6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding

Abstract

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, 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-OHDA-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-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-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 D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-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-OHDA-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 D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.

Fig. 1

SKF-38393 and LY-171555-induced locomotor activity after microinjection into the nucleus accumbens of neonatally 6-OHDA-treated rats. The dose-response curve for SKF-38393 is significantly different from that observed in control rats (P < .001). The responses obtained with the 0.3- and l.0-µg doses of LY-171555 in the neonatally lesioned rats are significantly different from control responses (P < .01). There are four to eight determinations at each dose of the drugs for the various groups.

Fig. 2

Time course of the locomotor response to the D₁- and D₂-agonists after microinjection of 0.3 µg into the nucleus accumbens of neonatally 6-OHDA-treated rats. These determinations were from five rats in each group.

Fig. 3

Representative placements of injector tips in 6-OHDA-treated animals and controls. Placement was determined by histological procedures performed in randomly selected rats. Each symbol represents tip placement of bilateral injections. A, nucleus accumbens placements; B, caudate nucleus placements. Numerals to the right indicate anterior/posterior position, in micrometers, according to Konig and Klippel (1963).

Fig. 4

Saturation analysis of [³H]spiperone binding to striatal membranes from control and neonatally 6-OHDA-treated rats. All determinations were in the presence of 0.12 M NaCl and 20 nM ketanserin. See table 8 for other values for rats lesioned with 6-OHDA when adults or rats treated chronically with haloperidol. Striatal tissue from three rats was pooled for each of the three independent determinations (i.e., total = 9). Data are presented as the mean of these separate determinations. [³H]-Spiperone binding is presented as a function of ligand concentration: a, Scatchard transformation; b, the calculated values for the K_D and B_max are provided in the insert. There were no significant differences between groups (P > .1). B/F, bound/free.

Fig. 5

Saturation analysis of [³H]SCH-23390 binding to striatal membranes from neonatally 6-OHDA-treated rats. Twelve controls and 12 neonatal 6-OHDA-treated rats were used. Striatal tissue from three rats was pooled to obtain four independent determinations. All binding was performed in the presence of 0.12 M NaCl. Data are presented as the mean of four separate saturation curves. Upper, [³H]SCH-23390 binding as a function of ligand concentration. Lower, Scatchard transformation of data in A. The calculated values for the K_d and B_max are provided in an insert. There are no significant differences between the groups (P > .1). B/F, bound/free.