Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0848237 (acute stress)
4,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most commonly reported precipitating factor for seizures is stress. However, the underlying mechanisms whereby stress triggers seizures are not yet fully understood. Here we demonstrate a potential mechanism underlying changes in neuronal excitability in the hippocampus following chronic stress, involving a shift in the reversal potential for GABA (EGABA) associated with a dephosphorylation of the potassium chloride co-transporter, KCC2. Mice subjected to chronic restraint stress (30min/day for 14 consecutive days) exhibit an increase in serum corticosterone levels which is associated with increased susceptibility to seizures induced with kainic acid (20mg/kg). Following chronic stress, but not acute stress, we observe a dephosphorylation of KCC2 residue S940, which regulates KCC2 cell surface expression and function, in the hippocampus. To determine the impact of alterations in KCC2 expression following chronic stress, we performed gramicidin perforated patch recordings to measure changes in EGABA and neuronal excitability of principal hippocampal neurons. We observe a depolarizing shift in EGABA in hippocampal CA1 pyramidal neurons after chronic stress. In addition, there is an increase in the intrinsic excitability of CA1 pyramidal neurons, evident by a shift in the input-output curve which could be reversed with the NKCC1 inhibitor, bumetanide. These data uncover a potential mechanism involving chronic stress-induced plasticity in chloride homeostasis which may contribute to stress-induced seizure susceptibility.
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PMID:Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility. 2552 38

Stress is known to alter GABAergic signaling in the ventral tegmental area (VTA), and this inhibitory plasticity is associated with increased alcohol self-administration. In humans, serotonin 2A receptor (5-HT_2AR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HT_2AR pharmacotherapies may ameliorate the stress-induced dysregulated inhibitory VTA circuitry that contributes to subsequent alcohol abuse. We found that acute stress exposure in mice compromised GABA-mediated inhibition of VTA GABA neurons corresponding with increased ethanol-induced GABAergic transmission. This stress-induced inhibitory plasticity was reversible by applying the 5-HT_2AR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HT_2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Through positive modulation of KCC2, TCB-2 also reduced elevated ethanol-induced GABAergic signaling after stress exposure that has previously been linked to increased ethanol consumption. Collectively, these findings provide mechanistic insights into the therapeutic action of 5-HT_2AR agonists at the neuronal and circuit levels of brain reward circuitry.
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PMID:5-HT_2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area. 3180 59

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