5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy.
Autor: Demireva, Elena Y.; Suri, Deepika; Morelli, Emanuela; Mahadevia, Darshini; Chuhma, Nao; Teixeira, Catia M.; Ziolkowski, Annette; Hersh, Marc; Fifer, James; Bagchi, Sneha; Chemiakine, Alexei; Moore, Holly; Gingrich, Jay A.; Balsam, Peter; Rayport, Stephen; Ansorge, Mark S.
Publication year: 2020
Molecular psychiatry
issn:1476-5578 1359-4184
doi: 10.1038/s41380-018-0227-x
Abstract:
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.
Language: eng
Rights:
Pmid: 30120415
Tags: Animals; Mice; Dopamine; *Receptor, Serotonin, 5-HT2C; *Selective Serotonin Reuptake Inhibitors; Basal Ganglia; Serotonin; Substantia Nigra
Link: https://pubmed.ncbi.nlm.nih.gov/30120415/
