RECRUITMENT OF INHIBITORY MEK/ERK SIGNALING IN BRAIN REWARD CIRCUITRY FOLLOWING A HISTORY OF ETHANOL DEPENDENCE

Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity. Here, the MEK inhibitor UO126 was used to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence. Ethanol (1.5 g/kg, i.p.) induced c-fos expression in brain regions associated both with rewarding and stressful ethanol actions. Under non-dependent conditions, alcohol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of medial amygdala (MeA), and a similar pattern in the paraventricular nucleus (PVN). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in orbitofrontal cortex (OFC) and nucleus accumbens shell (AcbSh), key components of circuitry mediating positive drug reinforcement. The suppressed ethanol response in these regions was returned to normal by pre-treatment with UO126, demonstrating a recruitment of an ERK mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA, PVN), a MEK/ERK mediated cellular activation by acute ethanol was lost following a history of dependence. These data reveal highly region-specifi c neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK mediated suppression of the ethanol response in OFC and AcbSh may refl ect devaluation of ethanol as a reinforcer, while loss of a MEK/ERK mediated response in MeA and PVN may reflect tolerance to its aversive actions. These two neuroadaptations could act in concert to facilitate progression into ethanol dependence

Neuroplasticity in brain reward circuitry following a history of ethanol dependence.

Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity. Here, we used the MEK inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (UO126) to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence. Ethanol (1.5 g/kg, i.p.) induced expression of the marker genes c-fos and egr-1 in brain regions associated with both rewarding and stressful ethanol actions. Under non-dependent conditions, ethanol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of the medial amygdala (MeA). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in the medial pre-frontal/orbitofrontal cortex (OFC), nucleus accumbens shell (AcbSh) and paraventricular nucleus (PVN). The suppressed ethanol response in the OFC and AcbSh, key regions involved in ethanol preference and seeking, was restored by pre-treatment with UO126, demonstrating a recruitment of an ERK/MEK-mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA and PVN), an MEK/ERK-mediated cellular activation by acute ethanol was lost following a history of dependence. These data reveal region-specific neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK-mediated suppression of the ethanol response in the OFC and AcbSh may reflect devaluation of ethanol as a reinforcer, whereas loss of an MEK/ERK-mediated response in the MeA and PVN may reflect tolerance to its aversive actions. These two neuroadaptations could act in concert to facilitate progression into ethanol dependence

SIGNAL TRANSDUCTION IN ALCOHOL-PREFERRING AA AND ALCOHOL-AVOIDING ANA RAT LINES

AA and ANA rats are one of the earliest and well established rodent models for ethanol preference. Several candidate genes have been suggested to confer genetic susceptibility for alcoholism in these lines including mitogen-activated protein kinases, Akt/PKB and GSK-3 pathways. The aim of the study was to compare the protein levels and phopshorylation of ERK 1/2, Akt and GSK-3 in AA and ANA rats under basal condition and after acute ethanol challenge. Animals were injected with either ethanol (1.5 g/kg) or saline and killed 20 or 45 minutes after injection. Brains were frozen and dissected, nucleus accumbens (NAcc) and cingulate cortex (CCx) were extracted and subject to immunobloting with total and phosphospecifi c antibodies. Baseline differences in ERK 1/2 phopshorylation were discovered between AA and ANA lines. Intraperitoneal injection of ethanol (1.5 g/kg) induced a rapid and transient decrease in ERK 1/2 phosphorylation in both CCx and NAcc within 20 minutes which was already reverting towards control levels at the 45 minute time point. There was no change in the total ERK levels. Phosphorylation of both GSK-3 and Akt in CCx of AA rats was increased 45 minutes after ethanol injection, however no changes were found in NAcc. In ANA rats there were no statistically signifi cant changes in all structures. Thus, AA rats are more susceptible to acute effects of ethanol involving some of the mitogen-activated protein kinases, Akt/PKB and GSK-3 pathways, and these differences are more prominent in the CCx compared to the NAcc

Acute ethanol challenge inhibits glycogen synthase kinase-3beta in the rat prefrontal cortex

Intracellular signalling pathways emerge as key mediators of the molecular and behavioural effects of addictive drugs including ethanol. Previously, we demonstrated that the innate high ethanol preference in AA rats is driven by dysfunctional endocannabinoid signalling in the medial prefrontal cortex (mPFC). Here, we report that acute ethanol challenge, at a dose commonly regarded as reinforcing, strongly phosphorylates glycogen synthase kinase-3beta (GSK-3beta) in this region with corresponding increased phosphorylation of AKT, a major regulator of GSK-3beta. In the non-preferring counterpart ANA line we found a weaker, AKT-independent phosphorylation of GSK-3beta by ethanol. Furthermore, AA rats showed rapid and transient dephosphorylation of ERK1/2 upon acute ethanol challenge in the medial prefrontal cortex (mPFC) and to a lesser degree in the nucleus accumbens; ANA rats were completely non-responsive for this mechanism. Together, these results identify candidate pathways for mediating high ethanol preference and emphasize the importance of the mPFC in controlling this behaviour

Опыт применения гипербарической оксигенации при лечении радионекроза, развившегося как осложнение стереотаксически ориентированного радиохирургического лечения менингиомы на примере клинического случая

In contrast to conventional microsurgery, stereotactic radiosurgery has an advantage in the treatment of intracranial masses, avoiding severe complications associated with open surgery. In rare cases, the use of the method is associated with the development of radiation-induced injuries, one of which is radiation necrosis (RN). This is a late complication of radiosurgery, developing mainly 6 months after radiation exposure. The neurological manifestations of this complication depend on location, and the clinical picture is very diverse. The method of magnetic resonance imaging (MRI) with intravenous contrast enhancement is quite often the first link in neuroimaging, which helps to suggest the presence of this complication based on the X-ray picture and to clarify the location of changes.We presented the experience of radiation necrosis treatment in a 47-year-old patient who was referred to our department with a diagnosis of frontal meningioma. The patient underwent stereotactic radiosurgical treatment using the Elekta Leksell Gamma Knife Perfextion device, and 6 months later the gradual deterioration began, the patient complained of headache, nausea; central prosoparesis developed. Considering the clinical picture and control MRI data, the changes were interpreted as radionecrosis. In order to control the complication, the patient underwent standard glucocroticosteroid therapy, supplemented by hyperbaric oxygenation (HBO), which made it possible to achieve regression of the adverse clinical and radiological manifestations of the complication. Thus, on a clinical example, it was demonstrated that the combined use of glucocorticosteroids and HBOs is highly effective in the treatment of RN.Стереотаксическая радиохирургия в отличие от обычной микрохирургии имеет преимущество в лечении интракраниальных объемных образований, позволяя избежать тяжелых осложнений, связанных с открытым вмешательством. В редких случаях применение метода связано с развитием радиационно-индуцированных повреждений, одним из которых является лучевой некроз (ЛН). Это позднее осложнение радиохирургии, развивающееся преимущественно через 6 месяцев после облучения. Неврологические проявления данного осложнения зависят от локализации, а клиническая картина очень разнообразна. Метод магнитно-резонансной томографии (МРТ) с внутривенным контрастным усилением достаточно часто является первым звеном нейровизуализации, помогающим предположить наличие данного осложнения на основании рентгенологической картины и уточнить локализацию изменений.Нами представлен опыт лечения ЛН, возникшего у пациентки 47 лет, направленной в наше отделение с диагнозом менингиомы лобной области. Больной было проведено стереотаксическое радиохирургическое лечение на аппарате “Elekta Leksell Gamma Knife Perfextion”, а спустя 6 месяцев у женщины стало развиваться постепенное ухудшение состояния, появились жалобы на головную боль, тошноту; развился центральный прозопарез. Учитывая клиническую картину и данные контрольного МРТ, изменения были интерпретированы как радионекроз. В целях контроля над осложнением пациентке провели стандартную терапию глюкокротикостероидами, дополненную гипербарической оксигенацией (ГБО), что позволило добиться регрессии неблагоприятных клинических и рентгенологических проявлений осложнения. Таким образом, на клиническом приме- ре было продемонстрировано, что комбинированное применение глюкокортикостероидов и ГБО имеет высокую эффективность при лечении ЛН