Role of serotonin2A receptors in the d‐amphetamine‐induced release of dopamine: comparison with previous data on α1b‐adrenergic receptors

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 α1b-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-HT2A) 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 µm 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-HT2A and α1b-adrenergic receptors control a common neural pathway responsible for the release of dopamine in the nucleus accumbens by psychostimulants.