α 1 ‐adrenergic, D 1 , and D 2 receptors interactions in the prefrontal cortex: Implications for the modality of action of different types of neuroleptics

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D 1 , D 2 , and α 1 ‐adrenergic receptors) (3–5 mg/ kg, i.v.), prazosin (an α 1 ‐adrenergic antagonist) (0.2 mg/ kg, i.v.), or sulpiride (a D 2 antagonist) (30 mg/ kg, i.v.), but not SCH 23390 (a D 1 antagonist) (0.2 mg/ kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA‐induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/ kg, i.v.), a D 2 antagonist which also blocks α 1 ‐adrenergic receptors, failed to reverse the VTA‐induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/ kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either “prazosin plus sulpiride” or “prazosin plus SCH 23390” were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D 2 , D 1 , and α 1 ‐adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical α 1 ‐adrenergic receptors hampers the functional activity of cortical D 1 receptors and suggest that the stimulations of cortical D 1 and D 2 receptors exert mutual inhibition on each other's transmission. Synapse 30:362–370, 1998. © 1998 Wiley‐Liss, Inc.