Combined intrastriatal dopamine d1 and serotonin 5-ht2 receptor stimulation reveals a mechanism for hyperlocomotion in 6-hydroxydopamine-lesioned rats

Abstract

Loss of dopaminergic innervation to the striatum increases the sensitivity of dopamine (DA) D1 and serotonin (5-HT) 5-HT2 receptor signaling. Previous work from our laboratory has shown that systemic co-administration of D1 and 5-HT2 receptor agonists leads to the synergistic overexpression of striatal preprotachykinin mRNA levels in the DA-depleted, but not intact animals. In the present study, we examined this mechanism as related to locomotor behavior. Adult male Sprague–Dawley rats were subject to bilateral i.c.v. 6-hydroxydopamine (6-OHDA; 200 μg in 10 μl/side) or vehicle (0.9% saline and 0.1% ascorbic acid). After 3 weeks, rats were tested for locomotor responses to bilateral intrastriatal infusions of vehicle (0.9% NaCl), the D1 agonist SKF82958 [(±)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-(1 H)-3-benzazepine hydrobromide; 0.1, 1.0 or 10.0 μg/side], the 5-HT2 agonist DOI [(±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; 0.1, 1.0 or 10.0 μg/side] or subthreshold doses of DOI and SKF82958 (0.1 μg+0.1 μg in 0.8 μl/side). Rats with DA loss demonstrated supersensitive locomotor responses to SKF82958, but not DOI. Combined administration of subthreshold SKF82958 and DOI doses (0.1 μg+0.1 μg) synergistically increased locomotor behavior only in 6-OHDA-lesioned rats. These effects were blocked by either the D1 antagonist SCH23390 3-methyl-1-phenyl-2,3,4,5-tetrahydro-7-chloro-8-hydroxy-(1H)-3-benzazepine or the 5-HT2 antagonist ritanserin (each 1.0 μg in 0.8 μl/side). The results of this study suggest that the behavioral synergy induced by local co-stimulation of D1 and 5-HT2 receptors within the 6-OHDA-lesioned striatum may lead to hyperkinesias that can occur with continued pharmacological treatment of Parkinson's disease.