Alcohol (Fayetteville, N.Y.)最新文献

Golgi cells (GoCs) are cerebellar inhibitory interneurons that provide both phasic and tonic GABAergic input to cerebellar granule cells. They receive inhibitory control from Lugaro cells, other GoCs, and cerebellar nuclear inhibitory neurons via GABAergic and glycinergic inputs. Although fetal alcohol exposure is known to impair cerebellar function, its impact on developing GoC physiology remains unclear. We investigated the acute effects of ethanol on GABA_A receptor-mediated transmission in GoCs during the mouse equivalent of the human third trimester, a critical window for inhibitory circuit formation. To identify GoCs, we used VGAT-Venus transgenic mice, in which the vesicular GABA transporter promoter drives expression of the Venus fluorescent protein. Whole-cell patch-clamp and loose-patch recordings from postnatal day (P) 6-10 mice revealed that ethanol exposure dose-dependently increased the frequency of action potential-dependent GABA_A receptor-mediated spontaneous postsynaptic currents (sPSCs) in GoCs. While ethanol produced variable effects on GoC firing rates, it more consistently enhanced GABA_A-sPSC frequency in granule cells. We also examined expression of the K⁺-Cl^- cotransporter 2 (KCC2), a chloride exporter whose developmental upregulation drives the shift in GABA_A receptor signaling from excitatory to inhibitory. Immunohistochemical analysis at P6 showed that GoCs express low levels of KCC2, suggesting that GABA_A receptor-mediated currents may remain depolarizing in a subset of GoCs. This property could contribute to ethanol-induced disruption of cerebellar circuit maturation. Together, these findings provide new insight into the cellular mechanisms by which ethanol perturbs inhibitory circuit development in the cerebellum.

Introduction: Alcohol dependence (AD) includes tolerance to alcohol's analgesic effects and increased pain sensitivity during withdrawal (i.e., hyperalgesia). Further, the reciprocal relationship between alcohol use and pain sensitivity is hypothesized to contribute to the maintenance of AD through negative reinforcement (i.e., self-medication). The neuropeptide S (NPS) system, known to regulate stress, arousal, and pain pathways, may offer a therapeutic target to ameliorate AD-induced hyperalgesia. Given previous reports on the antinociceptive properties of NPS, we hypothesized that central administration of NPS could attenuate the heightened pain sensitivity observed in AD rats.

Methods: Male (n=11) and female (n=7) Wistar rats were surgically implanted with an intracerebroventricular (ICV) cannula and assigned to either the AD or alcohol-naïve control group, matched in terms of their baseline thermal nociceptive thresholds. Pain sensitivity was tracked weekly using thermal (Hargreaves) and mechanical (robotic Von Frey, also known as the dynamic plantar aesthesiometer) assays to establish AD-induced hyperalgesia. After stable hyperalgesia emerged, rats received ICV NPS administrations (0, 0.1, or 1 nmol in 5 μL saline) 5 minutes prior to pain testing (Experiment 1: Hargreaves; Experiment 2: robotic Von Frey). In a follow-up experiment, three Von Frey methods (electronic, robotic, and manual) were compared to assess their efficacy in detecting AD-induced mechanical hyperalgesia.

Results: AD male and female rats developed significant hyperalgesia across both pain modalities. Central administration of NPS produced robust analgesia in a dose-dependent manner in both AD and alcohol-naïve control rats. No sex differences were observed in baseline nociception, AD-induced hyperalgesia, or NPS-induced analgesia. All three mechanical assays reliably detected AD-induced mechanical hyperalgesia, and the importance of adequate habituation procedures is discussed.

Conclusion: These findings indicate that NPS exerts a robust analgesic effect in male and female rats. This effect appears independent of ethanol-exposure history but produces sufficient analgesia to alleviate pain sensitivity in hyperalgesic AD rats to/beyond the level of sensitivity in vehicle treated, alcohol-naïve controls. The NPS system may therefore represent a promising, non-addictive target for treating pain-related symptoms in alcohol dependence.

Many animal models of alcohol dependence utilize forced alcohol exposure, including chronic intermittent exposure to alcohol vapor, to induce high blood alcohol concentrations (BACs) and withdrawal-associated behaviors similar to those seen in clinical contexts. Chronic alcohol exposure and withdrawal are especially important in influencing the expression of negative symptoms (e.g., negative affect and pain), which, in turn, increase alcohol consumption. However, cessation of chronic alcohol vapor exposure does not always lead to those "canonical" withdrawal behaviors in rodents. Environmental and genetic factors may modulate alcohol effects on behavior during withdrawal. Here, we used retrospective data analysis to determine associations between alcohol vapor exposure parameters (e.g., BACs, duration of exposure) and anxiety- or pain-like behavior in adult male and female Wistar rats. Our results indicate that specific vapor exposure parameters are predictive of thermal hyperalgesia in Wistar rats but less so for anxiety-like behavior during alcohol withdrawal; collectively, these data may be helpful in informing experiments designed to investigate chronic alcohol effects on behavioral outcomes.