free-operant psychophysical procedure. METHODS: Twenty-four rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement (0.6 M: , 50 microl) was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data [percent responding on B (%B) vs time from trial onset (t)], and quantitative indices of timing performance [T (50) (value of t corresponding to %B=50), Weber fraction, and mean time of switching from A to B, S (50)] were derived. RESULTS: Quipazine (0.5, 1, and 2 mg kg(-1)) altered timing performance, dose-dependently reducing T (50) and S (50); m-CPBG (2.5, 5, and 10 mg kg(-1)) had no significant effect. The effect of quipazine was antagonized by ketanserin (2 mg kg(-1)), but not by MDL-72222 (1 mg kg(-1)). CONCLUSIONS: The present results provide no evidence for the involvement of 5-HT(3) receptors in temporal differentiation and indicate that the effect of quipazine on performance was mediated by 5-HT(2A) receptor stimulation. The results are consistent with previous evidence for the involvement of 5-HT(2A) receptors in interval timing behaviour.

Comparison of the effects of clozapine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on progressive ratio schedule performance: evidence against the involvement of 5-HT1A receptors in the behavioural effects of clozapine.

RATIONALE: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105-172) affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, delta, expresses the minimum time needed to execute a response, and is regarded as an index of 'motor capacity'. Previously we found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine's behavioural effects are mediated by agonistic action at 5-HT(1A) receptors. OBJECTIVE: This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. METHODS: Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute doses of clozapine (4 mg kg(-1)) and 8-OH-DPAT (100 microg kg(-1)), alone and in combination with the 5-HT(1A) receptor antagonist N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 microg kg(-1)). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg(-1)) and 8-OH-DPAT (25, 50 and 100 microg kg(-1)) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT). RESULTS: In both experiments, clozapine and 8-OH-DPAT increased a and delta. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and delta, but did not alter clozapine's effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not differ between sham-lesioned and 5,7-DHT-lesioned rats. CONCLUSIONS: The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. 8-OH-DPAT's effects are probably mediated by post-synaptic 5-HT(1A) receptors; clozapine's effects are mediated by a different mechanism, which does not appear to involve 5-HT(1A) receptors and which does not depend upon an intact 5-HTergic pathway.

Effects of quipazine and m-chlorophenylbiguanide (m-CPBG) on the discrimination of durations: evidence for the involvement of 5-HT2A but not 5-HT3 receptors.

The ability of rats to discriminate durations of exteroceptive stimuli is disrupted by 5-HT(1A) receptor agonists; it is not known whether temporal discrimination is sensitive to stimulation of other 5-HT receptor subtypes. We examined the effect of quipazine, a 5-HT receptor agonist with nanomolar affinity for 5-HT(3) receptors and micromolar affinity for 5-HT(2A) receptors, and m-chlorophenylbiguanide (m-CPBG), a selective 5-HT(3) receptor agonist, on temporal discrimination. Twenty-four rats pressed levers for sucrose reinforcement under a discrete-trials psychophysical procedure. In each 50-s trial, a light was presented for t s, following which two levers (A and B) were presented. A response on A was reinforced if t < 25 s, and a response on B if t > 25 s. Logistic psychometric functions were fitted to the data, and timing parameters estimated (T(50): value of t corresponding to %B = 50; Weber fraction: [T(75)-T(25)]/2T(50), where T(75) and T(25) are values of t corresponding to %B = 75 and %B = 25). Quipazine (0.5-2 mg/kg) displaced the psychometric curve to the right and reduced its slope, reflected in increases in T50 and the Weber fraction; m-CPBG (2.5-10 mg/kg) had no effect. The effects of quipazine were reversed by the 5-HT(2A) receptor antagonist ketanserin (2 mg/kg) but not by the 5-HT3 receptor antagonist topanyl 3,5-dichlorobenzoate (MDL-72222) (1 mg/kg). The results indicate that 5-HT(2A) but not 5-HT(3) receptor stimulation disrupts temporal discrimination.

Quantitative analysis of the effects of some "atypical" and "conventional" antipsychotics on progressive ratio schedule performance.

RATIONALE: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the value or "efficacy" of reinforcers. A mathematical model affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. According to this model, the relation between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, alpha, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, delta, expresses the minimum time needed to execute a response, and is regarded as an index of "motor capacity". In a previous experiment we found that the "atypical" antipsychotic clozapine increased alpha, indicating an increase in the efficacy of a food reinforcer. OBJECTIVE: We examined the effects of four "atypical" and four "conventional" antipsychotics on progressive ratio schedule performance. METHODS: Rats responded for a sucrose reinforcer (0.6 M, 50 microl) on a time-constrained progressive ratio schedule (50-min sessions). After 90 preliminary training sessions, they received acute doses of antipsychotics (doses in mg kg(-1)): atypical: clozapine (2, 4, 8, IP; n=15), quetiapine (1.25, 2.5, 5, 10, SC; n=23), olanzapine (0.25, 0.5, 1, IP; n=15), ziprasidone (0.625, 1.25, 2.5, IP, n=15); conventional: haloperidol (0.025, 0.05, 0.1, IP, n=15), pimozide (0.125, 0.25, 0.5, IP; n=15), raclopride (0.25, 0.5, 1, SC; n=12), cis-flupenthixol (0.2, 0.4, 0.8, SC; n=15). Values of a and delta were estimated from the response rate functions obtained under each treatment condition, and were compared between drug and vehicle-alone treatments. RESULTS: The atypical antipsychotics significantly increased alpha (indicating enhancement of reinforcer efficacy), and also increased delta (indicating reduction of motor capacity). Haloperidol, pimozide and raclopride significantly increased delta; none of the conventional antipsychotics significantly altered alpha. CONCLUSIONS: The results extend previous findings with clozapine to other atypical antipsychotics and suggest that enhancement of the efficacy of reinforcers may be a common feature of atypical antipsychotics not shared by conventional antipsychotics.