Neurotensin-dopamine interactions in the substantia nigra of the rat brain

Abstract

Single or multiple doses of the potent dopamine releaser, methamphetamine (METH), increases the content of neurotensin (NT)-like immunoreactivity (NTLI) in the substantia nigra of the rat brain by 2- to 3-fold. Concurrent blockade of D-1 receptors with METH treatment completely antagonized the increase in nigral NTLI content induced by this drug. These results suggest that activation of D-1 receptors by endogenous dopamine results in an increase in the level of NTLI in the substantia nigra. The present study was performed to characterize further the mechanisms underlying dopaminergic regulation of nigral NT systems. Prior selective destruction of the nigrostriatal dopamine pathway completely prevented the increase in nigral NTLI content induced by treatment with METH, which suggests that the effects of METH on nigral NT systems are mediated by the nigrostriatal dopamine projections. However, unlike METH, treatment of rats with the direct-acting, D-1-selective agonist, SKF 38393, did not alter nigral NTLI content but when combined with stimulation of D-2 receptors, a significant increase in the level of NTLI occurred. Surprisingly, activation of only D-2 receptors caused a significant decrease in nigral NTLI content. These data suggest that although activation of D-2 receptors alone has an effect opposite to that of the D-1 subtype, in combination with D-1 stimulation they facilitate the effect of D-1 receptors on nigral NT systems. In addition to the effects of direct or indirect stimulation of dopamine activity on nigral NT levels, basally released dopamine also appeared to regulate the level of NTLI in the substantia nigra. Thus, interruption of tonic dopamine activity by reserpine-induced depletion of dopamine significantly reduced the level of NTLI in the substantia nigra. The role of D-1 receptors in this tonic dopaminergic regulation of nigral NT systems was evident when concurrent activation of D-1, but not D-2, receptors with reserpine treatment prevented or reversed the decrease in NTLI content caused by dopamine depletion. Additional evidence for the D-1-mediated tonic regulation of NT systems in the substantia nigra was that blockade of D-1 receptors with SCH 23390 decreased the nigral NTLI content but blockade of D-2 receptors with sulpiride had no effect.