Role of serotonin 2A receptors in the D-amphetamine-induced release of dopamine: comparison with previous data on alpha1b-adrenergic receptors

J Neurochem. 2004 Oct;91(2):318-26. doi: 10.1111/j.1471-4159.2004.02714.x.


D-amphetamine is known to induce an increase in dopamine release in subcortical structures, thus inducing locomotor hyperactivity in rodents. Previous data have indicated that only 15% of the D-amphetamine-induced release of dopamine in the nucleus accumbens is related to locomotor activity and that this 'functional' dopamine release is controlled by alpha1b-adrenergic receptors located in the prefrontal cortex. We show here that SR46349B (0.5 mg/kg, 30 min before D-amphetamine), a specific serotonin2A (5-HT(2A)) antagonist, can completely block 0.75 mg/kg D-amphetamine-induced locomotor activity without decreasing D-amphetamine-induced extracellular dopamine levels in the nucleus accumbens. Using the same experimental paradigm as before, i.e. a systemic injection of D-amphetamine accompanied by a continuous local perfusion of 3 microM D-amphetamine, we find that SR46349B (0.5 mg/kg) blocks completely the systemic (0.75 mg/kg) D-amphetamine-induced functional dopamine release in the nucleus accumbens. Finally, the bilateral injection of SR46349B (500 pmol/side) into the ventral tegmental area blocked both the D-amphetamine-induced locomotor activity and functional dopamine release in the nucleus accumbens, whereas bilateral injection of SR46349B into the medial prefrontal cortex was ineffective. We propose that 5-HT(2A) and alpha1b-adrenergic receptors control a common neural pathway responsible for the release of dopamine in the nucleus accumbens by psychostimulants.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dextroamphetamine / antagonists & inhibitors
  • Dextroamphetamine / pharmacology*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Drug Antagonism
  • Extracellular Fluid / metabolism
  • Fluorobenzenes / pharmacology
  • Male
  • Microdialysis
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Phenols / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists / pharmacology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology


  • Fluorobenzenes
  • Phenols
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-1
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • SR 46349B
  • Dextroamphetamine
  • Dopamine