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5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion

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Abstract

Rationale

Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT2A and 5-HT2C receptors have opposing effects on behaviour, and that the 5-HT2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.

Objectives

To assess the effects of 5-HT2A and 5-HT2C receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.

Methods

The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats.

Results

ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.

Conclusions

These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT2 receptor family is functionally heterogeneous. Although both 5-HT2A and 5-HT2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.

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Authors and Affiliations

  1. Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

    Catharine A. Winstanley, David E. H. Theobald, Jeffrey W. Dalley & Trevor W. Robbins

  2. Department of Biological Lead Optimisation, Solvay Pharmaceuticals, Weesp, 1380 DA, The Netherlands

    Jeffrey C. Glennon

Authors
  1. Catharine A. Winstanley
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  2. David E. H. Theobald
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  3. Jeffrey W. Dalley
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  4. Jeffrey C. Glennon
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  5. Trevor W. Robbins
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Correspondence to Catharine A. Winstanley.

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Winstanley, C.A., Theobald, D.E.H., Dalley, J.W. et al. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 176, 376–385 (2004). https://doi.org/10.1007/s00213-004-1884-9

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  • DOI: https://doi.org/10.1007/s00213-004-1884-9

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