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The steady state concept implies that the oxygen flow is invariant and equal at each level along the respiratory system. The same is the case with the carbon dioxide flow. This condition has several physiological consequences, which are analysed. First, we briefly discuss the mechanical efficiency of exercise and the energy cost of human locomotion, as well as the roles played by aerodynamic work and frictional work. Then we analyse the equations describing the oxygen flow in lungs and in blood, the effects of ventilation and of the ventilation - perfusion inequality, and the interaction between diffusion and perfusion in the lungs. The cardiovascular responses sustaining gas flow increase in blood are finally presented. An equation linking ventilation, circulation and metabolism is developed, on the hypothesis of constant oxygen flow in mixed venous blood. This equation tells that, if the pulmonary respiratory quotient stays invariant, any increase in metabolic rate is matched by a proportional increase in ventilation, but by a less than proportional increase in cardiac output.

Environmental conditioning is a major trigger for relapse in abstinent addicts. We showed that activation of the neuropeptide S (NPS) system exacerbates reinstatement vulnerability to cocaine and alcohol via stimulation of the hypocretin-1/orexin-A (Hcrt-1/Ox-A) system.Combining pharmacologic manipulations with immunohistochemistry techniques, we sought to determine how NPS and Hcrt-1/Ox-A systems interact to modulate reinstatement of alcohol seeking in rats.Intrahypothalamic injection of NPS facilitated discriminative cue-induced reinstatement of alcohol seeking. This effect was blocked by the selective Hcrt-1/Ox-A antagonist SB334867 microinjected into the hypothalamic paraventricular nucleus (PVN) or into the bed nucleus of the stria terminalis (BNST) but not into the ventral tegmental area or the locus coeruleus. Combining double labeling and confocal microscopy analyses, we found that NPS-containing axons are in close apposition to hypothalamic Hcrt-1/Ox-A positive neurons, a significant proportion of which express NPS receptors, suggesting a direct interaction between the two systems. Retrograde tracing experiments showed that intra-PVN or intra-BNST red fluorobead unilateral injection labeled bilaterally Hcrt-1/Ox-A somata, suggesting that NPS could recruit two distinct neuronal pathways. Confirming this assumption, intra-BNST or PVN Hcrt-1/Ox-A injection enhanced alcohol seeking similarly to hypothalamic NPS injection but to a lesser degree.Results suggest that the Hcrt-1/Ox-A neurocircuitry mediating the facilitation of cue-induced reinstatement by NPS involves structures critically involved in stress regulation such as the PVN and the BNST. These findings open to the tempting hypothesis of a role of the NPS system in modulating the interactions between stress and environmental conditioning factors in drug relapse.

Alcohol elicits a neuroimmune response in the brain contributing to the development and maintenance of alcohol use disorder (AUD). While pro-inflammatory mediators initiate and drive the neuroimmune response, anti-inflammatory mediators provide an important homeostatic mechanism to limit inflammation and prevent pathological damage. However, our understanding of the role of anti-inflammatory signaling on neuronal physiology in critical addiction-related brain regions and pathological alcohol-dependence induced behaviors is limited, precluding our ability to identify promising therapeutic targets. Here, we hypothesized that chronic alcohol exposure compromises anti-inflammatory signaling in the central amygdala, a brain region implicated in anxiety and addiction, consequently perpetuating a pro-inflammatory state driving aberrant neuronal activity underlying pathological behaviors. We found that alcohol dependence alters the global brain immune landscape increasing IL-10 producing microglia and T-regulatory cells but decreasing local amygdala IL-10 levels. Amygdala IL-10 overexpression decreases anxiety-like behaviors, suggesting its local role in regulating amygdala-mediated behaviors. Mechanistically, amygdala IL-10 signaling through PI3K and p38 MAPK modulates GABA transmission directly at presynaptic terminals and indirectly through alterations in spontaneous firing. Alcohol dependence-induces neuroadaptations in IL-10 signaling leading to an overall IL-10-induced decrease in GABA transmission, which normalizes dependence-induced elevated amygdala GABA transmission. Notably, amygdala IL-10 overexpression abolishes escalation of alcohol intake, a diagnostic criterion of AUD, in dependent mice. This highlights the importance of amygdala IL-10 signaling in modulating neuronal activity and underlying anxiety-like behavior and aberrant alcohol intake, providing a new framework for therapeutic intervention.

3-iodothyroacetic acid (TA1) is among the by-products of thyroid hormone metabolism suspected to mediate the non-genomic effects of the hormone (T3). We aim to investigate whether TA1 systemically administered to mice stimulated mice wakefulness, an effect already described for T3 and for another T3 metabolite (i.e. 3-iodothryonamine; T1AM), and whether TA1 interacted at GABA-A receptors (GABA-AR). Mice were pre-treated with either saline (vehicle) or TA1 (1.32, 4 and 11 μg/kg) and, after 10 min, they received ethanol (3.5 g/kg, i.p.). In another set of experiments, TA1 was administered 5 min after ethanol. The latency of sleep onset and the time of sleep duration were recorded. Voltage-clamp experiments to evaluate the effect of 1 μM TA1 on bicuculline-sensitive currents in acute rat hippocampal slice neurons and binding experiments evaluating the capacity of 1, 10, 100 μM TA1 to displace [3H]flumazenil from mice brain membranes were also performed. 4 μg/kg TA1 increases the latency of onset and at 1.32 and 4 μg/kg it reduces the duration of ethanol-induced sleep only if administered before ethanol. TA1 does not functionally interact at GABA-AR. Overall these results indicate a further similarity between the pharmacological profile of TA1 and that of T1AM.

It is generally agreed that lipid peroxides play an important role in the pathogenesis of ethanol-induced cellular injury and that free sulfhydryl groups are vital in cellular defense against endogenous or exogenous oxidants. It has been observed that oxidative stress induces the synthesis of the 70-kDa family of heat-shock proteins (HSPs). Induction of HSPs represents an essential and highly conserved cellular response to a variety of stressful stimuli. In the present study we measured in various brain areas and in liver the intracellular levels of HSP70 proteins, sulfhydryl groups and the antioxidant enzyme status after chronic administration of mild intoxicating doses of ethanol to rats. Expression of HSP70 in response to alcohol administration was particularly high in the hippocampus and striatum. In these brain areas, the increase in HSP70 protein levels occurred in absence of significant changes of antioxidant enzyme activities and was correlated with a marked depletion of intracellular bound thiols and with a decreased susceptibility to lipid peroxidation. Lower levels of HSP70 induction were found in cortex and cerebellum and were associated to decreases in SOD and CAT enzyme activities, with a lower depletion of protein bound thiols and with an increased susceptibility to lipid peroxidation. This study agrees with our previous results performed on acute alcohol intoxication and supports the hypothesis that HSP70 induction protects the different brain areas against oxidative stress.

AbstractCreatine kinases are important in maintaining cellular‐energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine‐like compounds. Herein we examine whether ablation of the cytosolic brain‐type creatine kinase (B‐CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B‐CK (B‐CK–/–) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra‐ and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr ⇆ ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B‐CK–/– animals showed diminished open‐field habituation. In the water maze, adult B‐CK–/– mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24‐month‐old, aged B‐CK–/– mice, on top of the age‐related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole‐induced seizures (creating a high‐energy demand) was observed in B‐CK–/– mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho‐creatine shuttle provides compensation for the loss of B‐CK in the brain. Our studies indicate a role for the creatine–phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B‐CK can be compensated for by other systems in the versatile and robust metabolic‐energy network of the brain.