Vol. 295, Issue 3, 1232-1240, December 2000

Differential Regulation of Dopamine D2 and D3 Receptors by Chronic Drug Treatments¹

Gregg D. Stanwood² , Irwin Lucki and Paul McGonigle³

Departments of Pharmacology (G.D.S., I.L., P.M.) and Psychiatry (I.L.), and Institute for Neurological Sciences (G.D.S., I.L., P.M.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Regulation of the expression of dopamine D2 and D3 receptors in the rat brain was examined using quantitative autoradiography after chronic (14 day) drug treatments designed to increase or decrease dopamine receptor stimulation. Reserpine treatment depleted endogenous dopamine by more than 90% and significantly increased the binding of [¹²⁵I]NCQ 298 to D2 receptors in the nucleus accumbens, ventral pallidum, and substantia nigra. In contrast, this treatment significantly decreased the binding of [¹²⁵I]7-OH-PIPAT to D3 receptors in each of these regions. Chronic stimulation of D2-like receptors with quinpirole (1 mg/kg/day) or 7-OH-DPAT (1 mg/kg/day) produced decreases in [¹²⁵I]NCQ 298 binding in the nucleus accumbens, ventral pallidum, and substantia nigra as expected. As with depletion, chronic stimulation elicited an opposite response from D3 receptors with significant increases observed in the ventral pallidum and substantia nigra. D3 receptor expression in the nucleus accumbens was unchanged. Baclofen (30 mg/kg/day) or continuous administration of the psychomotor stimulant cocaine (20 mg/kg/day) produced no significant changes in D2 or D3 receptor binding in any region examined. Acute administration of the irreversible antagonist EEDQ (10 mg/kg) nearly eliminated D2 receptor binding in all regions, but inactivated D3 receptors only in the VP and SN, suggesting subtype-specific and region-specific differences in receptor occupancy. The existence of regional and subtype-specific heterogeneities in the regulation of these receptors supports the contention that despite their similar pharmacological profiles, D2 and D3 receptors may mediate different functional responses.