The main goals of the lab are to unveil the neurobiological mechanisms underlying the transition to drug addiction and to develop novel pharmacological and non-pharmacological treatments to reduce compulsive drug seeking and taking.
Neurocircuitry of drug addiction
The goal of this project is to identify the neurocircuitry mediating the effects of:
drugs of abuse
compulsive drug seeking and taking
The video shows one of the approaches used. 3D reconstruction of the whole brain is performed using iDisco clearing techniques and light-sheet microscopy. Every single dot represents a neuron that has been activated by cocaine.
Our goal is to identify of a set of single-nucleotide polymorphisms (SNPs) associated with increased vulnerability to compulsive cocaine use and facilitate the identification of novel druggable targets.
We are generating data and creating a tissue bank from >1000 rats that have been characterized as vulnerable or resistant to cocaine addiction that we will make available to other institutions at no cost (excluding shipping and handling).
The CocaineBioBank includes brains, blood and other tissues using various storage methods to maximize compatibility with molecular and cellular approaches (perfused, snap frozen, iPS cells).
VTA CRF neurons in nicotine dependence
Neuronal ensembles and alcohol drinking
Discret neuronal ensembles are recruited in the Prefrontal Cortex and Central Nucleus of the Amygdala during withdrawal from alcohol drinking. We are investigating the causal role of these neuronal ensemble activations using transgenic rats (c-Fos-LacZ, Dr, Bruce Hope @ NIH-IRP) allowing us to inactivate specifically the neuronal ensembles activated during alcohol withdrawal.
CRF neurons and alcohol/nicotine dependence
We are investigating the causal role of CRF neurons activation in the Central Nucleus of the amygdala in the motivation for alcohol and nicotine using optogenetic and pharmacogenetic techniques.
New evidence suggest that a previously unidentified population of CRF neurons in the Ventral tegmental area is recruited after chronic exposure to nicotine and mediates the negative motivational effect of nicotine withdrawal. We are using behavioral, electrophysiological and molecular techniques to investigate these mechanisms.
Deep brain stimulation for heroin dependence
Deep Brain Stimulation (DBS) has been very succesful for the treatment of Parkinson's disease. We are developping the same approach targeting different brain regions to try to reduce compulsive heroin and cocaine intake in dependent rats.
Animal model of drug vapor inhalation
Inhalation is the main route of drug administration in humans and emergence of nicotine and alcohol vapor delivery device in humans raises concern about the validity of current animal models using intravenous self-administration. To address this problem, we are developing novel animal model of drug dependence using nose-only and whole body exposure to nicotine, alcohol and THC vapor.
Dynorphin system in dependence to nicotine, heroin and meth
Dynorphin is an endogenous opioid peptide with key function in pain, stress and anxiety. We are testing the causal role of dynorphin on escalation of drug intake using viral vector mediated downregulation of dynorphin in the accumbens and central nucleus of the amygdala combined with animal models of nicotine, heroin and methamphetamine dependence.
Microtubule, aging and motivation
Emerging evidence suggests that the pathogenesis of depressive disorders is associated with neuronal abnormalities in brain microtubule function, including changes in α-tubulin isoforms. We are collaborating with Prof Etienne-Emile Baulieu (MAPREG) to test if novel compounds targeting microtubules may reverse abnormal emotional and motivational behavior observed during aging.
Effect of drugs of abuse on neurogenesis
Neuronal plasticity is critical in the transition to drug addiction, and drugs of abuse have a powerful effect on neurogenesis. We are investigating in collaboration with Dr Chitra Mandyam the consequences of a history of drug dependence on neurogenesis in the hippocampus and prefrontal cortex.