Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i.e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 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 D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i.e., behavior was elicited by independent stimulation of D1 or D2 receptors). In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6-hydroxy-dopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 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 D2 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rats with unilateral 6-hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity.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 D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.