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

Abstract 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 serotonin 2A (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 µ m 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 α1b‐adrenergic receptors control a common neural pathway responsible for the release of dopamine in the nucleus accumbens by psychostimulants.