Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors

Psychopharmacology (Berl). 2007 Sep;194(1):11-20. doi: 10.1007/s00213-007-0810-3. Epub 2007 May 19.


Rationale: 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.

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, 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.

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists
  • Animals
  • Behavior, Animal / drug effects*
  • Behavior, Animal / physiology
  • Central Nervous System Stimulants / pharmacology
  • Dextroamphetamine / pharmacology*
  • Dose-Response Relationship, Drug
  • Fluorobenzenes / pharmacology
  • Histamine H2 Antagonists / pharmacology
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Phenols / pharmacology
  • Prazosin / pharmacology
  • Receptor, Serotonin, 5-HT2A / deficiency
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / physiology*


  • Adrenergic alpha-1 Receptor Antagonists
  • Central Nervous System Stimulants
  • Fluorobenzenes
  • Histamine H2 Antagonists
  • Phenols
  • Receptor, Serotonin, 5-HT2A
  • SR 46349B
  • Dextroamphetamine
  • Prazosin