Substantia nigra pars reticulata is a highly potent site of action for thebehavioral effects of the D1 antagonist SCH 23390 in the rat

Rationale: Considerable evidence indicates that dopaminergic drugs, includi ng drugs that act on DI receptors, exert their effects by actions on forebr ain dopamine terminal regions. Nevertheless, anatomical studies also have d emonstrated that there is a high concentration of D1 receptors in the subst antia nigra pars reticulata (SNr). The D1 receptors in SNr are located larg ely on the terminals of gamma -aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 a ntagonist SCH 23390 was effective if locally injected into SNr and to compa re the results of SNr injections with those obtained from other brain sites . Fixed ratio 5 (FR5) lever pressing and open-field locomotion were used as the behavioral tests because these tasks are sensitive to systemic SCH 233 90. Methods: Rats received bilateral implantations of guide cannulae into e ither nucleus accumbens, neostriatum, SNr, or control sites in the cortex o r brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 mul per side): vehicle, 0,25, 0,5, 1.0, or 2.0 mug SCH 23390. Results: In the FR5 study, the SNr w as by far the most potent site for suppression of lever pressing, with an E D50 (dose that produces half maximal response) of 0.33 mug per side. Nucleu s accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open field l ocomotion, the SNr, nucleus accumbens, and neostriatum were approximately e quipotent sites, and all three were more potent than the control sites. Con clusions: SNr was a very potent site for suppression of lever pressing and open-field locomotion. These data suggest that D1 antagonists have multiple sites of action, including not only the forebrain dopamine terminal region s but also the SNr, It is possible that blockade of SNr D1 receptors modula tes GABA release from striatonigral neurons.