Interleukin-1 reduces food intake and body weight in rat by acting in the arcuate hypothalamus.

A reduction in food intake is commonly observed after bacterial infection, a phenomenon that can be reproduced by peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1ß), a pro-inflammatory cytokine released by LPS-activated macrophages. The arcuate nucleus of the hypothalamus (ARH) plays a major role in food intake regulation and expresses IL-1 type 1 receptor (IL-1R1) mRNA. In the present work, we tested the hypothesis that IL-1R1 expressing cells in the ARH mediate IL-1ß and/or LPS-induced hypophagia in the rat. To do so, we developed an IL-1ß-saporin conjugate, which eliminated IL-R1-expressing neurons in the hippocampus, and micro-injected it into the ARH prior to systemic IL-1ß and LPS administration. ARH IL-1ß-saporin injection resulted in loss of neuropeptide Y-containing cells and attenuated hypophagia and weight loss after intraperitoneal IL-1ß, but not LPS, administration. In conclusion, the present study shows that ARH NPY-containing neurons express functional IL-1R1s that mediate peripheral IL-1ß-, but not LPS-, induced hypophagia. Our present and previous findings indicate that the reduction of food intake after IL-1ß and LPS are mediated by different neural pathways.

Brain Perivascular Macrophages Do Not Mediate Interleukin-1-Induced Sickness Behavior in Rats.

Sickness behavior, characterized by on overall reduction in behavioral activity, is commonly observed after bacterial infection. Sickness behavior can also be induced by the peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1ß), a pro-inflammatory cytokine released by LPS-activated macrophages. In addition to the microglia, the brain contains perivascular macrophages, which express the IL-1 type 1 receptor (IL-1R1). In the present study, we assessed the role of brain perivascular macrophages in mediating IL-1ß-induced sickness behavior in rats. To do so, we used intracerebroventricular (icv) administration of an IL-1ß-saporin conjugate, known to eliminate IL-R1-expressing brain cells, prior to systemic or central IL-1ß injection. Icv IL-1ß-saporin administration resulted in a reduction in brain perivascular macrophages, without altering subsequent icv or ip IL-1ß-induced reductions in food intake, locomotor activity, and social interactions. In conclusion, the present work shows that icv IL-1ß-saporin administration is an efficient way to target brain perivascular macrophages, and to determine whether these cells are involved in IL-1ß-induced sickness behavior.

Compulsive alcohol drinking in rodents.

Upon prolonged alcohol exposure, the behaviour of an individual can gradually switch from controlled to compulsive. Our review is focused on the neurobiological mechanisms that might underlie this transition as well as the factors that are influencing it. Animal studies suggest that temporally increased alcohol consumption during post-abstinence drinking is accompanied by a loss of flexibility of the behaviour and therefore, could serve as a model for compulsive alcohol drinking. However, studies using different alcohol-preferring rat lines in the post-abstinence drinking model suggest that high alcohol consumption does not necessarily lead to the development of compulsive drinking. This indicates the significance of genetic predisposition to compulsive behaviour. Neuroimaging data show that chronic alcohol consumption affects the activity of several brain regions such as the extrapyramidal motor system and several areas of the prefrontal cortex including the orbitofrontal and anterior cingulate cortex. Similar changes in brain activity is seen in patients suffering from obsessive-compulsive disorder at baseline conditions and during provocation of obsessive thoughts and urge to perform compulsive-like rituals. This indicates that dysfunction of these regions may be responsible for the expression of compulsive components of alcohol drinking behaviour. Several brain neurotransmitter systems seem to be responsible for the switch from controlled to compulsive behaviour. In particular, hypofunctioning of monoaminergic systems and hyperfunctioning of glutamatergic systems may play a role in compulsive alcohol drinking.

Brainstem metabotropic glutamate receptors reduce food intake and activate dorsal pontine and medullar structures after peripheral bacterial lipopolysaccharide administration.

During infection-induced inflammation food intake is reduced. Vagal and brainstem pathways are important both in feeding regulation and immune-to-brain communication. Glutamate is released by vagal afferent terminals in the nucleus of the solitary tract and by its neurons projecting to the parabrachial nuclei. We therefore studied the role of brainstem glutamate receptors in spontaneous food intake of healthy animals and during sickness-associated hypophagia after peripheral administration of bacterial lipopolysaccharides or interleukin-1beta. Brainstem group I and II metabotropic, but not ionotropic, glutamate receptor antagonism increased food intake both in saline- and lipopolysaccharide-treated rats. In these animals, expression of the cellular activation marker c-Fos in the lateral parabrachial nuclei and lipopolysaccharide-induced activation of the nucleus of the solitary tract rostral to the area postrema were suppressed. Group I metabotropic glutamate receptors did not colocalize with c-Fos or neurons regulating gastric function in these structures. Group I metabotropic glutamate receptors were, however, found on raphé magnus neurons that were part of the brainstem circuit innervating the stomach and on trigeminal and hypoglossal motor neurons. In conclusion, our findings show that brainstem metabotropic glutamate receptors reduce food intake and activate the lateral parabrachial nuclei as well as the rostral nucleus of the solitary tract after peripheral bacterial lipopolysaccharide administration. They also provide insight into potential group I metabotropic glutamate receptor-dependent brainstem circuits mediating these effects.