1. Impact of chronic cocaine on the cholesterol metabolism in the brain.
Josette ALSEBAALY1,2,3, Lydia Rabbaa Khabbaz2,3,Emilie Dugast1,Marcello Solinas1,Nathalie Thiriet1.
1-Laboratoire de Neurosciences Experimentales et Cliniques, University of Poitiers, INSERM U Rue George Bonnet, 86022, Poitiers-France
2- Faculty of Pharmacy,University of Saint-Joseph of Beirut, Beirut ,Lebanon
3-Laboratoire de Pharmacologie, Pharmacie clinique et Contrôle de Qualité des Médicaments (LPCQM), Lebanon
Introduction
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Results
Accumulating evidences suggest that brain cholesterol has not only structural functions but also plays a role in neurotransmission. Alterations in brain cholesterol synthesis and metabolism have been demonstrated in several brain disorders like Alzheimer’s, Parkinson’s or Huntington’s diseases, but little is known about the impact of cholesterol dysregulation in psychiatric disorders such as addiction. Our team has recently found that statins, pharmacological inhibitors of HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis, reduce the risk of relapse to cocaine and nicotine in rats suggesting that dysregulation of cholesterol homeostasis could play a role in addiction(1). In addition, a post-mortem transcriptomic study in in cocaine, cannabis and phencyclidine abusers has shown that the expression of genes encoding for proteins involved in cholesterol metabolism is altered in the prefrontal cortex(2). In this study we investigated whether a protocol of cocaine administration that induces behavioral sensitization (10 X 15mg/kg) could produce changes in the expression of gene expression of enzymes involved in cholesterol pathways in specific brain areas, which persist after 21 days of abstinence.
Behavioral sensitization
Cocaine reduces the expression of genes encoding the proteins involved in cholesterol homeostasis in the prefrontal cortex
Fig.2: Behavioral sensitization after repeated injections of cocaine.
Fig.1: Cholesterol synthesis pathway in the brain
References:
(1)Chauvet et al Statins Reduce the Risks of Relapse to Addiction in Rats. Neuropsychopharmacology. 41(6):
(2)Lehrmann et al.2006.Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PloS one 1:e114.
Methods
Twenty-four male Sprague-Dawley rats were subjected to a locomotor sensitization protocol over a period of ten sessions
Saline (n=12)
Abstinence (21 days)
Decapitation
Measure of locomotor activity
qPCR Analysis
1 inj /day (10days)
Cocaine (15mg/kg) (n=12)
 Fig.3: Increase in the distance traveled over one hour upon repeated exposure to cocaine.
On each experimental day, animals were treated with either 15 mg/kg intraperitoneal (ip) cocaine or saline (0.9%).
Immediately after the injections, locomotion activity was assessed for an hour in locomotor activity cages (50cm x 50cm x 45cm);
After a period of 21 days of withdrawal, rats were sacrificed, brain samples were obtained using dissection for further neurochemistry and gene expression procedures.
Gene expression levels were analyzed using qPCR.
Statistical significance was ascertained with ANOVA analysis followed by t-tests.
Fig.4 : Gene expression levels in the prefrontal cortex, *p<0.05 and **p<0.01 compared to cocaine.
Repetated injections of cocaine reduce the gene expression levels of Apo E (Apolopoprotein E) and ABCA1( ATP binding protein A type 1) involved in cholesterol trafficking in the brain.
Repeated injections of cocaine reduce the gene expression levels of FDFT1 and LXR beta respectively involved in cholesterol synthesis and regulation in the brain.
CONCLUSION
This study shows a decrease in the expression of Apo E, ABCA1 ,FDFT1 and LXR beta in the prefrontal cortex, these genes are respectively involved in the cholesterol synthesis and trafficking.
These results show that repeated cocaine administrations might modulate the cholesterol trafficking in the brain.
Acknowlegements: Societe des neurosciences francaises, CNRS-L