D 1 - and D 2 - Dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding

Behavioral responses to o, and Drdopamine agonists are enhanced when these agonists are administered systemically to 6hydroxydopamine (6-0HDA)-lesioned rats. In the present investigation, microinjectiOn of SKF-38393, a 0,-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-0HDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY171555, a Dragonist, elicited less locomotor activity than did SKF-38393 after microinjectiOn into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotiOn in unlesioned rats at the doses administered to lesioned animals. In adult-6-0HDA-lesioned rats, microinjectiOn of SKF-38393 into the nucleus accumbens also increased locomotiOn more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-0HDA-lesioned rats, whereas L Y-171555 produced a markedly enhanced response. Administration of SKF-38393 or L Y-171555 into the caudate nucleus of neonatally and adult-60HDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors ocThe loss of catecholamine-containing neurons has a dramatic effect on the responsiveness of animals to dopamine agonists (Ungerstedt, 1971; Uretsky and Schoenfeld. 1981; Schoenfeld and Uretsky, 1972; Hollister et al., 1974, 1979; Breese et al., Received for publication March 27, 1986. 1 This work was supported by U.S. Public Health Service Grants MH-36294, HL-31424, NS-21345 and HD-03110. • Present address: Department of Pharmacology & Experimental Therapeutics, Loyola University Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153. •Present address: Department of Community and Environmental Medicine, College of Medicine, University of California, Irvine, CA 92717. curred to a greater degree in the 6-0HDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of o, and Dz-dopamine agonists after microinjection into the brain of 6-0HDAlesioned rats, binding of [3H]spiperone (Drreceptor antagonist ligand) and [3H]SCH 23390 (O,-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-0HDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H)spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after o,and Drdopamine agonist administratiOn to neonatally or adult-6-0HDA-treated rats. 1979; Kilts et al., 1979; Setler et al., 1978). This is true of agonists acting on either Dior D2-dopamine receptor sites proposed by Kebabian and Caine (1979), although the age at which the lesion occurs has a dramatic effect on the degree of change (Breese et al., 1985b). For example, Breese et al. (1985b) found that locomotor activity is increased markedly after systemic administration of SKF-38393 (a Di-receptor agonist) to adult rats lesioned as neonates with 6-0HDA; less locomotor activity occurred after similar treatment with the Drdopamine agonist, LY-171555 (Tsuruta et al., 1981). Conversely, rats lesioned as adults with 6-0HDA exhibit more locomotor activ· ABBREVIATIONS: 6-0HOA, 6-hydroxydopamine; SMB, self-mutilation behavior; a..... maximum number of binding sites.