ABSTRACT
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 microM) reversed amphetamine-induced inhibition of firing activity similarly in A9 and A10. The dopamine D2 receptor antagonist (-)sulpiride (0.05 and 1 microM) reversed the amphetamine (10 microM)-induced inhibition of firing activity in A9 and A10 neurons. The selective 5-HT(2A) receptor antagonist MDL 100907 (0.05 microM), 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.
Subject(s)
Amphetamine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Mesencephalon/drug effects , Neurons/drug effects , Serotonin 5-HT2 Receptor Antagonists , Action Potentials/drug effects , Animals , Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Clozapine/pharmacology , Dopamine/physiology , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Fluorobenzenes/pharmacology , In Vitro Techniques , Male , Mesencephalon/physiology , Neural Inhibition/drug effects , Neurons/physiology , Olanzapine , Piperidines/pharmacology , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Dopamine D2/physiology , Sulpiride/pharmacologyABSTRACT
The antipsychotic drug quetiapine increases the firing rate of dopamine neurons in the substantia nigra and the ventral tegmental area of the rat. In the present study we used an in vitro midbrain slice preparation and found that 3 microM quetiapine increases the firing rate of dopamine neuron in both structures by approximately 30%. The magnitude of the increase was not correlated with the basal firing rate of the dopamine neurons. In addition, quetiapine was not able to antagonize the inhibition of the firing evoked by the dopamine D2 receptor agonist quinpirole. Only with a very high concentration (30 microM), quetiapine was able to counteract the amphetamine-induced inhibition of the firing of the ventral tegmental area neurons; this effect was less pronounced in substantia nigra neurons. These findings indicate that the increase in firing rate induced by quetiapine cannot solely be mediated through an interaction with the dopamine D2-like autoreceptor present on the dopamine neurons.
