Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors.
BACKGROUND
Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either alpha1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking alpha1b-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.


OBJECTIVE
To explore why there is a discrepancy between pharmacological and genetic 5-HT2A receptor blockade.


METHODS
Locomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, alpha1b-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.
Salomon
Lucas
L
CNRS UMR 7148, Collège de France, 11, Place Marcelin Berthelot, 75231, Paris Cedex 05, France.
Lanteri
Christophe
C
Godeheu
Gérard
G
Blanc
Gérard
G
Gingrich
Jay
J
Tassin
Jean-Pol
JP
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010636:Phenols / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000697:Central Nervous System Stimulants; D005464:Fluorobenzenes; D006635:Histamine H2 Antagonists; D010636:Phenols; D044402:Receptor, Serotonin, 5-HT2A; C076033:SR 46349B; D003913:Dextroamphetamine; D011224:Prazosin