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Catherine Le Moine, Cyril Dejean

Le système limbique otage des opiacés !

Le 2 octobre 2013

Opiate dependence induces network state shifts in the limbic system.
Dejean C, Boraud T, Le Moine C.
Neurobiol Dis. 2013 Nov; 59:220-9. University of Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France;


What is the conceptual framework of this work?
Catherine LE MOINE
Among the different theories of addiction, the homeostatic dysregulation theory predicts that brain systems, including the reward system, switch from a physiological state to a new “set point” (also named allostatic state) as the dependence develops. This phenomenon is thought to rely on neuronal adaptations and leads to both impaired brain function and withdrawal syndrome as drug intake is discontinued. These neuroadaptations are believed to be at the origin of the imbalance in brain function observed in drug addiction. Our group at the INCIA has previously shown that the prefrontal cortex (PFC), the nucleus accumbens (NAC) and the basolateral amygdala (BLA) are crucial substrates for opiate related dysregulations, and most notably for acute opiate withdrawal effects and associated memories. Taken individually these structures have thus been involved in drug addiction but they also form a functional and interconnected network within the limbic system. Since homeostatic dysregulation in addiction is thought to be a systemic phenomenon, neuronal adaptations should also occur at the network level. Our study recently published in Neurobiology of Disease investigates this hypothesis.

How was this study developed? 
Cyril DEJEAN
It is widely accepted that brain functions are distributed processes. For the sake of those functions, distant structures associated in operating networks interact through dynamic synchronization of their respective neuronal activities. We postulated that chronic morphine stimulation impairs PFC-NAC-BLA functional equilibrium (homeostasis) by disrupting those dynamics to promote the emergence of a drug-related de novo network balance. As pointed out by Catherine, most studies so far have focused on single structure and, testing our hypothesis required an original and global approach. For that purpose we used chronic simultaneous multi-unit recordings in PFC, NAC and BLA in morphine-dependent freely-moving rats. Those recordings revealed that our triad network is animated by complex, non-stationary interactions. To depict such rich and somewhat puzzling dynamics we developed multivariate analysis methods. This allowed us to take snapshots of the whole network under physiological or morphine conditions and to compare network states in both situations.

 What are the major results and perspectives of this study?
Catherine LE MOINE
Our work is the first direct evidence for opiate induced allostasis at the systemic level. In the PFC-NAC-BLA ensemble, this phenomenon can be described in two stages. First, the introduction of morphine in a drug naive brain induces a striking reorganization of the oscillatory profiles of neuronal activity that translate into a dramatic shift in network state. Second, even though morphine continues to chronically stimulate the brain, electrophysiological signatures progressively reorganize towards a physiological shape leading to a gradual normalization of network state. However this normalization is only apparent. Indeed, while totally ineffective in drug-naive animals, the blockade of the opioid receptors is able to disrupt this apparent stability in morphine treated rats together with the appearance of a withdrawal state. This phenomenon indicates that significant adaptations take place at the network scale, most probably allowing the PFC-NAC-BLA to regain functional interactions despite the constant presence of the drug. Interestingly altering drug impact with an opioid receptor antagonist, challenges network balance. This shows that after destabilizing the PFC-NAC-BLA network the drug has become a necessary component for its newly acquired equilibrium. 


Cyril Dejean
Our observations call to mind the Stockholm Syndrome in which hostages end up displaying sympathy for their captor and defiance towards the police. In our situation here, after massively disorganizing its “brain hostage”, morphine takes hold in PFC-NAC-BLA network organization to become a positive presence in it. This image left aside, given the well-known role of this limbic sub-network in reward, drug-associated memories and craving, our work opens new experimental perspectives to test the mechanisms underpinning both the coding of the rewarding effects of opiates, the aversive effect of withdrawal, and more generally the neuronal substrates of drug dependence.


Pubmed http://www.ncbi.nlm.nih.gov/pubmed/23911767

Abstract
Among current theories of addiction, hedonic homeostasis dysregulation predicts that the brain reward systems, particularly the mesolimbic dopamine system, switch from a physiological state to a new "set point." In opiate addiction, evidence show that the dopamine system principal targets, prefrontal cortex (PFC), nucleus accumbens (NAC) and basolateral amygdala complex (BLA) also adapt to repeated drug stimulation. Here we investigated the impact of chronic morphine on the dynamics of the network of these three interconnected structures. For that purpose we performed simultaneous electrophysiological recordings in freely-moving rats subcutaneously implanted with continuous-release morphine pellets. Chronic morphine produced a shift in the network state underpinned by changes in Delta and Gamma oscillations in the LFP of PFC, NAC and BLA, in correlation to behavioral changes. However despite continuous stimulation by the drug, an apparent normalization of the network activity and state occurred after 2 days indicating large scale adaptations. Blockade of μ opioid receptors was nonetheless sufficient to disrupt this acquired new stability in morphine-dependent animals. In line with the homeostatic dysregulation theory of addiction, our study provides original direct evidence that the PFC-NAC-BLA network of the dependent brain is characterized by a de novo balance for which the drug of abuse becomes the main contributor. 

Catherine Le Moine (catherine.lemoine @ u-bordeaux2.fr)
Dernière mise à jour le 02.10.2013

Focus



Catherine Le Moine
Directeur de Recherche CNRS
Equipe "Neuropsychopharmacologie de l'Addiction" Institut des Neuroscience Cognitives et Intégratives d’Aquitaine
UMR CNRS 5287




Cyril Dejean 
Post Doctorant Alumni
Equipe "Neuropsychopharmacologie de l'Addiction"
INCIA – UMR CNRS 5287

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Photo Catherine Le Moine
©CNRS photothèque
/François Vrignaud