Abstract
Rationale
Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either α1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking α1b-adrenergic receptors hardly respond to d-amphetamine. However, we show here that, paradoxically, mice lacking 5-HT2A receptors (5-HT2A-R KO) exhibit a twofold higher locomotor response to d-amphetamine than wild-type (WT) littermates.
Objectives
To explore why there is a discrepancy between pharmacological and genetic 5-HT2A receptor blockade.
Materials and methods
Locomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, α1b-adrenergic, and 5-HT2A receptor antagonists, respectively.
Results
Repeating amphetamine injections still increases 5-HT2A-R KO mice locomotor response to d-amphetamine at a level similar to that of sensitized WT mice. SR46349B (1 mg/kg) has, as expected, no effect in 5-HT2A-R KO mice. One milligrams per kilogram of prazosin completely blocks d-amphetamine-induced locomotor response in 5-HT2A-R KO naïve animals but 3 mg/kg is necessary in sensitized 5-HT2A-R KO mice.
Conclusions
Because naïve 5-HT2A-R KO mice exhibit an increased cortical noradrenergic response to d-amphetamine, our data suggest that repeated d-amphetamine modifies noradrenergic transmission in 5-HT2A-R KO mice. Stimulation of specific 5-HT2A receptors would inhibit noradrenergic neurons. Dramatic decrease in SR46349B efficiency in sensitized WT mice indicates that a disruption of the regulating role of 5-HT2A receptors on noradrenergic transmission occurs during sensitization and thus represents the physiological basis of behavioral sensitization to d-amphetamine.
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Acknowledgments
We thank L. Lanfumey and M. Hamon for 5-HT2A-R KO mice, S. Cotecchia for α1b-AR KO mice, J. Naudé for statistical advice, and P. Babouram for skilful technical assistance.
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Salomon, L., Lanteri, C., Godeheu, G. et al. Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors. Psychopharmacology 194, 11–20 (2007). https://doi.org/10.1007/s00213-007-0810-3
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DOI: https://doi.org/10.1007/s00213-007-0810-3