HT System Influence on D1 Agonist Induction of VCMs

The above series of studies demonstrated that both DA systems and 5-HT systems have a prominent influence on the induction of perioral movements, and that both systems exert enhanced effects when DA denervation of neostriatum is produced perinatally. Many years earlier, Zigmond's group demonstrated that perinatal 6-OHDA lesioning of the nigrostriatal DA tract was accompanied by 5-HT fiber hyperinnervation of neostriatum (Berger et al. 1985; Snyder et al. 1986). Therefore, it was natural to explore the influence on one system on the other in relation to VCM induction.

Initially we found that the 5-HT2 antagonist mianserin attenuated Dj agonist-induced VCMs in 6-OHDA-lesioned rats (Gong et al. 1992; Plech et al. 1995). In contrast, the Dj antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] did not attenuate mCPP induction of VCMs (Gong et al. 1992). This finding indicated that enhanced Dj agonist induction of VCMs was mediated through a 5-HT system, not vice versa (Kostrzewa et al. 1992). Moreover, when 5-HT innervation in brain was largely destroyed in perinatal 6-OHDA-lesioned rats by perinatal 5,7-dihydroxytryptamine (5,7-DHT) treatment, there was failure of development of the enhanced D1 agonist induction of VCMs in rats in adulthood (Brus et al. 1994). Similarly, in neonatally 6-OHDA-lesioned rats that already displayed enhanced D1 agonist induction of VCMs in adulthood, a subsequent 5-HT lesion with 5,7-DHT eliminated the enhanced Dj agonist effect (unpublished).

The series of findings implicate the 5-HT system as a regulator of the sensitivity status of DA D1 receptors at the receptor level (5-HT2) and as presumably neural mediators of D1 modulation of oral activity or oral dyskinesia.

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