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gamma-Aminobutyric acid (GABA) agonists have been proposed for the treatment of tardive dyskinesia, but their therapeutic potential has been limited by side effects and toxicity. To elucidate further the role of GABA in neuroleptic-induced dyskinesias, we evaluated tetrahydroisoxazolopyridinol (THIP), a new, less toxic GABA analog and GABA receptor agonist, in both a dose-finding (single-dose) pilot study with five patients and a longer (four-week) placebo-controlled study with 13 patients. The patients were videotaped during a standardized examination; tardive dyskinesia, parkinsonian symptoms, and eye-blinking rates were rated blindly and randomly. The maximal short-term dose of THIP was 10 to 25 mg, whereas in the longer-term study the highest daily dose ranged from 20 to 120 mg. Tardive dyskinesia was unchanged during THIP treatment, but preexisting parkinsonism increased significantly and eye-blinking rates decreased. Psychiatric symptoms showed no significant changes, although tension and depression lessened. Side effects included sedation, confusion, dizziness, vomiting, and myoclonic jerks. Although THIP is not an effective new treatment for tardive dyskinesia, more specific GABA agonists should be evaluated in future studies of this syndrome.

Analyses of heme-attached amino acid sequences in known hemoprotein superfamilies provide a basis for prediction of such sequences in hemoproteins of unknown three-dimensional structure. Among 11 histidine residues conserved in subunit I of 3 mammalian and 2 fungal cytochrome oxidases the sequence around His-233 (human) is the most conserved and shows remarkable similarity to the sequence of the oxygen binding site in globins. Furthermore, the gene coding for subunit I in Saccharomyces cerevisiae and the gene for leghemoglobin in soybean are both split by introns right after these similar histidine sequences. The predicted distal histidine sequence of subunit I provides for heme a3 and Cua3 binding and has an extraordinarily high content of aromatic residues. These aromatic groups may serve as a molecular electron capacitor. Transmembrane sequences and electron transfer sequences are proposed.