The 5‐HT 4 Agonist Prucalopride Stimulates L‐DOPA‐Induced Dopamine Release in Restricted Brain Regions of the Hemiparkinsonian Rat In Vivo

The efficacy of L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson’s disease (PD) is impaired by anxiety or depression in some patients and iatrogenic side effects such as dyskinesia [1]. Classical pharmacological tools such as selective serotonin reuptake inhibitors could be interesting to limit motor or nonmotor undesirable effects, but they directly target the activity of serotonergic neurons. Indeed, serotonergic (5-HT) neurons are responsible for L-DOPA-induced dopamine (DA) release and some of the inherent behavioral effects at the expense of 5-HT itself [2]. Therefore, the difficulty emerging with the therapies associated with L-DOPA is to enhance central DA tone, without further alteration of 5-HT transmission and excessive striatal DA tone correlated to the possible appearance of dyskinesia [2,3]. Our study makes reference to a recent work published by Mendez-David et al. [4] confirming that 5-HT4 ligands display interesting and fast onset of anxiolytic and antidepressant action [5]. Part of these effects would be related to their indirect modulatory action of 5-HT neuronal activity where 5-HT4 receptor stimulation and blockade could enhance and reduce dorsal raphe (DRN) 5-HT neuron activity and release at terminals, respectively [5]. Due to the expression of 5-HT4 receptors being preserved in the brain of Parkinsonian humans [6], the stimulation and blockade of 5-HT4 receptors could enhance and reduce the ability of L-DOPA to stimulate the depolarization-dependent outflow of DA from 5-HT neurons, respectively. We used multisite intracerebral microdialysis in the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to study the effect of the 5-HT4 agonist prucalopride or the 5-HT4 antagonist GR 125487 on the release of DA induced by intraperitoneal (i.p.) 12 mg/kg L-DOPA. Microdialysis probes were simultaneously implanted in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr), and the prefrontal cortex (PFC) [7]. We have chosen a dose for each 5-HT4 compound that guaranteed selective and efficient action toward 5-HT4 receptors [8]. The entire experimental procedures were similar to those recently reported [7] and agreed with French National Committee (d ecret 87/848, Minist ere de l’Agriculture et de la Forêt) and European Economic Community (86-6091 EEC) guidelines for the care and use of laboratory animals. As previously reported [3,7], L-DOPA (12 mg/kg, i.p.) increased DA outflow in the striatum, SNr, PFC, and the HIPP (Figure 1). The 5-HT4 antagonist GR 125487 (0.1 mg/kg, i.p.) did not modify the effect of L-DOPA suggesting that 5-HT4 receptors do not contribute to the regulation of the basal activity of 5-HT neurons in the presence of L-DOPA. This is consistent with the fact that LDOPA tends to decrease 5-HT extracellular levels in the brain [2]. Conversely, 5-HT4 receptor agonist prucalopride (5 mg/kg, i.p.) selectively enhanced L-DOPA-stimulated DA release in the SNr and the PFC (Figure 1). The use of multisite intracerebral microdialysis allows us to discard peripheral or central pharmacokinetic interaction because the prucalopride-dependent enhancement of L-DOPA-stimulated DA release was not observed in the striatum or the HIPP of the same rats. Consistently, the DA metabolite 3,4dihydroxyphenylacetic acid (DOPAC) extracellular levels, reflecting circulating L-DOPA, were homogeneously enhanced in all brain regions. The lack of effect of prucalopride on DOPAC extracellular levels further rules out regional changes of L-DOPA availability (data not shown). The pharmacodynamic interaction might involve the indirect stimulation of 5-HT neurons located in the raphe nuclei and