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

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.

SUBMITTER: Demireva EY

PROVIDER: S-EPMC6378140 | biostudies-literature |

REPOSITORIES: biostudies-literature

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| S-EPMC8045409 | biostudies-literature

Basal ganglia plus insula damage yields stronger disruption of smoking addiction than basal ganglia damage alone.

Project description:IntroductionThe main objective of this study was to elucidate the importance of the basal ganglia (BG) and insula (INS) for nicotine addiction and smoking behavior.MethodsWe used a lesion study examining the effects of BG and INS damage on changes in smoking behavior and nicotine dependence over time in a prospective manner. We studied whether combined BG and INS damage yields more substantial disruption of smoking and nicotine dependence than damage to the BG alone and compared with damage to other brain regions outside the BG and INS (brain-damaged comparison [BDC] group). We obtained neuroanatomical and behavioral data for 63 neurological patients with stroke at 1 month after onset and at 3-, 6-, and 12-month follow-ups. All patients were smokers at lesion onset.ResultsThe BG and BG + INS groups had significantly higher and more sustained rates of smoking cessation than patients with damage elsewhere. By 12 months after onset, only 14.3% of the patients in the BDC group were classified as nonsmokers. In the BG group, 37% were not smoking by the 12-month follow-up, and in the BG + INS group, smoking cessation was even more pronounced, as 75% of this group was not smoking at the 12-month epoch.ConclusionsThe findings show that damage to the BG alone can cause disruption of smoking addiction, and when BG damage is combined with INS damage, the disruption increases. The latter finding is consistent with the proposal that the INS has a key role in smoking addiction.

| S-EPMC3954424 | biostudies-literature

Vocal babbling in songbirds requires the basal ganglia-recipient motor thalamus but not the basal ganglia.

Project description:Young songbirds produce vocal "babbling," and the variability of their songs is thought to underlie a process of trial-and-error vocal learning. It is known that this exploratory variability requires the "cortical" component of a basal ganglia (BG) thalamocortical loop, but less understood is the role of the BG and thalamic components in this behavior. We found that large bilateral lesions to the songbird BG homolog Area X had little or no effect on song variability during vocal babbling. In contrast, lesions to the BG-recipient thalamic nucleus DLM (medial portion of the dorsolateral thalamus) largely abolished normal vocal babbling in young birds and caused a dramatic increase in song stereotypy. These findings support the idea that the motor thalamus plays a key role in the expression of exploratory juvenile behaviors during learning.

| S-EPMC3118735 | biostudies-literature

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