Riad, M. H. | Search bioRxiv

bioRxiv2019

The Habenular Receptor GPR151 Regulates Addiction Vulnerability Across Drug Classes

The habenula controls the addictive properties of nicotine but also densely expresses opioid and cannabinoid receptors. As such, identification of strategies to manipulate habenular activity may yield new approaches to treat substance use disorders. Here we show that GPR151, an orphan G protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents plays a critical role in regulating habenular function and behavioral responses to addictive drugs. We show that GPR151 is expressed on axonal and presynaptic membranes and synaptic vesicles, and regulates synaptic fidelity and plasticity. We find that GPR151 associates with synaptic components controlling vesicle release and ion transport and couples to the G-alpha inhibitory protein Go1 to reduce cAMP levels. Stable cell lines expressing GPR151 confirm that it signals via Gi/o and are amenable to ligand screens. Gpr151 null mice show diminished behavioral responses to nicotine, and self-administer greater quantities of the drug, phenotypes rescued by viral re-expression of Gpr151 in the habenula. Gpr151 null mice are also insensitive to the behavioral actions of morphine and cannabinoids. These data identify GPR151 as a critical modulator of habenular function that controls addiction vulnerability across different drug classes.\n\nHighlightsO_LIHabenula neurons are enriched in nicotinic, opioid, cannabinoid and GPR151 receptors\nC_LIO_LIGPR151 modulates synaptic fidelity and release probability at habenular terminals.\nC_LIO_LIHabenular GPR151 plays a role in drug abuse and food intake/weight control\nC_LIO_LIGPR151 couples to the G-alpha inhibitory protein Go1 to reduce cAMP levels.\nC_LI\n\neTOC BlurbAntolin-Fontes at al. identify a G protein-coupled receptor, GPR151, which is highly enriched in human habenular neurons. These neurons are primarily enriched with nicotinic, opioid and cannabinoid receptors. We find that GPR151 modulates habenular synaptic vesicle release probability and behavioral responses to these drugs of abuse.

neuroscience↗

bioRxiv2018

Individual-based network model for Rift Valley Fever in Kabale District, Uganda, to guide mitigation measures: A One Health Model

Rift Valley fever (RVF) is a zoonotic disease which causes significant morbidity and mortality among ungulate livestock and humans in endemic regions. In the major RVF epizootic regions of East Africa, the causative agent of the disease, Rift Valley fever virus (RVFV), is primarily transmitted by multiple mosquito species in Aedes, Culex, and Mansonia genera during both epizootic and enzootic periods in a complex transmission cycle largely driven by the environment. However, recent RVFV activity in Uganda demonstrated that RVFV could also spread into new regions through livestock movements, and underscored the need to develop effective mitigation strategies to reduce transmission and prevent spread among cattle operations. We simulated RVFV transmission among cattle in different sub counties of Kabale District in Uganda using real world livestock data in a network-based model. This model considered livestock as spatially explicit factors in different sub-counties subjected to specific vector mosquito and environmental factors, and was configured to investigate and quantitatively evaluate the relative impacts of mosquito control, livestock movement regulations, and diversity in cattle populations on the spread of the RVF epizootic. We concluded that cattle movement should be restricted during periods of high vector mosquito abundance to control the epizootic spreading among sub-counties. On the other hand we found that mosquito control would only be sufficient to control the epizootic when mosquito abundance was low. Importantly, simulation results also showed that cattle populations with a higher diversity with regard to indigenous combined with exotic breeds led to reduced numbers of infected cattle compared to more homogenous cattle populations.

epidemiology↗