A novel fatty acid analogue triggers CD36-GPR120 interaction and exerts anti-inflammatory action in endotoxemia.

Inflammation is a mediator of a number of chronic pathologies. We synthesized the diethyl (9Z,12Z)-octadeca-9,12-dien-1-ylphosphonate, called NKS3, which decreased lipopolysaccharide (LPS)-induced mRNA upregulation of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) not only in primary intraperitoneal and lung alveolar macrophages, but also in freshly isolated mice lung slices. The in-silico studies suggested that NKS3, being CD36 agonist, will bind to GPR120. Co-immunoprecipitation and proximity ligation assays demonstrated that NKS3 induced protein-protein interaction of CD36 with GPR120in RAW 264.7 macrophage cell line. Furthermore, NKS3, via GPR120, decreased LPS-induced activation of TAB1/TAK1/JNK pathway and the LPS-induced mRNA expression of inflammatory markers in RAW 264.7 cells. In the acute lung injury model, NKS3 decreased lung fibrosis and inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and nitric oxide (NO) production in broncho-alveolar lavage fluid. NKS3 exerted a protective effect on LPS-induced remodeling of kidney and liver, and reduced circulating IL-1ß, IL-6 and TNF-α concentrations. In a septic shock model, NKS3 gavage decreased significantly the LPS-induced mortality in mice. In the last, NKS3 decreased neuroinflammation in diet-induced obese mice. Altogether, these results suggest that NKS3 is a novel anti-inflammatory agent that could be used, in the future, for the treatment of inflammation-associated pathologies.

A premammillary lateral hypothalamic nuclear complex responds to hedonic but not aversive tastes in the male rat.

The lateral hypothalamic area (LHA) has two major roles: arousal/waking and food intake controls. Here, it is shown that a premammillary part of the LHA is neurochemically and cytoarchitectonically distinct from the tuberal LHA in male rats. This part contains nuclear masses, namely the parasubthalamic nucleus and the calbindin nucleus, involved in pathways that predict its participation in the control of food intake. Analyzing c-Fos expression in experiments related to feeding behavior, this region responded specifically to the ingestion of palatable nutriments.

Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption.

Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.

Fluoxetine potentiation of methylphenidate-induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons.

Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention-deficit hyperactivity disorder/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers. Results demonstrate that fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine-like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.

Effect of prenatal stress on alcohol preference and sensitivity to chronic alcohol exposure in male rats.

RATIONALE: In rats, prenatal restraint stress (PRS) induces persistent behavioral and neurobiological alterations leading to a greater consumption of psychostimulants during adulthood. However, little is known about alcohol vulnerability in this animal model. OBJECTIVES: We examined in adolescent and adult male Sprague Dawley rats the long-lasting impact of PRS exposure on alcohol consumption. METHODS: PRS rats were subjected to a prenatal stress (three daily 45-min sessions of restraint stress to the mothers during the last 10 days of pregnancy). Alcohol preference was assessed in a two-bottle choice paradigm (alcohol 2.5%, 5%, or 10% versus water), in both naïve adolescent rats and adult rats previously exposed to a chronic alcohol treatment. Behavioral indices associated with incentive motivation for alcohol were investigated. Finally, plasma levels of transaminases (marker of hepatic damages) and ΔFosB levels in the nucleus accumbens (a potential molecular switch for addiction) were evaluated following the chronic alcohol exposure. RESULTS: Alcohol preference was not affected by PRS. Contrary to our expectations, stressed and unstressed rats did not display signs of compulsive alcohol consumption. The consequences of the alcohol exposure on locomotor reactivity and on transaminase levels were more prominent in PRS group. Similarly, PRS potentiated alcohol-induced ΔFosB levels in the nucleus accumbens. CONCLUSION: Our data suggest that negative events occurring in utero do not modulate alcohol preference in male rats but potentiate chronic alcohol-induced molecular neuroadaptation in the brain reward circuitry. Further studies are needed to determine whether the exacerbated ΔFosB upregulation in PRS rats could be extended to other reinforcing stimuli.

Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum.

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.

Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: concerns for use of cognitive enhancers?

BACKGROUND: There is growing use of psychostimulant cognitive enhancers such as methylphenidate (Ritalin). Methylphenidate differs from the psychostimulant cocaine because it does not enhance synaptic levels of serotonin. We investigated whether exposure to methylphenidate combined with a serotonin-enhancing medication, the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac), would produce more "cocaine-like" molecular and behavioral changes. METHODS: We measured the effects of fluoxetine on gene expression induced by the cognitive enhancer methylphenidate in the striatum and nucleus accumbens of rats, by in situ hybridization histochemistry. We also determined whether fluoxetine modified behavioral effects of methylphenidate. RESULTS: Fluoxetine robustly potentiated methylphenidate-induced expression of the transcription factors c-fos and zif 268 throughout the striatum and to some degree in the nucleus accumbens. Fluoxetine also enhanced methylphenidate-induced stereotypical behavior. CONCLUSIONS: Both potentiated gene regulation in the striatum and the behavioral effects indicate that combining the SSRI fluoxetine with the cognitive enhancer methylphenidate mimics cocaine effects, consistent with an increased risk for substance use disorder.

Impact of an acute exposure to ethanol on the oxidative stress status in the hippocampus of prenatal restraint stress adolescent male rats.

Prenatal restraint stress (PRS) in rats is associated with hippocampal dysfunctions and several behavioural and endocrine disorders related to this brain area. Recently, we have reported that the PRS modifies the hypothalamic-pituitary-adrenal (HPA) response to an ethanol challenge in adolescent animals. Since hippocampus is particularly sensitive to the deleterious effects of ethanol during adolescence, we investigated in this study the combined effects of PRS and ethanol administration on the oxidative status in the hippocampus of 28-day-old male rats. Thirty minutes after an intraperitoneal (i.p.) injection of ethanol (1.5 g/kg), the activities of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) but also non-enzymatic antioxidant (reduced glutathione) were assayed. Thiobarbituric acid reactive substances (TBARS) levels were also measured as a marker of lipid peroxidation. Ethanol enhanced superoxide dismutase activity in control rats but not in PRS rats. At basal level, catalase activity was lower in PRS rats than in control rats, indicating a potentially higher sensitivity to oxidative damages after this early stress. However, the hippocampal TBARS levels were not significantly affected by the ethanol administration, showing that an acute ethanol exposure does not induce oxidative damage in adolescent male rats. In conclusion, our data suggest that PRS affects both basal antioxidant status in the hippocampus and antioxidant response after an acute ethanol exposure. These findings extend previous works showing that PRS leads to hippocampal dysfunctions and raise the question of the potential increase of the hippocampal oxidative damage in PRS rats after repeated exposure to ethanol.