Project

Addiction; Synapse; Plasticity; Cocaine; Dopamine; pharmacology; synapses; synaptic plasticity; optogenetics

Lead
Lay summary
Addiction is a disease that is characterized by the compulsive use of a drug despite the negative consequences. We pursue the hypothesis that pathological forms of learning eventually causing the loss of control. On the other hand many groups report that addictive drugs cause long-term changes of synaptic transmission, in particular in neurons of the reward system. The current project examines the molecular basis of such drug-evoked synaptic plasticity and how it is linked to behavior in mice that mimics core components of addiction.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Number	Title	Start	Funding scheme

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.