The ability to learn appropriate associations between environmental cues and their motivational valence represent a critical mechanism to shape individual's decision-making processes that guide behavior. This learning relies on the capacity of neurons to modify their connectivity (i.e. synaptic transmission), such as long-term potentiation (LTP) described at many synapses throughout the brain. Addiction, defined as transition from casual to compulsive pattern of drug use, involves enduring memories of drug experience. Drugs of abuse hijack synaptic plasticity mechanisms in key brain circuits for reward learning, especially the mesolimbic dopamine (DA) system comprising the ventral tegmental area (VTA) and its projections such as the nucleus accumbens. This leads to maladaptative learning of environmental stimuli associated with drug experience that promote the development of drug addiction and further precipitate relapse to drug intake.
Recently, a novel form of NMDA-type glutamate receptor (NMDAR)-mediated transmission onto VTA DA neurons has been described. This LTP requires activation of both voltage-gated Ca2+ channels (VGCCs) and NMDARs in a protocol that mimics the pre- and post-synaptic activity pattern experienced during cue-reward conditioning. Thus, the goal of my project is to investigate the role of NMDAR plasticity and VGCCs in VTA DA neurons to the learning of reward-associated environmental cues. For this purpose, I will combine ex-vivo approaches (electrophysiological recordings and confocal Ca2+ imaging in VTA brain slices) with in vivo paradigms (intra-VTA injections coupled to conditioned place preference, a widely used model of cue-reward learning) in order to determine the involvement of VGCCs in NMDAR LTP and their specific contribution to reward learning mechanisms.
Degoulet M, Degoulet M, Rostain JC, Abraini JH, David HN (2011). Short-term development of behavioral sensitization to amphetamine requires N-methyl-D-aspartate- and nicotinic-dependent mechanisms in the nucleus accumbens. Addict Biol. (In press). PubMed
David HN, Haelewyn B, Chazalviel L, Lecocq M, Degoulet M, Risso JJ, Abraini JH. (2009).Post-ischemic helium provides neuroprotection in rats subjected to middle cerebral artery occlusion-induced ischemia by producing hypothermia. J Cereb Bloo Flow Metab. 29:1159-65. PubMed
Degoulet M, Rostain JC, David HN, Abraini JH (2009). Repeated administration of amphetamine induces a shift of the prefrontal cortex and basolateral amygdala motor function. Int J Neuropsychopharmacol. 23:1/10. PubMed
Rouillon C, Degoulet M, Chevallier K, Abraini JH, David HN (2008). Modulation by group I mGLU receptor activation and group III mGLU receptor blockade of locomotor responses induced by D1-like and D2-like receptor agonists in the nucleus accumbens. Brain Res. 1198:44-54. PubMed
Degoulet M, Rouillon C, Rostain JC, David HN, Abraini JH (2008). Modulation by the dorsal, but not the ventral, hippocampus of the expression of behavioural sensitization to amphetamine. Int J Neuropsychopharmacol. 11:497-508. PubMed