Rationale: Considerable evidence indicates that dopaminergic drugs, including drugs that act on D1 receptors, exert their effects by actions on forebrain dopamine terminal regions. Nevertheless, anatomical studies also have demonstrated that there is a high concentration of D1 receptors in the substantia nigra pars reticulata (SNr). The D1 receptors in SNr are located largely on the terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 antagonist SCH 23390 was effective if locally injected into SNr and to compare 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 23390.
Methods: Rats received bilateral implantations of guide cannulae into either nucleus accumbens, neostriatum, SNr, or control sites in the cortex or brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 microl per side): vehicle, 0.25, 0.5, 1.0, or 2.0 microg SCH 23390.
Results: In the FR5 study, the SNr was by far the most potent site for suppression of lever pressing, with an ED50 (dose that produces half maximal response) of 0.33 microg per side. Nucleus accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open-field locomotion, the SNr, nucleus accumbens, and neostriatum were approximately equipotent sites, and all three were more potent than the control sites.
Conclusions: 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 regions but also the SNr. It is possible that blockade of SNr D1 receptors modulates GABA release from striatonigral neurons.