Functional downregulation of the neurokinin 1 receptor by antidepressant, neuroleptics and mood stabilizers

Neurokinin–1/–2-receptor antagonists have some efficiency in the treatment of affective and anxiety disorders. However, recent data from clinical trials are disappointing since large phase III studies could not confirm previous data. Nevertheless, animal models have shown clear „antidepressant“ and „anxiolytic“ effects of these substances in a wide variety of test systems. In the present study, we investigated acute effects (stimulation for 1h up to 2 days) of the antidepressants imipramine and fluvoxamine, the antipsychotics clozapine and haloperidol as well as the mood stabilizers valproic acid, lithium and carbamazepine on NK–1-receptor expression and receptor binding in human astrocytoma cells, which highly express the NK–1-receptor. We found that imipramine and fluvoxamine, haloperidol as well as valproic acid strongly downregulated NK–1-receptor mRNA-expression (quantitative RT-PCR) and protein synthesis (Western Blot). Furthermore, these drugs also decreased functional activity of the receptor as they downregulated substance P-induced gene expression and led to a decrease of SP binding sites as shown by binding assay studies using 3H-SP. In summary, we have shown that certain antidepressants, antipsychotics and mood stabilizers are able to downregulate the NK–1-receptor with the consequence of decreased SP binding to the receptor and decreased functional activity. This may indicate a new mechanism by which psychopharmacological agents exert their psychotropic effects.