Does activation of midbrain dopamine neurons promote or reduce feeding?

BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviour.

Phenotyping mouse chromosome substitution strains reveal multiple QTLs for febrile seizure susceptibility.

Febrile seizures (FS) are the most common seizure type in children and recurrent FS are a risk factor for developing temporal lobe epilepsy. Although the mechanisms underlying FS are largely unknown, recent family, twin and animal studies indicate that genetics are important in FS susceptibility. Here, a forward genetic strategy was used employing mouse chromosome substitution strains (CSS) to identify novel FS susceptibility quantitative trait loci (QTLs). FS were induced by exposure to warm air at postnatal day 14. Video electroencephalogram monitoring identified tonic-clonic convulsion onset, defined as febrile seizure latency (FSL), as a reliable phenotypic parameter to determine FS susceptibility. FSL was determined in both sexes of the host strain (C57BL/6J), the donor strain (A/J) and CSS. C57BL/6J mice were more susceptible to FS than A/J mice. Phenotypic screening of the CSS panel identified six strains(CSS1, -2, -6 -10, -13 and -X) carrying QTLs for FS susceptibility. CSS1, -10 and -13 were less susceptible (protective QTLs), whereas CSS2, -6 and -X were more susceptible (susceptibility QTLs) to FS than the C57BL/6J strain. Our data show that mouse FS susceptibility is determined by complex genetics, which is distinct from that for chemically induced seizures. This is the first dataset using CSS to screen for a seizure trait in mouse pups. It provides evidence for common FS susceptibility QTLs that serve as starting points to fine map FS susceptibility QTLs and to identify FS susceptibility genes. This will increase our understanding of human FS, working toward the identification of new therapeutic targets.

Characterization of febrile seizures and febrile seizure susceptibility in mouse inbred strains.

Febrile seizures (FS) are the most prevalent seizures in children. Although FS are largely benign, complex FS increase the risk to develop temporal lobe epilepsy (TLE). Studies in rat models for FS have provided information about functional changes in the hippocampus after complex FS. However, our knowledge about the genes and pathways involved in the causes and consequences of FS is still limited. To enable molecular, genetic and knockout studies, we developed and characterized an FS model in mice and used it as a phenotypic screen to analyze FS susceptibility. Hyperthermia was induced by warm air in 10- to 14-day-old mice and induced FS in all animals. Under the conditions used, seizure-induced behavior in mice and rats was similar. In adulthood, treated mice showed increased hippocampal Ih current and seizure susceptibility, characteristics also seen after FS in rats. Of the seven genetically diverse mouse strains screened for FS susceptibility, C57BL/6J mice were among the most susceptible, whereas A/J mice were among the most resistant. Strains genetically similar to C57BL/6J also showed a susceptible phenotype. Our phenotypic data suggest that complex genetics underlie FS susceptibility and show that the C57BL/6J strain is highly susceptible to FS. As this strain has been described as resistant to convulsants, our data indicate that susceptibility genes for FS and convulsants are distinct. Insight into the mechanisms underlying seizure susceptibility and FS may help to identify markers for the early diagnosis of children at risk for complex FS and TLE and may provide new leads for treatment.

Endogenous opioids are differentially involved in appetitive and consummatory aspects of sexual behavior of male rats.

The sexual activity of 40 male Wistar rats was tested weekly in a bilevel test chamber to evaluate the involvement of endogenous opioids in the appetitive and consummatory aspects of sexual behavior. It has been suggested that the increase of the anticipatory level-changing behavior over repeated testing, displayed before the introduction of a receptive female, is sexually motivated. Two doses of the opioid antagonist naloxone, 1 and 10 mg/kg, prevented the increase of the anticipatory level-changing over four repeated tests of sexually experienced rats without prior experience in the bilevel test chamber and decreased the number of level changes of rats displaying a high number of level changes. Analysis of the pattern of inhibition suggested that the lower dose of naloxone may reduce sexual reward and that, in addition, the higher dose may block the expression of motivation. In contrast, naloxone treatment facilitated the efficiency of the sexual performance, with less mounts and intromissions preceding ejaculation and a shorter ejaculation latency, implying an inhibitory role of endogenous opioids in the neural control of some aspects of sexual performance (e.g., ejaculatory threshold). These results suggest that endogenous opioids may increase sexual appetite and diminish sexual performance.