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Caractérisation des propriétés motivationnelles du sevrage des opiacés - analyse comparative des substrats neurobiologiques des effets inconditionnés et conditionnés

Abstract : Addictive behaviors are pathological states characterized by a loss of control over drug consumption and by a persistent vulnerability to relapse following abstinence from repeated drug use. Addiction involves motivational and emotional processes as well as associative-learning and affective memory. In former opiate addicts, re-exposure to environmental situations previously paired with withdrawal is able to induce strong craving episodes, and it has been proposed that these conditioned stimuli could be strongly involved in precipitating relapse in drug-taking behavior by re-activating the neurobiological networks which is engaged in an unconditioned manner by the withdrawal state itself. In this context, we have focused on the characterization of the motivational component of morphine withdrawal, by using behavioral models (naloxone-precipitated withdrawal using low doses in morphine-dependent rats, re-exposure to morphine withdrawal-paired environmental stimuli in a conditioned place aversion paradigm), which allow to assess the aversive and motivational properties of opiate withdrawal, both in the unconditioned and conditioned situations. Using these models, we have investigated the neuronal correlates of these processes, using extensive mapping of the neurobiological substrates recruited, in terms of localization and neuronal population, with an anatomical and functional approach using the detection of c-fos as a marker of neuronal reactivity, by in situ hybridization. On the whole, our results show that the neurobiological substrates underlying the motivational component of opiate withdrawal – which include in particular the structures of the extended amygdala (nucleus accumbens medial shell part, bed nucleus of the stria terminalis and central nucleus of the amygdala) and its associated limbic territories (basolateral nucleus of the amygdala, hippocampus, lateral septal nucleus and ventral tegmental area) – can be dissociated from a number of other cerebral structures, which, in contrast, are involved in the expression of the overt somatic symptoms of withdrawal. Within the ventral tegmental area (VTA), our phenotypical analysis of the neuronal populations which are recruited following naloxone-precipitated morphine withdrawal (unconditioned situation) and after re-exposure to withdrawal-paired environmental stimuli (conditioned situation) show an intense induction of the majority of GABAergic interneurons. Although such GABAergic activity should lead to dopaminergic neurons inhibition, we also demonstrate that a subset of the VTA dopaminergic neurons (about 15%) is activated in both the unconditioned and conditioned situations. Within the amygdala, our results show an anatomical and functional double-dissociation in the global response of the central (CeA) and basolateral (BlA) nuclei of the amygdala in terms of c-fos mRNA expression between the unconditioned and conditioned situations. In the BlA, although acute naloxone-precipitated withdrawal decreased c-fos expression in the majority of glutamatergic efferent neurons, a subpopulation of these neurons exhibited decreased c-fos mRNA expression. In contrast, re-exposure to withdrawal-conditioned stimuli enhanced c-fos expression in a large number of BlA glutamatergic efferents. Within GABAergic neurons of the CeA, c-fos responses were opposite to the global responses measured in the BlA, as c-fos mRNA expression in these neurons is increased in the unconditioned situation, whereas it is decreased in the conditioned situation. Altogether, our results emphasize that the pattern of c-fos mRNA expression that we detect within all these interconnected limbic structures could reflect 1/ the onset of associative-learning processes aimed to encode the incentive-value of morphine withdrawal-associated environmental stimuli, in the unconditioned situation, and 2/ the retrieval and expression of learned-associations, in the conditioned situation (withdrawal memories). Therefore, on the basis of our results, and together with a number of data in the literature, we propose a functional model for the acquisition and the retrieval of morphine withdrawal memories.
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https://tel.archives-ouvertes.fr/tel-00006055
Contributor : François Frenois <>
Submitted on : Tuesday, May 11, 2004 - 2:30:11 PM
Last modification on : Tuesday, January 22, 2019 - 11:00:09 AM
Long-term archiving on: : Friday, April 2, 2010 - 8:30:20 PM

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François Frenois. Caractérisation des propriétés motivationnelles du sevrage des opiacés - analyse comparative des substrats neurobiologiques des effets inconditionnés et conditionnés. Neurosciences [q-bio.NC]. Université Victor Segalen - Bordeaux II, 2003. Français. ⟨tel-00006055⟩

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