Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia

Abstract

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Keywords: L-Dopa; PET imaging; Parkinson’s disease; dyskinesia; experimental animal models; immunohistochemistry; movement disorders; parkinsonism; serotonin.

Fig. 1

Striatal upregulation of 5-HT₄R after dopamine depletion and L-Dopa exposure in the 6-OHDA lesioned rat. A) Histogram represents optical density measurements of 5-HT₄R (in arbitrary units) in the ipsilateral dorsolateral striatum for the 3 experimental groups. **p < 0.01 versus control; ^&&&p < 0.001 versus parkinsonian. B) Photomicrographs at high magnification (x16) of coronal sections of a dyskinetic rat, exemplifying spatio-temporal concomitance of 5-HT₄R and FosB increases in the ipsilateral dorsolateral striatum. Scale bar on B is 50μm. OD, optical density, Park, parkinsonian; Dysk, dyskinetic.

Fig. 2

Striatal upregulation of 5-HT₄R after dopamine depletion and L-Dopa exposure in MPTP-treated macaques. A) Histogram represents optical density measurements of 5-HT₄R (in arbitrary units) in the posterior putamen for the 3 experimental groups. *p < 0.05 versus control; ^&p < 0.05 versus parkinsonian. B) [¹¹C]PE2I PET averaged images (in color) on coronal planes at the level of the posterior caudate and putamen for each condition. C) Histogram represents ¹¹C-PE2I BP_ND in the posterior putamen for each condition. D) [¹¹C]SB207145 PET averaged images (in color) on coronal planes at the level of the posterior caudate and putamen for each condition. E) Histogram represents ¹¹C-SB207145 BP_ND in the posterior putamen for each condition. *p < 0.05, **p < 0.01 versus baseline. Color represents the level of BP_ND using the cerebellum as the reference region (red indicates high whereas bleu indicates low BP_ND on each scale). a.u., arbitrary units; BP_ND, non-displaceable binding potential; Dysk, dyskinetic; OD, optical density; Park, parkinsonian.