Host brain regulation of dopaminergic grafts function: Role of the serotonergic and noradrenergic systems in amphetamine‐induced responses

Abstract

The indirect dopaminergic (DA) agonist amphetamine has frequently been used to study functional responses of DA grafted neurons. However, it is not known if striatal responses, primarily related to DA release by the grafted neurons, are modulated by the host striatal afferents. We investigated the changes in amphetamine-induced rotational behavior and striatal expression of Fos in DA-denervated and grafted rats subjected to serotonergic denervation and/or treatment with the alpha(1)-adrenergic receptor antagonist Prazosin. Acute serotonergic lesions with p-chlorophenylalanine suppressed the expression of Fos induced by 1 mg/kg of amphetamine in both the grafted and the contralateral striatum. Chronic serotonergic denervation with 5,7-dihydroxytryptamine induced a significant reduction in Fos expression in both the grafted and nongrafted striata and a nonsignificant reduction in the contraversive rotation. In DA-innervated striata, Prazosin significantly reduced the expression of Fos but only in the presence of serotonergic innervation. However, Prazosin did not decrease the expression of Fos induced by grafts located in striata not subjected to serotonergic denervation. The present results suggest functional integration of transplanted DA neurons and major host striatal afferent systems, particularly the serotonergic system, in modulating responses of the host striatal neurons. However, indirect effects exerted by the noradrenergic system on the normal striatum were not observed in the DA-denervated and grafted striata.

Serotonin decreases generation of dopaminergic neurons from mesencephalic precursors via serotonin type 7 and type 4 receptors

“…Clarification of these signals is highly relevant not only in understanding brain development but also in obtaining DA neurons for possible cell therapy in Parkinson's disease (Lindvall and Björklund, 2004;Winkler et al, 2005). In addition, clarification of the relationships between 5-HT and DA populations differentiated within the grafts may be relevant for understanding of L-dopainduced dyskinesias observed in some grafted patients (Lopez et al, 2001;Freed et al, 2001;Muñoz et al, 2003;Olanow et al, 2003).…”