The actions of several neuroleptic and tricyclic compounds were examined on the large conductance Ca(2+)-activated K+ (BKCa) channel present in neurones isolated from the rat motor cortex. 2. Classical neuroleptic compounds including chlorpromazine and haloperidol applied to the intracellular surface of inside-out patches produced a concentration-dependent reduction in BKCa channel activity. Similar effects were observed when these compounds were applied to the extracellular surface of outside-out patches. 3. In contrast, the atypical neuroleptic compounds clozapine and sulpiride did not affect BKCa channel activity (100 nM-1 mM) in either inside-out or outside-out patches, while 10 microM pimozide produced 73% of the inhibition produced by 10 microM chlorpromazine. 4. BKCa channel activity was also unaffected by application of structurally related tricyclic compounds including the anti-cholinesterase tacrine and the anti-epileptic carbamazepine. The tricyclic antidepressant drug amitriptyline was found to inhibit BKCa channel activity but was much less effective than the classical neuroleptic compounds. 5. It is concluded that compounds belonging to the classical neuroleptic group of drugs inhibit BKCa channel activity in the rat motor cortex in a structurally-specific manner. This observation may be of clinical significance as it may contribute to some of the side effects associated with classical neuroleptic drug therapy.
