Microglial IL-1ß progressively increases with duration of alcohol consumption.

Chronic alcohol abuse leads to severe brain damage. Although the underlying neuropathological processes are largely unknown, recent studies show that chronic alcohol consumption leads to neuroinflammation and may result in neurodegeneration and impaired neuronal connectivity. Long-term alcohol consumption promotes the production of pro-inflammatory cytokines, such as TNF-α and IL-1ß, and activates microglia cells in the brain. As it has not yet been investigated to what extent these processes dependent on the duration of alcohol consumption or whether microglia are source of pro-inflammatory cytokines in vivo, this study investigated the expression of the pro-inflammatory cytokine, IL-1ß, in microglia at different time points in mice chronically exposed to alcohol. In the present study, we exposed mice to 2, 6, and 12 months of alcohol consumption, and using immunohistochemistry, analyzed the expression of the microglial marker, Iba1, together with the pro-inflammatory cytokine IL-1ß in several cortical regions. Moreover, we investigated the effect of pro-inflammatory activation of microglia on neuronal density. We found that alcohol drinking progressively enhanced IL-1ß expression in microglia, which was paralleled with an overall increased microglial density after long-term alcohol consumption. However, we did not find changes in the neuronal density or cortical volume after long-term alcohol consumption. These data show that 12 months of alcohol drinking leads to a pro-inflammatory activation of microglia, which may contribute to impaired neuronal connectivity in the cortex. Anti-inflammatory drug treatment during or after chronic alcohol consumption may thus provide a strategy for restoring brain homeostasis.

Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice.

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.

Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption.

Genetic and environmental factors contribute nearly in equal power to the development of alcoholism. Environmental factors, such as negative life events or emotionally disruptive conditions, initiate and promote alcohol drinking and relapse. The endocannabinoid system is involved in hedonic control and modulates stress reactivity. Furthermore, chronic alcohol drinking alters endocannabinoid signalling, which in turn influences the stress reactivity. Recently, it has been shown that CB2 receptor activity influences stress sensitivity and alcohol drinking. We hypothesized that CB2 receptors influence the impact of environmental risk factors on alcohol preference and consumption. Therefore, in this study, we investigated the alcohol-drinking pattern of wild-type and CB2-deficient animals under single- and group-housing conditions using different alcohol-drinking models, such as forced drinking, intermittent forced drinking and two-bottle choice paradigms. Our data showed that CB2 receptor modulates alcohol consumption and reward. Interestingly, we detected that lack of CB2 receptors led to increased alcohol drinking in the intermittent forced drinking paradigm under group-housing conditions. Furthermore, we found that CB2 knockout mice consumed more food and that their body weight gain was modulated by social environment. On the basis of these data, we conclude that social environment critically affects the modulatory function of CB2 receptors, especially in alcohol intake. These findings suggest that a treatment strategy targeting CB2 receptors may have a beneficial effect on pathological drinking, particularly in situations of social stress and discomfort.

Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice.

There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.

Long-term ethanol effects on acute stress responses: modulation by dynorphin.

The brain stress-response system is critically involved in the addiction process, stimulating drug consumption and the relapse to drug taking in abstinent addicts. At the same time, its functioning is affected by chronic drug exposure. Here, we have investigated the role of the endogenous opioid peptide dynorphin as a modulator of effects of long-term ethanol consumption on the brain stress-response system. Using the two-bottle choice paradigm, we demonstrate an enhanced ethanol preference in male dynorphin knockout mice. Exposure to mild foot shock increased ethanol consumption in wild-type control littermates, but not in dynorphin-deficient animals. Blood adrenocorticotropic hormone levels determined 5 minutes after the shock were not affected by the genotype. We also determined the neuronal reactivity after foot shock exposure using c-Fos immunoreactivity in limbic structures. This was strongly influenced by both genotype and chronic ethanol consumption. Long-term alcohol exposure elevated the foot shock-induced c-Fos expression in the basolateral amygdala in wild-type animals, but had the opposite effect in dynorphin-deficient mice. An altered c-Fos reactivity was also found in the periventricular nucleus, the thalamus and the hippocampus of dynorphin knockouts. Together these data suggest that dynorphin plays an important role in the modulation of the brain stress-response systems after chronic ethanol exposure.

Anandamide effects on 5-HT(3) receptors in vivo.

Studies in knockout mouse strains have shown that some cannabimimetic effects persist in animals lacking cannabinoid CB(1) and CB(2) receptors. These residual effects are thought to result, in part, from a cannabinoid-modulation of ion channels. This study investigates the role of 5-HT(3) receptors as a potential in vivo target for cannabinoids. Mice deficient in CB(1) and CB(2) receptors were treated with Delta(9)-tetrahydrocannabinol and anandamide, in the presence of the 5-HT(3) antagonist ondansetron. We show that the cannabinoid receptor-independent anandamide analgesia, but not catalepsy, is completely blocked by ondansetron. Thus, 5-HT(3) receptors seem to be involved in cannabinoid analgesia.