Elsevier

Drug and Alcohol Dependence

Volume 152, 1 July 2015, Pages 147-156
Drug and Alcohol Dependence

Differential effects of cocaine exposure on the abundance of phospholipid species in rat brain and blood

https://doi.org/10.1016/j.drugalcdep.2015.04.009Get rights and content

Highlights

  • Electrospray ionization-mass spectrometry assessed the lipidome of rat brain/blood.

  • Cocaine conditioning induced brain region-specific changes in the lipidome.

  • Persisting changes were also observed in the blood lipidome following cocaine exposure.

  • Changes in the relative abundance of specific lipids were correlated to the initial locomotor response and the behavioral sensitization to cocaine.

Abstract

Background

Lipid profiles in the blood are altered in human cocaine users, suggesting that cocaine exposure can induce lipid remodeling.

Methods

Lipid changes in the brain tissues of rats sensitized to cocaine were determined through shotgun lipidomics using electrospray ionization-mass spectrometry (ESI-MS). We also performed pairwise principal component analysis (PCA) to assess cocaine-induced changes in blood lipid profiles. Alterations in the abundance of phospholipid species were correlated with behavioral changes in the magnitude of either the initial response to the drug or locomotor sensitization.

Results

Behavioral sensitization altered the relative abundance of several phospholipid species in the hippocampus and cerebellum, measured one week following the final exposure to cocaine. In contrast, relatively few effects on phospholipids in either the dorsal or the ventral striatum were observed. PCA analysis demonstrated that cocaine altered the relative abundance of several glycerophospholipid species as compared to saline-injected controls in blood. Subsequent MS/MS analysis identified some of these lipids as phosphatidylethanolamines, phosphatidylserines and phosphatidylcholines. The relative abundance of some of these phospholipid species were well-correlated (R2 of 0.7 or higher) with either the initial response to cocaine or locomotor sensitization.

Conclusion

Taken together, these data demonstrate that a cocaine-induced sensitization assay results in the remodeling of specific phospholipids in rat brain tissue in a region-specific manner and also alters the intensities of certain types of phospholipid species in rat blood. These results further suggest that such changes may serve as biomarkers to assess the neuroadaptations occurring following repeated exposure to cocaine.

Introduction

The Substance Abuse and Mental Health Services Administration (2014) estimates 1.1 million people over the age 12 used cocaine in 2013, and that over 850,000 of these individuals met the Diagnostic and Statistical Manual of Mental Disorders criteria for dependence or abuse of cocaine (2014). Cocaine is responsible for more emergency room visits in the United States than any other illegal drug (http://www.oas.samhsa.gov/2k10/DAWN034/EDHighlights.htm) and there are currently no FDA-approved treatments for cocaine substance use disorder.

Although an extensive effort has been made to characterize and evaluate various mechanisms involved in cocaine-induced alterations of brain function, few studies have assessed the effect of cocaine use on brain lipid metabolism in humans (Ross et al., 1996, Ross et al., 2002), and none have identified the specific lipid species in the brain that are altered following drug exposure. It is known that a history of cocaine use alters blood levels of cholesterol (Buydens-Branchey and Branchey, 2003) and fatty acids (Buydens-Branchey et al., 2003). These findings are consistent with the premise that altered cell membrane remodeling activity is occurring in individuals exposed to cocaine. Given that lipid remodeling would be inherent to the changes in neuronal morphology and synaptic plasticity thought to underlie the neuroadaptations associated with substance use disorder, it is somewhat surprising that so few studies have assessed changes in lipid profiles after cocaine exposure, and that none have been described using animal models of addiction.

In addition to data demonstrating that cocaine can induce changes in the lipid profiles, one study reported a link between the brain dopaminergic and phospholipid catabolic systems (Ross and Turenne, 2002), suggesting that changes in phospholipid profiles in cocaine-treated subjects may mirror changes in dopaminergic signaling. Additionally, changes in fatty acid levels in the blood have been correlated with relapse (Buydens-Branchey et al., 2003), supporting the hypothesis that blood lipids can serve as biomarkers of cocaine-induced neurological dysfunction. The hypothesis that blood lipids can be related to neurological dysfunction and behavior is further bolstered by a recent finding in Alzheimer's patients demonstrating that select serum glycerophospholipids predicted cognitive impairment over 2–3 years with 90% accuracy (Mapstone et al., 2014). Finally, another study has demonstrated that cocaine-induced hepatotoxicity in mice resulted in concurrent changes in serum lipids (Shi et al., 2012).

While the aforementioned studies support the rationale for investigating cocaine-induced alterations in lipidomic profiles, a practical consideration impeding such studies is that thousands of lipids exist in biological tissues, making it difficult to identify specific changes in select lipid species. Furthermore, until recently, the methods used to isolate and characterize such lipids were somewhat laborious and time consuming. One productive approach has been to use matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) imaging in rat brain tissue sections to identify lipid species (Jackson et al., 2005a, Jackson et al., 2005b). Subsequent studies have described discrete localization of lipids throughout both the rat (Delvolve et al., 2011, Mikawa et al., 2009) and the human brain (Veloso et al., 2011a, Veloso et al., 2011b). These observations suggest that heterogeneity in the relative abundance of lipid species both within and between brain regions may have functional relevance.

We performed shotgun lipidomics using electrospray ionization–mass spectrometry (ESI–MS) to assess the persisting effects of cocaine on the relative abundance of phospholipid species in both brain tissues and blood of rats repeatedly exposed to the drug. The resulting data significantly contribute to our understanding of how cocaine alters lipid remodeling within specific brain regions and further suggests that changes in the blood lipidome may be useful as prognostic and/or diagnostic indicators of behavioral responses to cocaine and of drug exposure history.

Section snippets

Behavior assays

Cocaine conditioning and the induction of locomotor sensitization: Male Sprague-Dawley rats, 8 weeks of age (Harlan, Indianapolis, IN, USA) were housed in pairs in clear plastic cages and maintained on a 12 h light/dark cycle (0700/1900 h). Food and water was available ad libitum except during the behavioral sessions. Animals were allowed to adapt to the lab conditions for a week before behavioral testing began. Behavioral sessions were conducted daily between 0900 and 1600 h.

The apparatus and

Induction of locomotor sensitization (LMS)

We assessed locomotor movement as an indicator of behavioral sensitization to cocaine in rats by comparing locomotion after the initial “Activity” administration of the drug (10 mg/kg, i.p.) on day 4 to the movement observed after the “Challenge” administration on day 15 (Fig. 1A). Following habituation to the open field environment during the first 30 min, cocaine caused an increase in total horizontal movement in rats compared to those treated with saline (Fig. 1B). One week following

Discussion

This study demonstrates that undergoing a cocaine conditioning protocol that induces locomotor sensitization results in region-specific changes in select lipid species in the rat brain. The repeated cocaine conditioning protocol also changed the lipidomic profile of the blood. Importantly, the changes in the lipidome of these tissues were present one week following the final administration of cocaine, suggesting that these effects are not merely acute responses following drug exposure. Rather,

Role of funding source

This work was supported by the National Institutes of Health NIBIB EB008153 and EB011610 to BSC and NIDA DA16302 to JJW; a Sloan Graduate Minority Fellowship and an Interdisciplinary Toxicology Program Graduate Stipend to NES and by an International Visiting Scholar Award from Cumhuriyet University to SHB. These organizations had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for

Contributors

The authors of this paper designed the study (BSC & JJW), collected and oversaw collection of the data (NES, PM, JKC), completed the statistical analyses (SP, SS, POT), and wrote the manuscript (BSC & JJW).

Conflict of interest

The authors of this manuscript declare they have no conflicts of interest to report.

Acknowledgements

This research was funded in part by the NIH NIBIB (EB08153 and EB0116100) to BSC, by NIH NIDA (DA016302) to JJW, by a Sloane Graduate Minority Fellowship and an Interdisciplinary Toxicology Program Graduate Stipend to NES, and by an International Visiting Scholar Award from Cumhuriyet University to SHB.

References (36)

  • B.M. Ross et al.

    Chronic cocaine administration reduces phospholipase A(2) activity in rat brain striatum

    Prostaglandins Leukot. Essent. Fatty Acids

    (2002)
  • C.M. Seymour et al.

    Simultaneous expression of cocaine-induced behavioral sensitization and conditioned place preference in individual rats

    Brain Res.

    (2008)
  • X. Shi et al.

    Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity

    J. Lipid Res.

    (2012)
  • R.S. Snider et al.

    Cerebellar pathways to ventral midbrain and nigra

    Exp. Neurol.

    (1976)
  • L. Zhang et al.

    The effect of inhibition of Ca2+-independent phospholipase A2 on chemotherapeutic-induced death and phospholipid profiles in renal cells

    Biochem. Pharmacol.

    (2005)
  • X. Zhou et al.

    Improved procedures for the determination of lipid phosphorus by malachite green

    J. Lipid Res.

    (1992)
  • S. Akiba et al.

    Cellular function of calcium-independent phospholipase A2

    Biol. Pharm. Bull.

    (2004)
  • E.G. Bligh et al.

    A rapid method of total lipid extraction and purification

    Can. J. Biochem. Physiol.

    (1959)
  • Cited by (13)

    • Citrate shuttling in astrocytes is required for processing cocaine-induced neuron-derived excess peroxidated fatty acids

      2022, iScience
      Citation Excerpt :

      Low cholesterol and FA levels in the blood of people addicted to cocaine are associated with relapse (Buydens-Branchey and Branchey 2003; Buydens-Branchey et al., 2003a; Buydens-Branchey et al., 2003b). In fact, extensive cocaine-induced changes in brain lipidomics in rodents contribute to addiction, supporting these findings in humans (Cummings et al., 2015; Bodzon-Kulakowska et al., 2017; Lin et al., 2017a, 2017b). A recent systematic review discussed studies addressing proteomic and metabolic changes associated with neurocognitive function in people with HIV (PWH) and reported alterations in several proteins and metabolites related to neurochemical pathways (Williams et al., 2021).

    • Localization and expression of CTP: Phosphocholine cytidylyltransferase in rat brain following cocaine exposure

      2019, Journal of Chemical Neuroanatomy
      Citation Excerpt :

      Furthermore, Ross et al., reported reduced CCT activity in postmortem brain tissue obtained from cocaine users (Ross et al., 2002), identifying a potential rationale for the efficacy of CDP-choline treatment. Prior work from our laboratory demonstrated the persisting effects of cocaine conditioning on brain phospholipid alterations where the majority of changes occurred in PC species, region-specifically in the hippocampus and the cerebellum (Cummings et al., 2015a). The hippocampus is characterized by its role in learning and memory and is directly involved in the reinstatement of drug-seeking behavior.

    • Cocaine modifies brain lipidome in mice

      2017, Molecular and Cellular Neuroscience
      Citation Excerpt :

      Changes in fatty acid levels in the blood are correlated with relapse, suggesting that blood lipids can serve as biomarkers of cocaine-induced neurological dysfunction (Buydens-Branchey et al., 2003). A recent study focusing on defined lipid species showed cocaine can modify some phospholipids, such as phosphatidylethanolamines (PE), phosphatidylserines (PS) and phosphatidylcholines (PC), in the hippocampus and cerebellum of cocaine-treated rats (Cummings et al., 2015). However, there are very few studies conducted to explore the global changes of lipidome in addiction model.

    View all citing articles on Scopus

    Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org/10.1016/j.drugalcdep.2015.04.009.

    1

    Present address: Gerstner Sloan-Kettering School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 441, New York, NY 10065, USA.

    2

    Present address: 660 W. Barry Apt 27, Chicago, IL 60657, USA.

    View full text