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Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms

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Abstract

Rationale

The psychostimulant d-amphetamine, the D2/3 dopamine receptor agonist quinpirole and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behaviour. There is evidence that tolerance develops to the effects of psychostimulants on timing performance during chronic treatment; this tolerance is generally attributed to behavioural adaptation rather than to pharmacological desensitisation. There have been no previous investigations of tolerance to the effect of DOI on free-operant timing behaviour.

Objective

To demonstrate tolerance to DOI’s effect on timing performance and to examine the nature of this tolerance.

Materials and methods

Rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 80-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 8-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).

Results

In experiment 1, DOI (0.25 mg kg−1) reduced T 50 compared to vehicle; tolerance to this effect was seen after repeated daily treatments with DOI if the rats were exposed to behavioural training during the period of treatment but not if the repeated treatments took place during a ‘holiday’ from behavioural training. In experiment 2, repeated treatment with DOI resulted in tolerance to the effect of DOI on T 50 and cross-tolerance to the effect of d-amphetamine (0.4 mg kg−1), but no cross-tolerance was seen to the effect of quinpirole (0.08 mg kg−1).

Conclusions

The results indicate that behavioural adaptation is involved in the development of tolerance to DOI’s effect on timing. The finding of cross-tolerance to d-amphetamine but not to quinpirole suggests that the reduction of T 50 in the free-operant psychophysical procedure may be brought about by two distinct pharmacological mechanisms, one activated by DOI and d-amphetamine, and the other by quinpirole.

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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.

  2. For the purposes of this paper, the term tolerance is used, without any mechanistic or theoretical connotations, to refer to the phenomenon of a declining effect of a drug during chronic treatment. We distinguish between two processes, not necessarily mutually exclusive, which may contribute to tolerance: pharmacological desensitization, which occurs independently of any behavioural training (e.g. receptor down-regulation or enzyme induction), and behavioural adaptation, which requires exposure to a behavioural contingency during continued drug treatment. Hypothetical mechanisms underlying behavioural adaptation include the postulated ‘blunting’ of the hedonic quality of reinforcers during chronic treatment with conventional antipsychotics (Wise 1982) and the postulated ‘recalibration’ of the hypothetical internal clock during chronic treatment with drugs that are believed to alter the period of the pacemaker (Meck 1996).

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Acknowledgments

This work was supported by the BBSRC. We are grateful to Mrs. Victoria Bak for her skilled technical assistance.

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Authors and Affiliations

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

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

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

    K. C. F. Fone

Authors
  1. T. H. C. Cheung
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  2. G. Bezzina
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  3. S. Body
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  4. K. C. F. Fone
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  5. C. M. Bradshaw
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  6. E. Szabadi
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Correspondence to C. M. Bradshaw.

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Cheung, T.H.C., Bezzina, G., Body, S. et al. Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms. Psychopharmacology 192, 521–535 (2007). https://doi.org/10.1007/s00213-007-0743-x

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