TY - JOUR
T1 - Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors
T2 - Implications for extrapyramidal side effects of serotonin reuptake inhibitors
AU - Bonsi, Paola
AU - Cuomo, Dario
AU - Ding, Jun
AU - Sciamanna, Giuseppe
AU - Ulrich, Sasha
AU - Tscherter, Anne
AU - Bernardi, Giorgio
AU - Surmeier, D. James
AU - Pisani, Antonio
N1 - Funding Information:
We thank Professor Nicola Mercuri for critical reading of the manuscript; Mr Massimo Tolu and Mr Franco Lavaroni for excellent technical assistance. This work was supported by grants from Dystonia Medical Research Foundation, Ministero Istruzione Università Ricerca (FIRB 2001), and Progetto Finalizzato Ministero Salute, to AP, GB, and PB.
PY - 2007/8
Y1 - 2007/8
N2 - The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3-300 μM), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT reuptake blockers citalopram and fluvoxamine. In voltage-clamped neurons, 5-HT induced an inward current, whose reversal potential was close to the K+ equilibrium potential. Accordingly, the involvement of K+ channels was confirmed either by increasing extracellular K+ concentration and by blockade of K + channels with barium. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) profiling demonstrated the presence of 5-HT2C, 5-HT6, and 5-HT7 receptor mRNAs in identified cholinergic interneurons. The depolarization/inward current induced by 5-HT was partially mimicked by the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine and antagonized by both ketanserin and the selective 5-HT2C antagonist RS102221, whereas the selective 5-HT3 and 5-HT4 receptor antagonists tropisetron and RS23597-190 had no effect. The depolarizing response to 5-HT was also reduced by the selective 5-HT6 and 5-HT7 receptor antagonists SB258585 and SB269970, respectively, and mimicked by the 5-HT7 agonist, 5-CT. Accordingly, activation of either 5-HT6 or 5-HT7 receptor induced an inward current. The 5-HT response was attenuated by U73122, blocker of phospholipase C, and by SQ22,536, an inhibitor of adenylyl cyclase. These results suggest that 5-HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons.
AB - The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3-300 μM), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT reuptake blockers citalopram and fluvoxamine. In voltage-clamped neurons, 5-HT induced an inward current, whose reversal potential was close to the K+ equilibrium potential. Accordingly, the involvement of K+ channels was confirmed either by increasing extracellular K+ concentration and by blockade of K + channels with barium. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) profiling demonstrated the presence of 5-HT2C, 5-HT6, and 5-HT7 receptor mRNAs in identified cholinergic interneurons. The depolarization/inward current induced by 5-HT was partially mimicked by the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine and antagonized by both ketanserin and the selective 5-HT2C antagonist RS102221, whereas the selective 5-HT3 and 5-HT4 receptor antagonists tropisetron and RS23597-190 had no effect. The depolarizing response to 5-HT was also reduced by the selective 5-HT6 and 5-HT7 receptor antagonists SB258585 and SB269970, respectively, and mimicked by the 5-HT7 agonist, 5-CT. Accordingly, activation of either 5-HT6 or 5-HT7 receptor induced an inward current. The 5-HT response was attenuated by U73122, blocker of phospholipase C, and by SQ22,536, an inhibitor of adenylyl cyclase. These results suggest that 5-HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons.
KW - 5-HT
KW - Cholinergic interneuron
KW - Electrophysiology
KW - Slices
KW - Striatum
KW - TANs
UR - http://www.scopus.com/inward/record.url?scp=34250191571&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250191571&partnerID=8YFLogxK
U2 - 10.1038/sj.npp.1301294
DO - 10.1038/sj.npp.1301294
M3 - Article
C2 - 17203014
AN - SCOPUS:34250191571
SN - 0893-133X
VL - 32
SP - 1840
EP - 1854
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 8
ER -