5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy

被引：30

作者：

Demireva, Elena Y. ^{[1
,2
]}

Suri, Deepika ^{[1
]}

Morelli, Emanuela ^{[1
]}

Mahadevia, Darshini ^{[1
]}

Chuhma, Nao ^{[1
,3
]}

Teixeira, Catia M. ^{[1
,2
]}

Ziolkowski, Annette ^{[1
,2
]}

Hersh, Marc ^{[1
]}

Fifer, James ^{[1
]}

Bagchi, Sneha ^{[1
]}

Chemiakine, Alexei ^{[1
]}

Moore, Holly ^{[1
,4
]}

Gingrich, Jay A. ^{[1
,2
]}

Balsam, Peter ^{[1
,2
]}

Rayport, Stephen ^{[1
,3
]}

Ansorge, Mark S. ^{[1
,2
]}

机构：

[1] Columbia Univ, Dept Psychiat, New York, NY 10032 USA

[2] New York State Psychiat Inst & Hosp, Dept Dev Neurosci, New York, NY 10032 USA

[3] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA

[4] New York State Psychiat Inst & Hosp, Div Syst Neurosci, New York, NY 10032 USA

来源：

MOLECULAR PSYCHIATRY | 2020年 / 25卷 / 12期

关键词：

SEROTONIN 2C RECEPTOR; NIGRA DOPAMINERGIC-NEURONS; DORSAL RAPHE NUCLEUS; PARS RETICULATA NEURONS; OF-THE-LITERATURE; SUBSTANTIA-NIGRA; EXTRAPYRAMIDAL SYMPTOMS; REUPTAKE INHIBITORS; MESSENGER-RNA; ANTIDEPRESSANT TREATMENT;

D O I：

10.1038/s41380-018-0227-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.

引用

页码：3304 / 3321

页数：18

共 91 条

[11] Raphe serotonin neurons are not homogenous: Electrophysiological, morphological and neurochemical evidence [J].

Calizo, Lyngine H. ;

Akanwa, Adaure ;

Ma, Xiaohang ;

Pan, Yu-zhen ;

Lemos, Julia C. ;

Craige, Caryne ;

Heemstra, Lydia A. ;

Beck, Sheryl G. .

NEUROPHARMACOLOGY, 2011, 61 (03) :524-543

[12]

Cases O, 1998, J NEUROSCI, V18, P6914

[13]

Cassano Paolo, 2004, Ann Clin Psychiatry, V16, P15, DOI 10.1080/10401230490281618

[14] 5-HT2C receptors in psychiatric disorders: A review [J].

Chagraoui, A. ;

Thibaut, F. ;

Skiba, M. ;

Thuillez, C. ;

Bourin, M. .

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 2016, 66 :120-135

[15] Dopamine and serotonin signals for reward across time scales [J].

Cohen, Jeremiah Y. .

SCIENCE, 2015, 350 (6256) :47-48

[16] Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice [J].

Compan, V ;

Zhou, MM ;

Grailhe, R ;

Gazzara, RA ;

Martin, R ;

Gingrich, J ;

Dumuis, A ;

Brunner, D ;

Bockaert, J ;

Hen, R .

JOURNAL OF NEUROSCIENCE, 2004, 24 (02) :412-419

[17] The significance of action potential bursting in the brain reward circuit [J].

Cooper, DC .

NEUROCHEMISTRY INTERNATIONAL, 2002, 41 (05) :333-340

[18]

Damsa C, 2004, J CLIN PSYCHIAT, V65, P1064

[19]

De Deurwaerdere P., 2016, Progress in Neurobiology

[20] Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function:: A combined in vivo electrophysiological and microdialysis study [J].

Di Giovanni, G ;

De Deurwaerdére, P ;

Di Mascio, M ;

Di Matteo, V ;

Esposito, E ;

Spampinato, U .

NEUROSCIENCE, 1999, 91 (02) :587-597

← 1 2 3 4 5 6 7 8 9 10 →