No abstract

In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D 3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[ 3 H]hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in D 1 or D 2 receptor mRNAs. D 3 receptor induction by levodopa is mediated by repeated D 1 receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two D 2 receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized D 3 receptor, since it is antagonized by nafadotride, a preferential D 3 receptor antagonist, in low dosage, which has no such effect before D 3 receptor induction. D 3 receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to D 3 receptor induction, is responsible for behavioral sensitization.Behavioral sensitization, also termed reverse tolerance, is a process by which repeated stimulation of neurotransmitter receptors in brain results in a progressive enhancement of responsiveness (1, 2). This process, particularly well illustrated in the case of direct or indirect dopamine agonists, is involved in the longterm effects of several drugs of abuse as well as of agents used to treat patients with Parkinson disease (PD). In these patients, the reduction in striatal dopamine levels, which results in reduced movement, can be compensated by administration of levodopa, the amino acid precursor of dopamine (3).Long-term administration of levodopa results in both beneficial and unwanted changes in responsiveness to this drug. Thus, although acute administration of levodopa initially reduces rigidity, repeated administration appears necessary for the resumption of complex motor behavior (4, 5). On the other hand, long-term use of levodopa is associated with development of abnormal involuntary movements as well as psychological disturbances such as hallucinations, both suggestive of excessive response to dopamine.Behavioral sensitization is also observed in animal models of PD. In agreement, in rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine (6-OHDA), the motor-stimulatory e...