Event Abstract

Back to Event

RESTING STATE CONNECTIVITY SHOWS DIFFERENTIAL EFFECTS FOR SUBSETS OF THE MESOCORTICOLIMBIC CIRCUIT DURING DRUG ADDICTION IN RATS

Bart De Laat1, 2*, Willy Gsell1, 3, Kristof Govaerts1, 3, Uwe Himmelreich1, 3, Cindy Casteels1, 2 and Koen Van Laere1, 2
  • 1 KU Leuven, MoSAIC - Molecular Small Animal Imaging Center, Belgium
  • 2 UZ Leuven, Nuclear Medicine, Belgium
  • 3 KU Leuven, Biomedical MRI unit, Belgium

Objective: Cocaine addiction is a major health concern, for which currently no approved treatment exists. This is largely due to the neurobiological complexity of addiction, with several neurotransmitter systems and different brain regions involved in different phases of the addiction process. Preclinical studies have shown that altered resting state functional-MRI (rs-fMRI) can be shown in the mesocorticolimbic circuit (MLC), involved in the acquisition of reward memory differences during cocaine self-administration in rats. Therefore, we followed up animals subjected to cocaine self-administration in a longitudinal design to investigate the temporal dynamic of the intrinsic neurobiological interactions between the different brain regions involved in this circuit. Methods: Eighteen male adult Wistar rats were surgically implanted with an IV-catheter before training self-administration with oral sucrose rewards. Hereafter baseline measurements were performed before starting two cocaine exposure weeks, and 2 weeks of withdrawal. Additionally, animals regained access to cocaine for 1 week to mimic a relapse. During the drug-exposure and relapse phase animals had free access to cocaine via lever presses in 3 hour sessions. Animals were followed up with weekly rs-fMRI scans while being anesthetized with 1.5% isoflurane. As previously described, data were obtained with an EPI sequence on a 9.4T Bruker scanner. Obtained scans were motion corrected using FSL FEAT, spatially smoothed and normalized. Hereafter, brains were extracted and registered to the Schwarz rat atlas, before being subjected to temporal band-pass filtering. Included a priori regions of interest were the left and right (L/R) striatum (S), nucleus accumbens (NAC), prefrontal cortex (PFC) and cingulate cortex (CC). To obtain the most sensitive signal, clusters of 200 voxels were identified within these ROIs with a homemade R script that iteratively calculated the cluster with maximal inter-voxel correlations. Reported correlations were calculated between each ROI’s cluster. Associations between cocaine self-administration and functional connectivity between regions were assessed with linear mixed models allowing random intercepts per animal. Results: Animals readily self-administered cocaine when available. Additionally, during two drug-exposure weeks high inter-subject variability was observed. Mean correlation between assessed parts of the MLC showed an increase of functional connectivity during drug-exposure (7.5±3.1%, p = 0.03) and withdrawal (15.0±3.7%, p < 0.001) as compared to baseline. However, no difference between relapse and baseline was found. Furthermore, within the MLC, 4 connections showed significant association with self-administration; CC – RS, PFC – LS, RS * RNAC, and LS * RS. Interestingly, the negative relation between prefrontal regions (PFC & CC) and LS suggests an inhibitory effect on self-administration. Conclusions: Cocaine was readily and increasingly self-administered over time, as has been reported before. Using an iteratively selected cluster, we could show that the average functional connectivity between MLC clusters increased during drug-exposure and withdrawal, but normalized in relapse. This could be suggestive for the self-medicating hypothesis of addiction, but needs to be substantiated in future studies. Furthermore, the connection between the CC and PFC, and the LS and RS respectively was negatively associated with cocaine self-administration. Conversely, the connectivity between the RS * RNAC, and the LS * RS was positively associated with drug intake. These findings corroborate the inhibitory influence of the prefrontal brain regions over the reward-oriented structures, such as the nucleus accumbens and striatum. Résumé en Français: L’addiction à la cocaïne est un problème majeur de santé publique pour lequel aucun traitement satisfaisant n’existe. Afin de mieux comprendre les mécanismes de l’addiction, des modèles animaux ont été développés. Ces modèles basés sur l’auto-administration de drogue chez le rat, permettent d’étudier les différentes régions du cerveau impliqués dans ce processus. Dans ce travail, la technique d’imagerie fonctionnelle par résonance magnétique (IRMf) permet d’analyser les régions du cerveau dont l’activité est corrélée à la prise de drogue et à la privation de cette même drogue et à la rechute. Les résultats ont montré qu’une région située à l’avant du cerveau, dans le lobe préfrontal, inhibent les centres cérébraux impliqués dans la prise de substances addictives. Samenvatting in het Nederlands : De verslaving aan cocaïne is een groot probleem voor de publieke gezondheid waarvoor geen enkele bevredigende behandeling bestaat. Om beter de mechanismen van deze verslaving te begrijpen zijn diermodellen ontwikkeld. Deze basisdiermodellen, gebaseerd op de autonome toediening van de drug bij ratten, laten toe de verschillende gebieden van de hersenen die betrokken zijn bij dit proces te bestuderen. In dit werk maakt de techniek van functionele magnetische resonantie (fMRI) het mogelijk om de gebieden van de hersenen, waarvan de activiteit verband houdt met het innemen van de drug of met de ontbering of het terug innemen ervan, te analyseren. De resultaten tonen aan dat een gebied vooraan in de hersenen, in de frontale kwab, betrokken is bij de inname van verslavende middelen.

Keywords: Addiction, fMRI BOLD, animal model, Cocaine, Substance Abuse, Intravenous

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Poster Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: De Laat B, Gsell W, Govaerts K, Himmelreich U, Casteels C and Van Laere K (2016). RESTING STATE CONNECTIVITY SHOWS DIFFERENTIAL EFFECTS FOR SUBSETS OF THE MESOCORTICOLIMBIC CIRCUIT DURING DRUG ADDICTION IN RATS. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00063

Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.

The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.

Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.

For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.

Received: 08 Jul 2016; Published Online: 13 Jul 2016.

* Correspondence: DVM. Bart De Laat, KU Leuven, MoSAIC - Molecular Small Animal Imaging Center, Leuven, Belgium, bart.delaat@kuleuven.be