Recent observations from human and animal studies indicate that the traditional dopamine supersensitivity theory in tardive dyskinesia (TD) is insufficient. Instead, a new hypothesis is proposed: TD may be due to an increased D-1 receptor function or an increased ratio between D-1/D-2 receptor functions in the brain, maybe associated with a diminished activity in certain striatofugal GABA neurons. This hypothesis is based on experiments with selective D-1 and D-2 drugs in rodents and monkeys, but has not yet been tested clinically due to lack of D-1 agonists and antagonists for human use. In a Nordic multicenter study, various neuroleptics (haloperidol, perphenazine, chlorprothixene) were given to 33 elderly psychiatric patients with TD. The main result of this study was the demonstration of 1) an inverse relationship between parkinsonism and TD, and 2) an inconsistent response to withdrawal of various neuroleptics. Following withdrawal, 38% of the patients had a TD aggravation, 27% a TD reduction, and 35% no TD change, all compared with the TD level before the neuroleptic test period and independent of the neuroleptic given. This observation speaks against the dopamine hypersensitivity theory and is more in accordance with the new hypothesis proposed above. The GABA part of the TD hypothesis has been tested with different GABA agonists such as gamma-acetylenic GABA, gamma-vinyl GABA and THIP, but most studies suggest that the therapeutic effect of these drugs in TD is limited and maybe secondary to parkinsonism and sedation. Clinicians are eagerly awaiting new GABA agonists with selective affinity to subgroups of GABA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)