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Thèse Anne-Ruth Reisiger

Pathology of the reward system: Long-lasting effects of chronic exposure to nicotine.

Le 17 octobre 2013

Dept. Neuropsychopharmacology of addiction INCIA-CNRS UMR 5287 Université Victor Segalen Bordeaux 2

Soutenance  à l'  ENSTBB   à 14h 

Pathology of the reward system: Long-lasting effects of chronic exposure to nicotine.

The bed nucleus of stria terminalis (BNST), part of the extended amygdala, is innervated by the infralimbic cortex (ILCx), which is involved in different aspects of addiction-related behavior. The team has previously shown that learning mechanisms associated with active responding for nicotine, rather than nicotine itself, enhanced the excitability of the ILCx-BNST pathway.

The main objective of my project was to better understand the involvement of the ILCx-BNST pathway in different stages of nicotine taking and seeking. Moreover, the endocannabinoid system controls nicotine reinforcement and nicotine-induced synaptic modifications. Therefore, I examined the role of the endocannabinoid system in nicotine-induced neuronal adaptations.

Rats were trained to voluntary take nicotine in a model of intravenous nicotine self-administration (IVSA) during an extended period after which they were subjected to in vivo electrophysiological recordings. We were able to characterize neuroplastic changes at the ILCx-BNST synapse and showed that extended cue-dependent voluntary nicotine consumption is associated with facilitation of persistent evoked-spike potentiation in the BNST in response to 10Hz-stimulation of ILCx afferents. Concurrently, we discovered that this stimulation of this pathway temporarily induced aberrant responding when nicotine was unavailable, which is blocked by intra-BNST CB1 antagonist.

Based on these results, we examined the role of CB1 receptors in the BNST at different stages of nicotine addiction. Using intra-BNST pharmacology, we examined the behavioral implication of BNST CB1 receptors before and after a history of nicotine exposure. We revealed that CB1 receptors in the BNST are involved in the development of associative learning. Before a history of nicotine exposure, CB1 agonist enhances sensitivity to nicotine-paired cue. In contrast, after a prolonged history of nicotine intake, stimulation of BNST CB1 receptors block the incentive properties of both nicotine and nicotine-paired cue when nicotine is not available.

Together, our work shows that the ILCx-BNST pathway is involved in the development of maladaptive stimulus-response behavior to nicotine, controlled by CB1 receptors in the BNST. Further characterization of this pathway will have great impact in the understanding of nicotine seeking.

Keywords: Nicotine, infralimbic cortex, bed nucleus of stria terminalis, CB1 receptor, in vivo electrophysiology.

Anne-Ruth Reisiger, Jennifer Kaufling, Olivier Manzoni, Martine Cador, François Georges* and Stephanie Caille*. Acquisition of nicotine self-administration facilitates the induction of long term potentiation within the bed nucleus of the stria terminalis: a mechanism depending on CB1 receptors. * Contributed equally to this work. Submitted.


Véronique Deroche-Gamonet
Philippe Faure
Marcello Solinas
Thesis supervisor
Stéphanie Caillé

Directrice de thèse

Stéphanie Caille-Garnier
de l'addiction
Team leader Martine Cador