Dopaminergic hypersensitivity and cholinergic hypofunction in the pathophysiology of tardive dyskinesia

The so-called counterbalancing dopaminergic-cholinergic system has been studied in a clinical pharmacological investigation of neuroleptic-induced tardive dyskinesia. Eight hospitalized patients between the ages of 20 and 69 years were treated with -methyl-para-tyrosine (AMPT), l-Dopa, physostigmine, scopolamine and biperiden. The results were evaluated blind with the help of video-technique. AMPT (3 g daily for 3 days) significantly reduced, while l-Dopa (1200 mg daily together with a peripheral decarboxylase inhibitor for 14 days) and biperiden (18 mg daily for 14 days) significantly precipitated/aggravated the dyskinesia. The effects of physostigmine and scopolamine have varied, which is discussed in relation to the existence of both hypo- and hypercholinergic stereotype.It is concluded that dopaminergic hypersensitivity, cholinergic hypofunction and a reduced biological buffer capacity comprise important elements in the pathophysiology of tardive dyskinesia. Simple prophylactic and therapeutic directions are given based upon this conclusion.