About 280 million people suffer from depression as the most common neurological disorder and the most common cause of death worldwide. Exercise with serotonin released in the brain by the 5-HT3-IGF-1 mechanism can lead to antidepressant effects. Swimming exercise has antidepressant effects by increasing the sensitivity of serotonin 5-HT2 receptors and postsynaptic 5-HT1A receptors, increasing 5-HT and 5HIAA levels, increasing TPH and serotonin, and decreasing inflammatory levels of IFN-γ and TNF-α. Anaerobic and aerobic exercises increase beta-endorphin, enkephalin, and dynorphin and have antidepressant effects. Exercise by increasing dopamine, D1R, and D2R leads to the expression of BDNF and activation of TrkB and has antidepressant behavior. Exercise leads to a significant increase in GABAAR (γ2 and α2 subunits) and reduces neurodegenerative disorders caused by GABA imbalance through anti-inflammatory pathways. By increasing glutamate and PGC1α and reducing glutamatergic neurotoxicity, exercise enhances neurogenesis and synaptogenesis and prevents neurodegeneration and the onset of depression. Irisin release during exercise shows an important role in depression by increasing dopamine, BDNF, NGF, and IGF-1 and decreasing inflammatory mediators such as IL-6 and IL-1β. In addition, exercise-induced orexin and NPY can increase hippocampal neurogenesis and relieve depression. After exercise, the tryptophan to large neutral amino acids (TRP/LNAA) ratio and the tryptophan to branched-chain amino acids (BCAA) ratio increase, which may have antidepressant effects. The expression of M5 receptor and nAChR α7 increases after exercise and significantly increases dopamine and acetylcholine and ameliorates depression. It appears that during exercise, muscarinic receptors can reduce depression through dopamine in the absence of acetylcholine. Therefore, exercise can be used to reduce depression by affecting neurotransmitters, neuromodulators, cytokines, and/or neurotrophins.

01 Dec 2022·Molecular Neurobiology

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson’s Disease

Article

Author: Liu, Lu-Bing ; Mao, Cheng-Jie ; Dong, Li-Guo ; Wang, Fen ; Dai, Yong-Ping ; Li, Cheng-Jie ; Liu, Chun-Feng ; Gu, Han-Ying ; An, Meng-Qi ; Zhang, Li-Ge

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 μmol/L) and palosetron (10 μmol/L), but not 5-HT3 receptor agonist m-CPBG (30 μmol/L) and SR 57,727 (10 μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 μmol/L) and eptapirone (10 μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 μmol/L) and p-MPPI (10 μmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

01 Sep 2019·NeuropharmacologyQ2 · MEDICINE

Galanin (1–15)-fluoxetine interaction in the novel object recognition test. Involvement of 5-HT1A receptors in the prefrontal cortex of the rats

Q2 · MEDICINE

Article

Author: Gago, Belen ; Narváez, José Angel ; Coveñas, Rafael ; Díaz-Cabiale, Zaida ; Santín, Luis ; Cantero-García, Noelia ; García-Durán, Laura ; Flores-Burgess, Antonio ; Fuxe, Kjell ; Millón, Carmelo

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes.

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