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Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors

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Abstract

Rationale

The dopamine-releasing agent d-amphetamine and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behavior. The selective D1 dopamine receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), but not the D2 dopamine receptor antagonist haloperidol, can antagonize the effect of d-amphetamine, and the selective 5-HT2A receptor antagonist (±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)-methanol (MDL-100907) can antagonize the effect of DOI. However, it is not known whether the effect of d-amphetamine can be reversed by MDL-100907 and the effect of DOI by dopamine receptor antagonists.

Objective

The objective of this work is to examine the interactions of d-amphetamine and DOI with MDL-100907, SKF-83566, and haloperidol on timing performance.

Materials and methods

Rats (n = 12–15 per experiment) were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices [T 50 (time corresponding to %B = 50); Weber fraction]. Rats were treated systemically with d-amphetamine or DOI, alone and in combination with haloperidol, SKF-83566, or MDL-100907.

Results

d-Amphetamine (0.4 mg kg−1) reduced T50 compared to vehicle; this effect was antagonized by SKF-83566 (0.03 mg kg−1) and MDL-100907 (0.5 mg kg−1), but not by haloperidol (0.05, 0.1 mg kg−1). DOI (0.25 mg kg−1) also reduced T50; this effect was reversed by MDL-100907 (0.5 mg kg−1), but not by SKF-83566 (0.03 mg kg−1) or haloperidol (0.05 mg kg−1).

Conclusions

The results suggest that both 5-HT2A and D1 receptors, but not D2 receptors, are involved in d-amphetamine’s effect on timing behavior in the free-operant psychophysical procedure. DOI’s effect on timing is mediated by 5-HT2A receptors, but neither D1 nor D2 receptors are involved in this effect.

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Notes

  1. Most drugs acting at D1 dopamine receptors do not discriminate between D1 and D5 dopamine receptors and are, therefore, more precisely designated as D1-like receptor agonists and antagonists. Similarly, most drugs acting at D2 receptors do not discriminate between D2, D3, and D4 receptors and are, therefore, designated as D2-like receptor agonists and antagonists (Seeman and van Tol 1994; Strange 2001). Throughout this paper, for the sake of simplicity, they are referred to as D1 and D2 receptor agonists and antagonists.

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Acknowledgements

This work was supported by the BBSRC. We are grateful to Ms. V.K. Bak and Mr. R.W. Langley for skilled technical help.

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Authors and Affiliations

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

    S. Body, T. H. C. Cheung, G. Bezzina, K. Asgari, C. M. Bradshaw & E. Szabadi

  2. School of Biomedical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK

    K. C. F. Fone

  3. Solvay Pharmaceuticals, Weesp, The Netherlands

    J. C. Glennon

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  1. S. Body
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Body, S., Cheung, T.H.C., Bezzina, G. et al. Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors. Psychopharmacology 189, 331–343 (2006). https://doi.org/10.1007/s00213-006-0575-0

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