Maternal Environment Influences Cocaine Intake in Adulthood in a Genotype-Dependent Manner

Background: Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors. Methodology/Principal Findings: For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain. Conclusions/Significance: Our experimental approach could contribute to the identification of the psychobiological factor

Développement et caractérisation d'un modèle d'addiction chez le rat (du comportement aux transcriptomes)

L'addiction est une pathologie chronique qui se caractérise par une recherche compulsive de la drogue, une perte de contrôle sur la prise et une très forte probabilité de rechute. Cette pathologie n'affecte que 15 à 20 % des personnes exposées. Elle résulterait donc de l'interaction entre un phénotype vulnérable et l'exposition à la drogue. La recherche fondamentale et clinique s'est focalisée ces 40 dernières années sur la compréhension des processus psychobiologiques sous-tendant la consommation des drogues. Dans cette démarche, cette recherche a contribué à une très bonne compréhension des bases neurobiologiques des effets inconditionnés et conditionnés de la prise de drogue. Cependant, l'addiction ne correspond pas à une simple consommation de la drogue. Par conséquent, aujourd'hui encore les bases neurobiologiques de l'addiction restent inconnues. C'est certainement l'absence de modèle animal pertinent de la pathologie qui a conduit à cette impasse. En effet, seul un modèle animal de l'addiction permettrait d'en caractériser les mécanismes neurobiologiques associés. Au cours de notre travail de thèse, nous avons : 1, testé le pouvoir addictogène de la cocaine chez le rongeur. Pour ce faire, nous avons opérationnalisé, chez le rat, les 3 principaux critères diagnostiques du DSM IV symptomatiques d'une recherche compulsive et d'une perte de contrôle sur la prise de drogue ; 2, étudié de possibles déterminants psychologiques de l'addiction. Nous avons notamment caractérisé les niveaux d'anxiété et de désinhibition comportementale associés à l'addiction et recherché, avant tout contact avec la drogue, des indices comportementaux prédictifs de l'addiction ; 3, étudié des bases biologiques de l'addiction. Nous avons analysé les modifications transcriptionnelles associées à l'addiction au niveau des structures cérébrales constituant le système de récompense ; système central dans le contrôle des comportements motivés. Comme chez l'homme, seul 17 % de la population exposée développe les critères d'addiction et uniquement après plusieurs mois d'autoadministration intraveineuse de la drogue. De plus, à l'image de l'homme, les animaux dépendants, positifs pour les 3 critères d'addiction, présentent une forte rechute du comportement même après un sevrage de longue durée et une incapacité à limiter la prise (lors d'un accès prolongé à la drogue). De plus, le comportement spécifique de ces animaux ne résulte ni d'une plus grande consommation de la drogue, ni d'une désinhibition comportementale ou d'unniveau d'anxiété particuliers. Enfin, avant exposition à la drogue, ils présentent dans leur majorité un phénotype particulier intégrant des dimensions d'anxiété et de recherche de nouveauté. L'analyse biologique a permis de mettre en évidence l'implication particulière du PFM dans l'addiction. En effet, dans cette structure, l'addiction s'accompagne d'une modification de l'expression de 5 fois plus de gènes que dans les autres structures clés du système de récompense. Ces gènes différentiellement exprimés, correspondant à des protéines impliquées dans la structure des synapses, reflètent une complète réorganisation neuronale et fonctionnelle du réseau. Ces travaux ont permis 1) la caractérisation comportementale du premier modèle animal d'addiction, 2) une meilleure connaissance des indices de vulnérabilité, 3) la détermination de bases cellulaires et moléculaires de la pathologie. A travers ces 3 aspects, ces travaux contribuent à la détermination de nouvelles cibles thérapeutiques pour l'élaboration de traitements efficaces de la pathologie.Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use ("addiction") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. This addiction-like behaviour seems to be associated with a compulsive seeking of the drug but neither with a differential intake of the drug nor with a disinhibited behaviour or a different anxiety level. This addiction-like behaviour is predicted by behavioural factors relative to anxiety and novelty seeking and is associated with transcriptionnal regulations mainly in the prefrontal cortex.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

A decrease in gamma-synuclein expression within the nucleus accumbens increases cocaine intravenous self-administration in the rat

Except as a marker of cancer progression, gamma-synuclein (GSyn) had received little attention. Recent data showed however that GSyn modulates cocaine-induced locomotor effects, suggesting that it could also play a role in cocaine reinforcing effects. In the rat, siRNAs targeting GSyn expression were injected in the nucleus accumbens and cocaine reinforcing effects were evaluated by means of intravenous self-administration. A dose-response curve was followed by procedures of progressive ratio, extinction, cocaine- and cue-induced reinstatements. Decrease of GSyn expression increased self-administration over a large range of doses. This effect was associated with an increase in cocaine-induced reinstatement. The present data reveal that GSyn exert a specific negative control on cocaine-induced reinforcing and incentive effects

Individual variations in motives for nicotine self-administration in male rats: evidence in support for a precision psychopharmacology

Abstract The significant heterogeneity in smoking behavior among smokers, coupled with the inconsistent efficacy of approved smoking cessation therapies, supports the presence of individual variations in the mechanisms underlying smoking. This emphasizes the need to shift from standardized to personalized smoking cessation therapies. However, informed precision medicine demands precision fundamental research. Tobacco smoking is influenced and sustained by diverse psychopharmacological interactions between nicotine and environmental stimuli. In the classical experimental rodent model for studying tobacco dependence, namely intravenous self-administration of nicotine, seeking behavior is reinforced by the combined delivery of nicotine and a discrete cue (nicotine+cue). Whether self-administration behavior is driven by the same psychopharmacological mechanisms across individual rats remains unknown and unexplored. To address this, we employed behavioral pharmacology and unbiased cluster analysis to investigate individual differences in the mechanisms supporting classical intravenous nicotine self-administration (0.04 mg/kg/infusion) in male outbred Sprague–Dawley rats. Our analysis identified two clusters: one subset of rats sought nicotine primarily for its reinforcing effects, while the second subset sought nicotine to enhance the reinforcing effects of the discrete cue. Varenicline (1 mg/kg i.p.) reduced seeking behavior in the former group, whereas it tended to increase in the latter group. Crucially, despite this fundamental qualitative difference revealed by behavioral manipulation, the two clusters exhibited quantitatively identical nicotine+cue self-administration behavior. The traditional application of rodent models to study the reinforcing and addictive effects of nicotine may mask individual variability in the underlying motivational mechanisms. Accounting for this variability could significantly enhance the predictive validity of translational research

Maternal behavior displayed by AKR and C3H mothers toward C57 and DBA pups.

<p>Graphs show the percentage of time spent in pup licking, nursing posture and nest reorganizing activity with C57 pups (left panels) and DBA pups (right panels) averaged over 4 postnatal days (PD 2, 4, 6 and 9). Behavior of the reference mothers (bio mothers) is shown as horizontal hatched bands. Bars represent mean±SEM. AKR mothers (white bars) <i>n</i> = 9 dams for each pup strain. C3H mothers (black bars) <i>n</i> = 7 dams for each pup strain. Bio mothers (hatched bands) <i>n</i> = 15 for C57 dams and <i>n</i> = 8 for DBA dams. * p<0.05, ** p<0.01 and *** p<0.001 compared to C3H mothers. # p<0.05, ## p<0.01 and ### p<0.001 compared to bio mothers.</p

Impact of maternal environment on anxiety- and depression-related behaviors in (a) C57 and (b) DBA mice.

<p><i>EPM:</i> Graphs show the total number of entries into the closed arms, an index of exploration (left panels) and the percentage of time spent on the open arms, a measure of anxiety (right panels). <i>FST:</i> Graphs show total immobility time in a 6 min test, a measure of depression-related behavior. Behavior of the reference groups (-<i>bio</i>) is shown as horizontal hatched bands. Bars represent mean±SEM. C57-<i>AKR</i> (white bars) <i>n</i> = 12, C57-<i>C3H</i> (black bars) <i>n</i> = 14, C57-<i>bio</i> (hatched bands) <i>n</i> = 14, DBA-AKR (white bars) <i>n</i> = 8, DBA-C3H (black bars) <i>n</i> = 10, DBA-<i>bio</i> (hatched bands) <i>n</i> = 11. ** p<0.01 compared to DBA-<i>C3H</i>. ## p<0.01 compared to DBA-<i>bio</i>.</p

Impact of maternal environment on cocaine intravenous SA in C57 and DBA mice.

<p>Graphs show the number of self-infusions obtained in (a) C57 mice in acquisition at 1 mg/kg/infusion (left panel) and dose-response curve (right panel) (b) DBA mice in acquisition at 0.5 mg/kg/infusion (left panel) and dose-response curve (right panel). The symbols in the dose-response graph represent the last two days of stable intake on a dose. Behavior of the reference groups (-<i>bio</i>) is shown with grey lines and symbols. Horizontal lines show the data submitted to statistical analysis. Symbols represent mean±SEM. C57-<i>AKR</i> (white circles) <i>n</i> = 5, C57-<i>C3H</i> (black circles) <i>n</i> = 8, C57-<i>bio</i> (grey circles) <i>n</i> = 8, DBA-<i>AKR</i> (white circles) <i>n</i> = 8, DBA-<i>C3H</i> (black circles) <i>n</i> = 11, DBA-<i>bio</i> (grey circles) <i>n</i> = 10. * p<0.05 compared to DBA-<i>C3H.</i></p

Cocaine self-administration in C57 and DBA mice in a study where both strains acquired at 1 mg/kg/infusion.

<p>The graph shows the number of self-infusion on the last 5 days of acquisition (day 6–10) and the transition to a 0.5 mg/kg/infusion dose (day 11–14). At the 0.5 mg/kg dose, DBA mice show a number of self-infusions that is comparable to that of the C57 mice at the 1 mg/kg/infusion dose. Symbols represent mean±SEM. C57 (squares) <i>n</i> = 8, DBA (triangles) <i>n</i> = 5.</p

The impact of maternal environment on bodyweight.

<p>The table shows bodyweight (BW) data at birth, weaning and 16 weeks of age of male C57 and DBA offspring raised by an AKR, a C3H or their biological mother. Values represent mean±SEM.</p