LOSS OF D-1/D-2 DOPAMINE-RECEPTOR SYNERGISMS FOLLOWING REPEATED ADMINISTRATION OF D-1 OR D-2 RECEPTOR-SELECTIVE ANTAGONISTS - ELECTROPHYSIOLOGICAL AND BEHAVIORAL-STUDIES

Many effects resulting from D-2 dopamine (DA) receptor stimulation are manifest only when D-1 DA receptors are stimulated by endogenous DA. When D-1 receptor stimulation is enhanced by administration of selective D-1 receptor agonists, the functional effects of selective D-2 agonists are markedly increased. These qualitative and quantitative forms of D-1/D-2 DA receptor synergism are abolished by chronic DA depletion when both D-1 and D-2 DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D-1 and D-2 receptor supersensitivity, induced by repeated administration of selective D-1 or D-2 receptor antagonists, on the synergistic relationships between D-1 and D-2 receptors. Daily administration of the selective D-2 antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D-2 agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D-1 agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D-2 receptors from the necessity of D-1 receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D-1 receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D-1, receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also some-what enhanced in SCH 23390-pretreated rats. When such D-1-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D-1-sensitized rats are due to a heterologous sensitization of D-2 receptors rather than to enhanced enabling resulting from supersensitive D-1 receptors. It is suggested that supersensitivity of either D-1 or D-2 receptors can lead to an uncoupling of normal qualitative and quantitative D-1/D-2 synergisms and that the heterologous regulation of D-2 receptor sensitivity by D-1 receptors may be related to uncoupling of functional D-1/D-2 synergisms. (C) 1994 Wiley-Liss, Inc.