European Journal of Pharmacology, 212 (1992) 43-49 43 © 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00 EJP 52296 Co-administration of progabide inhibits haloperidol-induced oral dyskinesias in rats Hiroyuki Kaneda i, Osamu Shirakawa, James Dale, Leslie Goodman, Susan E. Bachus 2 and Carol A. Tamminga Maryland Psychiatric Research Center, Department of Psychiatry, Unit,ersityof Maryland, School of Medicine, Baltimore, MD 21228, U.S.A. Received 22 October 1991, revised MS received 19 November 1991, accepted 26 November 1991 Vacuous chewing movements in rats may be an animal analogue of the human motor disorder, tardive dyskinesia. The movements are phenomenologically and pharmacologically similar to tardive dyskinesia. The pathophysiology of these involun- tary oral movements, and perhaps of tardive dyskinesia, are likely to include both dopamine receptor changes, and alterations in GABA (y-aminobutyric acid) system function. In an attempt to test the involvement of GABA system dysfunction in these movements, we treated rats chronically with water alone, haloperidol alone, the GABA agonist progabide alone, and haioperidol plus progabide. Sprague-Dawley rats received haloperidol (1.5 mg/kg per day) in their drinking water and progabide (100 mg/kg per day) in their food for 12 months. After 12 months of treatment, haloperidol had induced vacuous chewing movements when administered alone, but the prevalence of the movements was decreased by 40% with the coadministration of progabide. Moreover, the haloperidol-progabidc-treated animals did not merely demonstrate movement suppression but actual inhibition of movement onset, as determined by an additional progabide-withdrawal experiment. These data would suggest that progabide and perhaps other GABAmimetic compounds can prevent the development of tardive dyskinesia in man. Tardive dyskinesia; Vacuous chewing movements; Haloperidol (chronic); Progabide 1. Introduction Neuroleptic drugs when used chronically in the treatment of human disease have been associated with a delayed-onset hyperkinetic movement disorder called tardive dyskinesia. The most characteristic features of this disorder are choreoathetotic, sometimes dystonic, movements of the mouth, face, extremities and trunk (Marsden et al., 1975; Klawans and Rubovits, 1972; Tarsy and Baldessarini, 1974). This syndrome is a clini- cal problem because of its frequency (Kane et al., 1985), its occasional intensity, and its medical-legal implications. Despite its known etiology, the patho- physiology of this syndrome is unknown. Many investi- gators suppose that chronic blockade of dopamine re- ceptors resulting in dopamine receptor supersensitivity, Correspondence to: C.A. Tamminga, Maryland Psychiatric Research Center, Department of Psychiatry, Universityof Maryland, School of Medicine, Baltimore, MD 21228, U.S.A. Tel. 1.301.455 7915, fax 1.301.788 3394. t Now at Kobe University, School of Medicine, Kobe 650, Japan. 2 Present address: Laboratory of Cell Biology, National Institute of Mental Health, Building 36, Room 2D-10, Bethesda, MD 20892, U.S.A. is the mechanism of this motor disorder (Clow et al., 1980; Rupniak et al., 1984). Other investigators have postulated additional or alternative hypotheses, involv- ing GABA (y-aminobutyric acid) system dysfunction, dopamine Dl/dopamine D 2 receptor imbalance, or cholinergic or peptidergic systems (Thaker et al., 1987). More specific knowledge about the pathophysiology of tardive dyskinesia might lead to the development of drugs for preventing this syndrome in patients who require continual neuroleptic treatment. An animal model of tardive dyskinesia could facili- tate study of specific pathophysiologic hypotheses of the motor disorder. Chronic administration of neu- roleptic drugs has been reported to induce sponta- neous mouth movements in rats (Clow et al., 1980; Ellison et al., 1987; Iversen et al., 1980; Gunne et al., 1986; Waddington et al., 1983; Mithani et al., 1987; Rosengarten et al., 1988). These movements are called 'vacuous chewing movements' and reliable techniques have been described to rate them (Gunne et al., 1982; Waddington et al., 1983). Some disagreement exists in the literature about the similarities of these movements to tardive dyskinesia and their validity as an animal model of tardive dyskinesia (see Waddington et al. 1986; Waddington, 1990). Differences have been re-