Addiction; Synapse; Plasticity; Cocaine; Dopamine; pharmacology; synapses; synaptic plasticity; optogenetics
Lüscher Christian, Pascoli Vincent (2012), [Optogenetic reversal of cocaine-evoked synaptic potentiation normalizes behavioural sensitization]., in Médecine sciences : M/S
, 28(4), 353-5.
Tan Kelly R, Yvon Cédric, Turiault Marc, Mirzabekov Julie J, Doehner Jana, Labouèbe Gwenaël, Deisseroth Karl, Tye Kay M, Lüscher Christian (2012), GABA neurons of the VTA drive conditioned place aversion., in Neuron
, 73(6), 1173-83.
Padgett Claire L, Lalive Arnaud L, Tan Kelly R, Terunuma Miho, Munoz Michaelanne B, Pangalos Menelas N, Martínez-Hernández José, Watanabe Masahiko, Moss Stephen J, Luján Rafael, Lüscher Christian, Slesinger Paul A (2012), Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA., in Neuron
, 73(5), 978-89.
Lüscher Christian, Malenka Robert C (2012), NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD)., in Cold Spring Harbor perspectives in biology
, 4(6), 1-5.
Pascoli Vincent, Turiault Marc, Lüscher Christian (2012), Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour., in Nature
, 481(7379), 71-5.
Terrier Jean, Ort Andres, Yvon Cédric, Saj Arnaud, Vuilleumier Patrik, Lüscher Christian (2011), Bi-directional effect of increasing doses of baclofen on reinforcement learning., in Frontiers in behavioral neuroscience
, 5, 40-40.
Mameli Manuel, Bellone Camilla, Brown Matthew T C, Lüscher Christian (2011), Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area., in Nature neuroscience
, 14(4), 414-6.
Lüscher Christian, Malenka Robert C (2011), Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling., in Neuron
, 69(4), 650-63.
Tan Kelly R, Rudolph Uwe, Lüscher Christian (2011), Hooked on benzodiazepines: GABAA receptor subtypes and addiction., in Trends in neurosciences
, 34(4), 188-97.
Bellone Camilla, Mameli Manuel, Lüscher Christian (2011), In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA., in Nature neuroscience
, 14(11), 1439-46.
Lalive Arnaud L, Rudolph Uwe, Lüscher Christian, Tan Kelly R (2011), Is there a way to curb benzodiazepine addiction?, in Swiss medical weekly
, 141, 13277-13277.
Brown Matthew T C, Korn Clio, Lüscher Christian (2011), Mimicking synaptic effects of addictive drugs with selective dopamine neuron stimulation., in Channels (Austin, Tex.)
, 5(6), 461-3.
Mameli Manuel, Lüscher Christian (2011), Synaptic plasticity and addiction: learning mechanisms gone awry., in Neuropharmacology
, 61(7), 1052-9.
Brown Matthew T C, Bellone Camilla, Mameli Manuel, Labouèbe Gwenael, Bocklisch Christina, Balland Bénédicte, Dahan Lionel, Luján Rafael, Deisseroth Karl, Lüscher Christian (2010), Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation., in PloS one
, 5(12), 15870-15870.
Lüscher Christian, Slesinger Paul A (2010), Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease., in Nature reviews. Neuroscience
, 11(5), 301-15.
Nassirpour Rounak, Bahima Laia, Lalive Arnaud L, Lüscher Christian, Luján Rafael, Slesinger Paul A (2010), Morphine- and CaMKII-dependent enhancement of GIRK channel signaling in hippocampal neurons., in The Journal of neuroscience : the official journal of the Society for Neuroscience
, 30(40), 13419-30.
BACKGROUND: Drug addiction is a disease without cure that is defined by the compulsive use of a substance despite the negative consequences. Contrary to general perception, a majority of persons can recreationally use drugs without ever losing control. In fact even cocaine, one of the most addictive drugs, causes only one out of five users to meet the clinical criteria for the diagnosis of addiction. It is therefore key to understand how the transition from controlled recreational use to compulsive consumption comes about in order to identify the mechanism underlying the individual vulnerability and propose specific treatments. While no animal model fully mimics all aspects of the human disease, mouse models of core components of addiction do exist, which permit mechanistic investigations not possible in humans. Addictive drugs initially target the mesocorticolimbic dopamine (DA) system that projects from the VTA to the nucleus accumbens (NAc) causing a surge of DA levels, which drives molecular adaptations, and elicits synaptic plasticity of excitatory afferents onto DA neurons. The NAc then back-projects to more lateral parts of the midbrain, from where axons are sent to dorsal parts of the striatum. There are several loops until the final projection from DA neurons of the SNc to the most dorsal striatum. Given this spiraling connectivity, the idea has been put forward that the gradual recruitment of more and more dorsal parts of the striatum may underlie the switch to compulsive use. Experimental evidence based on surgical lesion experiments support this idea. However neither the identity of the neurons involved nor the molecular mechanism underlying the network organization have been identified. HYPOTHESIS: Chronic consumption of addictive drugs induces synaptic plasticity in the mesolimbic systems such that nigro-striatal projections are recruited, eventually leading to compulsive drug use and relapse. AIMS: We therefore propose to carry out the following specific aims in mice:1. elucidate the molecular mechanisms of drug-evoked synaptic plasticity in the midbrain and striatum.2. determine whether the activation of VTA DA neurons using optogenetic tools is sufficient to drive a network reorganization similar to the changes observed with addictive drugs.3. establish protocols to prevent or reverse-induced network organization and the progression towards compulsion. RESEARCH DESIGN: To achieve these aims, we will express channelrhodopsin, halorhodpsin and optoXRs (light-activatable ion channels and G protein coupled receptors) in a cell type-specific manner to manipulate components of the mesolimbic network. In combining advanced electrophysiological and pharmacological tools in vivo and ex vivo in acute slices of the VTA and the striatum will allow us to precisely control the activity in the spiraling network. We will also use imaging of single neurons (2-photon line scanning microscopy, 2PLSM) as well as 2P uncaging to probe synaptic connectivity. Finally we will monitor the effects of our interventions using behavioral tasks in mice. Our previous work in the field will serve as a basis to successfully address the questions raised here.EXPECTED VALUE: A successful completion of the present proposal may unravel the mechanism responsible for the switch from controlled to compulsive drug use. This will narrow the search for the determinants of the individual vulnerability. Moreover our experiments with optogenetic circuit-breakers may inspire future deep brain stimulation protocols in humans in order to treat addiction.