A QUANTITATIVE ESTIMATE OF THE ROLE OF STRIATAL D-2 RECEPTOR PROLIFERATION IN DOPAMINERGIC BEHAVIORAL SUPERSENSITIVITY - THE CONTRIBUTION OF MESOLIMBIC DOPAMINE TO THE MAGNITUDE OF 6-OHDA LESION-INDUCED AGONIST SENSITIVITY IN THE RAT

被引:21
作者
MANDEL, RJ
HARTGRAVES, SL
SEVERSON, JA
WOODWARD, JJ
WILCOX, RE
RANDALL, PK
机构
[1] UNIV ILLINOIS, DEPT PSYCHOL, CHAMPAIGN, IL 61820 USA
[2] UNIV TEXAS, COLL NURSING & ALLIED HLTH, PHYS THERAPY PROGRAM, EL PASO, TX 79902 USA
[3] UNIV SO CALIF, SCH MED, DEPT PSYCHIAT, LOS ANGELES, CA 90033 USA
[4] VIRGINIA COMMONWEALTH UNIV MED COLL VIRGINIA, DEPT PHARMACOL & TOXICOL, RICHMOND, VA 23298 USA
[5] INST NEUROSCI, DEPT PHARMACOL & TOXICOL, AUSTIN, TX 78712 USA
[6] UNIV TEXAS, INST NEUROL SCI RES, AUSTIN, TX 78712 USA
关键词
DOPAMINE-2; RECEPTOR; MESOLIMBIC DOPAMINE; 6-HYDROXYDOPAMINE ROTATIONAL MODEL; AGONIST SENSITIVITY; STRIATAL EFFERENT; RAT;
D O I
10.1016/0166-4328(93)90151-F
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D-2 receptor proliferation occurs (20-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. This study was designed to investigate the quantitative aspects of the rotational behavior model utilizing constrained non-linear curve fitting routines. A dose-response curve for the rotational response arising from apomorphine stimulation of the normosensitive striatum was obtained in animals bearing unilateral lesions of striatal efferents (predominantly the striato-nigral pathway as previously described). After the control dose-response experiment, rats received a dopamine- (DA) depleting lesion in the contralateral hemisphere. In one group, 6-OHDA was infused into the medial forebrain bundle (MFB), a placement which is common in the literature and is known to deplete DA in both the striatum and nucleus accumbens. In a second group of rats, 6-OHDA was infused into the globus pallidus at a site which depletes caudate DA, but leaves n. accumbens DA relatively intact. The two experimental groups were tested in identical apomorphine-induced rotation dose-response experiments. The ED(50)'s of the MFB- and caudate-lesioned rats were reduced by 36 and 5.8 fold, respectively, as compared to the control dose-response curve. The MFB and caudate lesions depleted striatal DA and produced a 30 and 36% increase in striatal D-2 binding sites, respectively. Modeling the behavioral and biochemical data with the null model for receptor occlusion indicated that increased striatal D-2 receptor density could account for the magnitude of behavioral supersensitivity in neither the MFB-lesioned group, nor even in the caudate-lesioned group. Thus simple up-regulation or D-2 receptors is unlikely to account for supersensitization as measured in the rotational model. Further, we suggest that quantitative modeling of such hypotheses is a valuable experimental technique for assessing relationships between biochemical and behavioral variables.
引用
收藏
页码:53 / 64
页数:12
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