Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

Abstract

Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline-treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell.

M1and M2Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

“…Although pirenzepine has restricted access to the central nervous system upon systemic dosing, higher doses have proven to gain functional access central muscarinic receptors (Witkin et al, 1988) (Table 3). Indeed, pirenzepine administered directly into the nucleus accumbens was shown to engender an antidepressant-like phenotype in rats in studies by Hoebel's group (Chau et al, 1999(Chau et al, , 2011 as did the analog telenzepine (Voleti et al, 2013). Behavioral effects of pirenzepine, like those of scopolamine, were absent in M 1 2/2 receptor mice in this study.…”

“…Local injection of pirenzepine into the shell of the nucleus accumbens also has antidepressant-like effects in rats (Chau et al, 1999). In addition, acetylcholine efflux in this brain area has been implicated in the antidepressant effects of fluoxetine (Chau et al, 1999(Chau et al, , 2011. Taken together, these data implicate this dopamine projection area in the M 1 receptor regulation of mood and the behavioral symptoms of despair.…”

Dopamine Signaling inC. elegansIs Mediated in Part by HLH-17-Dependent Regulation of Extracellular Dopamine Levels

“…A more attractive, alternative possibility is that HLH-17 influences acetylcholine release, as the phenotypic effects of both reserpine (Saharia et al 2012) and fluoxetine (Bolanos et al 2002; Chau et al 2011) are dependent on acetylcholine. In support of this possibility, the inhibitory effect of fluoxetine on acetylcholine release in rats is dependent on activity of the dopaminergic D2 receptors (Bolanos et al 2002).…”

Antidepressant-like effects of Dipyrone researched with forced swim test

“…Depresyon tedavisinde kullanılan selektif serotonin reuptake inhibitörü fluoksetinin, serotonin düze-yinde artmaya neden olmasının yanı sıra yükselen sitokin düzeylerini azalttığı ve beyinde neurorejenerasyonu sağladığı böylece antidepresan etkinliğinin olduğu bildirilmektedir 31,32 . Selekoksib, asetil salisilik asit, parasetamol gibi çeşitli analjezik ilaçların da serotonin seviyesini artırdığı, IL6 ve TNFα gibi sitokinlerin düzeyinin azalttığı yapılan çalışmalarla gösterilmiştir 30,31,33 .…”

“…Selekoksib, asetil salisilik asit, parasetamol gibi çeşitli analjezik ilaçların da serotonin seviyesini artırdığı, IL6 ve TNFα gibi sitokinlerin düzeyinin azalttığı yapılan çalışmalarla gösterilmiştir 30,31,33 . Parasetamol'ün antidepresif etkisinin araştırıldığı bir çalışmada ise, farelere akut parasetamol uygulanması sonucu zorunlu yüzdürme testi ve kuyruk süspansiyon testlerinde antidepresif etkiye benzer bulgular elde edilmiş, ayrıca parasetamolün fluoksetinle sinerjistik etkileşmesi olduğu görülmüştür 33 .…”