European Journal of Pharmacology, 147 (1988) 153-154 153 Elsevier EJP 0109R Rapid communication Altered haloperidol-sensitive o receptors in the genetically dystonic (dt) rat Wayne D. Bowen *'1 j. Michael Walker 2 Alyson G. Yashar a, Rae R. Matsumoto 2 Francis O. Walker 3 and Joan F. Lorden 4 1 Sectton of Bwchemtstry, Dwlston of Btology and Medtcme, and e Walter S Hunter Laboratory of Psychology, Brown Unwersity, Promdence, Rhode Island 02912, s Department of Neurology, Bowman Gray School of Medtcme, Wake Forest Unwerstty, Wmston-Salem, North Carohna 27103, and 4 Department of Psychology, Unwerstty of Alabama at Bwmmgham, Bwmmgham, Alabama 35294, USA Recewed 21 January 1988, accepted 22 January 1988 Haloperldol-sensltlVe o receptors (Oh) are umque non-dopamlnerglc, non-opiate receptors found throughout many brain areas involved in motor function. Some of the most densely popu- lated sites include the cerebellum, red nucleus, locus coeruleus, substantla mgra pars compacta and select motor nuclei of spinal and cramal nerves (Gundlach et al., 1986). An important role of o h receptors in movement was suggested by the potent dystomc effects of a h hgands occurnng after nucromjectlon in the red nucleus and the orchng behawor induced by ln- tranigral admamstratlon of the selective o h hgand 1,3-dl-o-tolylguanldme (DTG) (Weber et al, 1986, Walker et al., in press) Since o h receptors brad many neuroleptlc drugs, these findings suggest that some of the motor effects of antlpsychotlc drugs might be mediated by o h receptors rather than dopamlne receptors as is commonly thought These effects further suggest that o h receptors might be involved m dystoma, a movement dis- order winch frequently results from neuroleptlc drug therapy (cf Fahn, 1982) Idiopathic forms of dystoma also occur In humans either sponta- neously or as an lnhented disorder (Fahn, 1982). Lorden et al. (1988) reported that Sprague-Dawley rats with the autosomal recessive mutation (dt) * To whom all correspondence should be addressed exinblt severe dystonla. A mechanism lnvolwng a h receptors was suggested by findings that these ammals show normal doparmne, fl-adrenerglc and muscarlnlC chohnerglc bindmg parameters, yet they fall to become cataleptic after administration of haloperldol (Walker et al, in press). We report that these ammals exhibit markedly abnormal o h binding in whole brain suggesting that defectwe a h receptors may underhe tins and perhaps other forms of dystoma The brains of 4 dystomc (dt) rats and 4 normal littermates (2 males and 2 females) were homoge- mzed in ice-cold 10 mM Tns-HC1 pH 7 4 contain- Ing 320 mM sucrose using a Potter-Elvehjem ho- mogemzer with a motor-driven pestle. A crude synaptosomal (P2) fraction was then prepared by differential centrlfugatlon, with final resuspenslon in 10 mM Trls-HC1 pH 7 4 at a protein concentra- tion of 18 mg/ml Membranes (325 #g protelfi) were incubated with 3 nM [3H]DTG and 13 con- centraUons of unlabeled DTG ranging from 1-200 nM. Incubations were carned out in 0.5 ml of 50 mM Tns-HC1 pH 8.0 for 60 mln at 25 °C Non- specific binding was deterrmned in the presence of 1 /zM halopendol Assays were terminated by addition of 5 ml ice-cold 10 mM Tns-HC1 pH 7.4 and rapid filtration through glass fiber filters usmg a Brandel Cell Harvester Filters were then washed twice with 5 ml of buffer Filters were soaked at least 30 mln in 0.5% polyethylenelmlne prior to use 0014-2999/88/$03 50 © 1988 ElsevxerScience Pubhshers B V (BlomedxcalDlwslon)