Gene targeting in mice to study the role of neuropeptide receptors in ethanol dependence has recently yielded fascinating results. Knockout of the mu opioid receptor (MOP) gene blocks ethanol drinking and operant responding for ethanol. Knockout of the Corticotropin Releasing Factor receptor 1 (CRF1) gene reduces levels of anxiety under basal and alcohol withdrawal conditions. Altogether data demonstrate that blockade of these receptor systems reduce alcohol intake. Limitations of these """"""""conventional"""""""" gene targeting studies are that (i) gene knockout occurs early, therefore compensatory mechanisms could take place during development, and (ii) knockout of the receptors occurs throughout the entire animal, therefore no information on the recruited neurocircuitry is provided. To address these issues, we will induce the knockout of MOP and CRF1 receptor genes specifically in the extended amygdala (EA) of adult animals, based on the overall hypothesis of INIA (Integrative Neuroscience Initiative on Alcoholism) regarding the role of the EA in excessive alcohol consumption. First, we will take advantage of two existing mutant mouse lines, one with a floxed MOP receptor gene (recently created in our laboratory), and another with a floxed CRF1 receptor gene (collaboration). Second, we will develop a novel transgenic mouse line expressing Cre recombinase in the EA. To do this, we will use a BAG promoter for the WFS1 (Wolfram syndrom 1) gene, that we have recently identified as an EA marker gene (Specific Aim 1). Third, we will breed floxed mice with the WFS1-Cre mouse to produce the conditional knockout of MOP (Specific Aim 2) and CRF1 (Specific Aim 3) receptor genes in the EA of adult mice. The two conditional lines will be fully characterized for receptor expression throughout the brain, for morphine responses (MOP) and for basal behaviors (Specific Aims 2 and 3). The two conditional lines will finally be extensively studied in behavioral models of excessive alcohol drinking, including the DID and WID models, as well as for acute ethanol responses and ethanol withdrawal (Specific Aim 4). Importantly, the WFS1-Cre transgenic mice generated in Specific Aim 1 will represent a unique tool for the conditional deletion of any other gene of interest in the extended amygdala, and will be generally useful in addiction research. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016658-02
Application #
7292796
Study Section
Special Emphasis Panel (ZAA1-DD (70))
Program Officer
Neuhold, Lisa
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$111,998
Indirect Cost
Name
Institute/Genetique/Biologie Molec/Cell
Department
Type
DUNS #
771980620
City
Illkirch
State
Country
France
Zip Code
67404
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
Ben Hamida, Sami; Mendonça-Netto, Sueli; Arefin, Tanzil Mahmud et al. (2018) Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks. Biol Psychiatry 84:202-212
Maroteaux, G; Arefin, T M; Harsan, L-A et al. (2018) Lack of anticipatory behavior in Gpr88 knockout mice showed by automatized home cage phenotyping. Genes Brain Behav 17:e12473
Ehrlich, Aliza T; Semache, Meriem; Bailly, Julie et al. (2018) Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing. Brain Struct Funct 223:1275-1296
Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie (2017) Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. Addict Biol 22:1205-1217
Meirsman, A C; de Kerchove d'Exaerde, A; Kieffer, B L et al. (2017) GPR88 in A2A receptor-expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating. Eur J Neurosci 46:2026-2034
Boulos, Laura-Joy; Darcq, Emmanuel; Kieffer, Brigitte Lina (2017) Translating the Habenula-From Rodents to Humans. Biol Psychiatry 81:296-305
Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena et al. (2017) Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. Biol Psychiatry 81:778-788
Meirsman, Aura C; Le Merrer, Julie; Pellissier, Lucie P et al. (2016) Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist. Biol Psychiatry 79:917-27
Chu Sin Chung, Paul; Keyworth, Helen L; Martin-Garcia, Elena et al. (2015) A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. Biol Psychiatry 77:404-15

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