Alterations of second messenger systems in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle

Abstract

We studied the sequential changes in second messenger systems in the striatum and substantia nigra (SN) after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. [ 3H]Phorbol-12,13-dibutyrate (PDBu), [ 3H]forskolin and [ 3H]rolipram were used to label protein kinase C (PKC), adenylyl cyclase and calcium/calmodulin-independent cyclic-AMP phosphodiesterase, respectively. The degeneration of nigrostriatal pathway produced a significant increase in [ 3H]PDBu binding in the ventromedial part of the ipsilateral striatum from 2 to 8 weeks postlesion. In the contralateral side, [ 3H]PDBu binding showed a transient increase in the SN only 4 weeks after lesioning. [ 3H]Forskolin binding showed a significant increase in the ipsilateral and contralateral striatum from 2 to 4 weeks postlesion. In the ipsilateral SN, a significant increase in [ 3H]forskolin binding was observed at 4 weeks after lesioning. However, no significant change in [ 3H]forskolin binding was observed in the contralateral SN during postlesion. On the other hand, [ 3H]rolipram binding showed no conspicuous alteration in the brain during postlesion. These results demonstrate that rats made hemiparkinsonism by unilateral 6-hydroxydopamine injection have a significant increase in [ 3H]PDBu and [ 3H]forskolin binding in the striatum and/or SN, whereas no significant change in [ 3H]rolipram binding is observed in these areas during postlesion. Our findings also suggest that the increase in [ 3H]forskolin binding is more pronounced than that in [ 3H]PDBu binding in the brain after unilateral 6-hydroxydopamine injection. Thus, our studies may provide valuable information concerning degeneration of the nigrostriatal pathway such as Parkinson’s disease.