The role of 5-HT(2A) receptor antagonism in amphetamine-induced inhibition of A10 dopamine neurons in vitro

The role of the 5-HT(2A) receptor in modulating amphetamine-induced inhibition of dopamine neuronal firing in A9 and A10 was investigated in rat midbrain slices. The antipsychotic drugs olanzapine and clozapine more potently reversed the amphetamine-induced inhibition in A10 neurons compared to A9 neurons. Risperidone (0.03 and 0.1 muM) reversed amphetamine-induced inhibition of firing activity similarly in A9 and A10. The dopamine D2 receptor antagonist (-)sulpiride (0.05 and 1 muM) reversed the amphetamine (10 muM)-induced inhibition of firing activity in A9 and A10 neurons. The selective 5-HT(2A) receptor antagonist MDL100907 (0.05 muM), strongly enhanced the reversal of amphetamine-induced inhibition by (-)sulpiride in A10, but its effectiveness was much smaller in A9 dopamine neurons. We conclude that 5-HT(2A) receptor antagonism enhanced reversal of amphetamine-induced inhibition by dopamine D2 antagonism in A10, suggesting that dopamine D(2) receptor antagonism combined with 5-HT(2A) receptor antagonism may play a role in antipsychotic drug atypicality.