Neurochemical and electrophysiological evidence that 5-HT4 receptors exerta state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function

In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin(4) (5-HT4) receptors in the control of ni grostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow i nduced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HA L). Intrastriatal infusion of GR 125487 (1 mum) had no influence on basal D A outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic adm inistration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulat ed accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 1 25487, without effect by itself, failed to modify the changes in accumbal a nd striatal DA outflow elicited by electrical stimulation (300 muA, 1 ms, 2 0 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 mug/kg, i.v.), whilst not affecting basal firing of DA neurons within either the su bstantia nigra or the ventral tegmental area, reduced HAL-stimulated (1-300 mug/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striata l DA release and nigral DA neuron impulse flow only when nigrostriatal DA t ransmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exe rted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditi ons.