Serotonergic signaling: multiple effectors and pleiotropic effects

Yang

J of Applied Toxicology

et al. 2016

The underlying mechanism of polybrominated diphenyl ether (PBDE)-induced neurotoxicity is still a major concern due to its ubiquitous nature and persistence. Here, zebrafish embryos (2 h postfertilization, hpf ) were exposed to different concentrations of the commercial PBDE mixture DE-71 (0-100 μg l -1 ) until 120 hpf, and the impact on neural development and serotonergic system was investigated. The in vivo results revealed significantly reduced transcription of genes involved in neurogenesis (fgf8, shha, wnt1), and contents of proteins in neuronal morphogenesis (myelin basic protein, synapsin IIa), suggesting an impairment of neural development in zebrafish embryos. Further results demonstrated a reduction of 5-hydroxytryptamine neuron and a dose-dependent decrease of whole-body serotonin levels, as well as the transcription of genes involved in serotonergic synthesis (tph1, tph2, trhr) and neurotransmission (serta/b, htr1aa/b). In addition, we predicted possible targets of PBDEs by molecular docking, and the results indicated that PBDE congeners showed high binding affinities with fibroblast growth factor 8 other than SHH and HTR1B. Taken together, this study demonstrated that PBDE exposure during embryogenesis could damage neural development and cause impairment of the serotonergic system as secondary effects in the zebrafish larvae.

Section: Introductionmentioning

confidence: 99%

The neurotoxicity of DE‐71: effects on neural development and impairment of serotonergic signaling in zebrafish larvae

Yang

J of Applied Toxicology

et al. 2016

“…5‐HT may mediate its action either directly via 5‐HT 2B receptor signaling which leads to activation of guanosine triphosphatase (GTPase) and the ERK pathway (Figure a) or by conversion of latent TGF‐β1 in plasma to active TGF‐β1 or by inducing its expression . TGF‐β1 may mediate fibrosis via Smad and non‐Smad dependent pathways.…”

Section: Discussionmentioning

confidence: 99%

5‐HT₂ and 5‐HT_2B antagonists attenuate pro‐fibrotic phenotype in human adult dermal fibroblasts by blocking TGF‐β1 induced non‐canonical signaling pathways including STAT3 : implications for fibrotic diseases like scleroderma

et al. 2018

Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-β1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders.

“…Interestingly, ERK phosphorylation was decreased in both the PFC and hippocampus to chronic morphine treatment. Although activation of 5-HT 2A Rs can increase pERK1/2 formation (Millan et al, 2008; Masson et al, 2012), ERK phosphorylation is regulated by multiple cellular signals, and the inconsistency between 5-HT 2A R expression and pERK accumulation may be attributed to other factors.…”

Section: Discussionmentioning

confidence: 99%

“…5-HT 2A Rs are widely distributed across the central nervous system. 5-HT 2A Rs regulate cellular function via G protein-dependent, ligand-dependent and ligand-independent signaling pathways, including phospholipase signaling, extracellular signal-regulated kinases (ERK) pathway and tyrosine kinase pathway in neural tissues (Millan et al, 2008; Masson et al, 2012). Pharmacological blockade of 5-HT 2A Rs presents antipsychotic and antidepressant properties, however, receptor activation possesses cognition enhancement and hallucinogenic properties (Zhang and Stackman, 2015).…”

Section: Introductionmentioning

confidence: 99%

Blockade of Serotonin 5-HT2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice

Pang

Tao

et al. 2016

Front. Pharmacol.

The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate – even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders.HighlightsBlockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization.Blockade of 5-HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.