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. 2016 Jun 1;90(5):955–968. doi: 10.1016/j.neuron.2016.04.017

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© 2016 The Authors

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PMC Copyright notice

Treatment with 5-HT6 Agonist ST-1936 Induces DA Release and GIDs through Direct Action on the Grafted DA Neurons

(A) Rotational behavior following treatment of 5-HT agonists specifically targeting each of the three metabotropic, Gs-coupled, serotonin (5-HT) receptors, with 5-HT4 agonist BIMU8 (green) and 5-HT7 agonist AS19 (black) not inducing any rotational behavior, while 5-HT6 agonist ST-1936 (blue) induced a strong contralateral rotation in grafted hM3Dq + KORD animals (L-DOPA naive and not previously displaying GIDs on CNO), but not Lesion Ctrls (red).

(B) Treatment with 5-HT6 agonist ST-1936 induced substantial AIMs in grafted hM3Dq + KORD animals (green) with only a weak, transient AIM score in Lesion Ctrls (red).

(C) Comparison of the different manifestations of AIMs between treatments with CNO, apomorphine, and ST-1936. CNO induced mainly locomotor (blue), axial (green), and orolingual (purple) AIMs in hM3Dq + rM3Ds animals. Grafted animals displayed a marked reduction in AIMs following treatment with apomorphine, with limb AIMs (red) being abolished. AIMs following treatment with ST-1936 induced mainly orolingual and axial AIMs, with a relatively small proportion of limb and locomotor AIMs in hM3Dq + KORD-grafted animals. In contrast, Lesion Ctrls mainly exhibited locomotor AIMs with a very small proportion of AIMs being orolingual.

(D–G) Electrochemical recordings of DA release in response to local ligand administration, with CNO (D) and ST-1936 (E) inducing a prolonged DA release with very similar kinetics in hM3Dq + KORD-grafted animals, while both KCl (F) and ST-1936 (G) induced a short spike of DA with very different kinetics when applied in the intact, nongrafted striatum (see also Figure S6).

(H) LSM image showing strong expression of 5-HT6 (red) colocalized with virally transduced (green) TH (blue)-positive neurons within the dopaminergic fetal graft.

(I–L) Magnified z stack of a dopaminergic neuron (taken from dashed square in H) showing the colocalization between virally transduced KORD expression (I), 5-HT6 (J), and TH (K) together with an overlay composite (L) (see also Figure S5).

All values reported as arithmetic mean ± 1 SEM. ^∗AUC significantly different from the Lesion Ctrl group, p < 0.05 using Kruskal-Wallis test followed by Bonferroni corrected all-pair comparison, using the Mann-Whitney U test in (A) and using Student’s t test in (B). Scale bar, 100 μm (H) and 10 μm (L).