Premium
Dopamine supersensitivity and D 1 /D 2 synergism are unrelated to changes in striatal receptor density
Author(s) -
Lahoste Gerald J.,
Marshall John F.
Publication year - 1992
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.890120103
Subject(s) - quinpirole , agonist , chemistry , medicine , endocrinology , haloperidol , dopamine receptor , stimulation , dopamine receptor d2 , dopamine , sch 23390 , receptor , pharmacology
Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D 1 /D 2 synergism (i. e., the requirement of concomitant stimulation of D 1 and D 2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D 1 /D 2 synergism was found to be independent of striatal D 1 or D 2 receptor density in rats as: (1) increasing striatal D 1 and/or D 2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D 1 /D 2 synergism as determined by behavioral responsiveness to agonist stimulation of D 1 or D 2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D 1 or D 2 receptor density, induced a breakdown in D 1 /D 2 synergism (i. e., behavior was elicited by independent stimulation of D 1 or D 2 receptors). In addition, the density of striatal D 2 binding sites was not indicative of behavioral sensitivity to D 2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D 2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6‐hydroxydopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D 2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6‐hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D 2 receptor binding. By contrast, when rats with unilateral 6‐hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity. The results support the hypothesis that two distinct types of dopamine supersensitivity exist: A modest one associated with increased D 2 density, and a more profound one associated with a breakdown in D 1 /D 2 synergism and independent of D 2 density.