Full Length ArticleIn situ metabolomic changes in rat hippocampus after acute cocaine administration
Graphical abstract
Introduction
Molecular mechanisms involved in the development of addiction disorder are complex and diverse. Chronic drug consumption results in maladaptive behavioural changes which cause inability to control compulsive drug taking and hold a high risk of relapse [1,2]. Those changes develop progressively with the repetition of drug intake and some effects can persist for a lifetime [3,4]. Indeed, drug memories that associate contextual cues with the effects of drugs are known to shape and maintain persistent drug seeking behaviors [[5], [6], [7], [8]]. Those behavioural effects are associated with synaptic plasticity linked with long-term associative memory [4]. Addictions and especially cocaine addiction is a socio-medical issue throughout the world. Therefore, a better understanding of its mechanism could help to better address signs of dependence. Cocaine is a psychostimulant acting on the reward-related brain system [9,10]. Notably, it interacts with aminergic neurotransmitters by inhibiting their reuptake via cocaine binding to their transporter sites [11,12]. Chronic cocaine consumption has different impact on cognition including impairments of verbal memory and various learning deficits [13,14]. In contrary, acute cocaine consumption enhances learning, memory and improves cognition [15,16]. Since the association between memory and addiction has been enlightened, brain regions involved in learning and memorising processes could be targeted for studying cocaine-induced toxicodynamic responses. For instance, Guan et al. investigated the impact of cocaine exposure on the proteomic profile focusing the medial prefrontal cortex [3]. Another study focused on the effect of cocaine on two specific transcription factor targeting the limbic system [17]. They showed that this system constituted of nucleus accumbens, hippocampus, amygdala and prefrontal cortex has clearly an impact on the memorisation and on the notion of pleasure [18]. Gao et al. have also been targeting the prefrontal cortex as well as the striatum [19], while Zhou et al. [5], and Kutlu et al. [4], focused on the hippocampus. Interestingly, all those regions play a role in addiction and memory processes with a high degree of plasticity [20].
Recently omics approaches, including transcriptomics, proteomics, and metabolomics have received a growing interest in the field of addiction. Interestingly, perturbation of metabolite levels reflects the ultimate response of biological system to genetic or environmental changes [21]. Among the recent development in the field, mass spectrometry imaging (MSI) provides a powerful metabolomic approach for investigating the spatial toxicodynamics of drugs of abuse in rodent brain models. Indeed, MSI allows the simultaneous label-free detection and possibly identification of hundreds of metabolites with limited sample preparation and without any homogenisation allowing to maintain the spatial information [22,23]. Among the different ionization sources, matrix assisted laser desorption and ionization (MALDI) is currently the most widely used for MSI [24]. In addition, the development of high-resolution mass spectrometers (HRMS) has made MALDI-MSI a promising technique for metabolomic studies in the field of pharmacodynamics and toxicodynamics [25].
To date, few MSI studies have been focused on the biological changes driven by addiction or drug consumption [26]. In a first report, Caprioli and al. demonstrated the possibility of linking protein changes to drug localization and pharmacodynamic response [27]. Indeed, their results showed the distribution of olanzapine and its metabolites in whole-body rat tissue sections by MALDI-MSI. They simultaneously analyzed the proteins changes induced by this drug consumption in regions of interest.
In this work, we used MALDI-MSI to compare the metabolomic changes in the hippocampus of rat brain after a single administration of cocaine and a single concomitant administration of cocaine and alcohol. This work demonstrates the potential of MALDI-MSI to decipher the spatial metabolome changes associated with the drug distribution in different brain regions, emerging a new horizon for future investigations.
Section snippets
Cocaine and alcohol rat administration
Male Wistar rats (n = 6) were bred in-house in the animal facility of the Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital. They were approximately 12 weeks old and weighed 420–470 g. They were kept in reversed 12-h light/dark cycle (lights off at 8.30 a.m.) and housed in controlled temperature and humidity conditions. All experiments were conducted in accordance with the Swiss National Institutional Guidelines on Animal Experimentation, and approved
Results and discussion
Addiction and especially cocaine addiction is a complex process involving several molecular mechanisms in different brain regions [7]. A better understanding of drug-induced molecular changes could bring new insights into the molecular mechanisms of addiction and the discovery of potential therapeutic targets. Cocaine addiction has been reported to have a high overlap of neural and molecular mechanisms associated with memory and learning. Therefore, this study focuses on the metabolites changes
Conclusion
This work presents a MSI approach to map the in situ metabolomic changes in rat brain induced by drugs of abuse. Herein, we demonstrated significant changes of metabolite levels occurring in hippocampus after acute administration of cocaine and alcohol. However, this first study needs to be confirmed using a larger set of samples and in different experimental conditions, like for instance by investigating the toxicodynamic changes after chronic administration of cocaine. In addition, MSI could
Acknowledgements
The authors acknowledge financial support from the Federal Office of Public Health (contract no. 14.013792/204.0001/-1300) and the Swiss National Science Foundation (project no. 310030-156771).
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