D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.     

Chronicl-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronicl-dihydroxyphenylalanine (l-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response forl-DOPA activation of the dopamine denervated striatum. Following 30 dailyl-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization tol-DOPA was not reversed by a three-day period ofl-DOPA withdrawal. In contrast with the emergence of behavioral sensitization tol-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acutel-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronicl-DOPA treatment produces a partial tolerance in the conversion ofl-DOPA to extracellular dopamine. The emergence ofl-DOPA sensitization-overstimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects ofl-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion ofl-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect ofl-DOPA therapy.     

In vivo changes in responsiveness of the caudate nucleus tol-DOPA infusion as a function of the estrous cycle

In the present experiment we measured changes in the responsiveness of the nigrostriatal dopaminergic system tol-DOPA as a function of the estrous cycle in the freely behaving animal with push-pull perfusion. Intact female rats were implanted with a push-pull cannula directed at the caudate nucleus and perfused repetitively on each day of their estrous cycle. During the perfusion, the response of the caudate nucleus was tested with two successive increasing doses ofl-DOPA (1.0 and 10 μM) infused directly through the push side of the cannula. In response to 1.0 μMl-DOPA, significantly greater dopamine release was obtained for female rats perfused on proestrus, with all 6 females showing maximal responsiveness at this estrous cycle stage. There was an overall 3–4 fold greater increase in dopamine release to the 10 μMl-DOPA infusion, regardless of estrous cycle day. However, with the use of this 10 μMl_DOPA dose, the significant effect at proestrus was maintained. These results demonstrate that the responsiveness of the caudate nucleus tol-DOPA is maximal at proestrus. These data together with previous work from our laboratory indicate that the natural physiological changes which occur in hormone levels, in particular changes in progesterone during proestrus, exert a substantial influence upon this extra-hypothalamic central nervous system site.