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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

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Abstract

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, δ, 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-HT1A 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 μg kg−1), alone and in combination with the 5-HT1A receptor antagonist N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 μg kg−1). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg−1) and 8-OH-DPAT (25, 50 and 100 μg 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 δ. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and δ, 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-HT1A receptors; clozapine’s effects are mediated by a different mechanism, which does not appear to involve 5-HT1A receptors and which does not depend upon an intact 5-HTergic pathway.

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Acknowledgements

This work was supported by the Wellcome Trust (Travelling Fellowship awarded to Z.Z.). We are grateful to Ms.V. K. Bak and Mr. R. W. Langley for skilled technical help.

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Author notes

  1. Z. Zhang

    Present address: Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, P.O. Box 33932, Shreveport, LA, 71130-3932, USA

Authors and Affiliations

  1. Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Room B109, Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH, UK

    Z. Zhang, J. F. Rickard, S. Body, K. Asgari, C. M. Bradshaw & E. Szabadi

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  1. Z. Zhang
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  2. J. F. Rickard
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  3. S. Body
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Correspondence to C. M. Bradshaw.

Additional information

Jonathan Francis Rickard (1977–2003), a gifted and dedicated Ph.D. student, made a major contribution to this work

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Zhang, Z., Rickard, J.F., Body, S. et al. 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. Psychopharmacology 181, 381–391 (2005). https://doi.org/10.1007/s00213-005-2258-7

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  • DOI: https://doi.org/10.1007/s00213-005-2258-7

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