Large-scale neurochemical metabolomics analysis identifies multiple compounds associated with methamphetamine exposure

Abstract

Methamphetamine (MA) is an illegal stimulant drug of abuse with serious negative health consequences. The neurochemical effects of MA have been partially characterized, with a traditional focus on classical neurotransmitter systems. However, these directions have not yet led to novel drug treatments for MA abuse or toxicity. As an alternative approach, we describe here the first application of metabolomics to investigate the neurochemical consequences of MA exposure in the rodent brain. We examined single exposures at 3 mg/kg and repeated exposures at 3 mg/kg over 5 days in eight common inbred mouse strains. Brain tissue samples were assayed using high-throughput gas and liquid chromatography mass spectrometry, yielding quantitative data on >300 unique metabolites. Association testing and false discovery rate control yielded several metabolome-wide significant associations with acute MA exposure, including compounds such as lactate (p = 4.4 × 10−5, q = 0.013), tryptophan (p = 7.0 × 10−4, q = 0.035) and 2-hydroxyglutarate (p = 1.1 × 10−4, q = 0.022). Secondary analyses of MA-induced increase in locomotor activity showed associations with energy metabolites such as succinate (p = 3.8 × 10−7). Associations specific to repeated (5 day) MA exposure included phosphocholine (p = 4.0 × 10−4, q = 0.087) and ergothioneine (p = 3.0 × 10−4, q = 0.087). Our data appear to confirm and extend existing models of MA action in the brain, whereby an initial increase in energy metabolism, coupled with an increase in behavioral locomotion, gives way to disruption of mitochondria and phospholipid pathways and increased endogenous antioxidant response. Our study demonstrates the power of comprehensive MS-based metabolomics to identify drug-induced changes to brain metabolism and to develop neurochemical models of drug effects.

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

“…Extracts reconstituted in acidic conditions were gradient eluted using water and methanol, both containing 0.1% formic acid, while the basic extracts, which also use water/methanol, contained 6.5 mM ammonium bicarbonate. The MS analysis was alternated between MS and data-dependent MS 2 scans using dynamic exclusion (McClay et al, 2013). …”

“…Ions with counts under two million required more effort to characterize. Fragmentation spectra (MS/MS) were typically generated in data dependent manner, but where necessary, targeted MS/MS was employed, such as in the case of lower level signals (McClay et al, 2013). …”

“…We have previously employed methods to assay the neurochemical metabolic effects of CNS drugs in mice (McClay et al, 2013), measuring over 300 unique compounds using a mix of MS methods, and considered that application of these methods to haloperidol could shed light on biochemical mechanisms. A particular advantage of our strategy is the use of focused beam microwave irradiation (FBMI) to instantaneously and permanently denature all enzymes in the brain at time of sacrifice (de Graaf et al, 2009).…”

Circadian Time Structure of Circulating Plasma Lipid Components in Healthy Indians of Different Age Groups

“…Metabolomics provides a useful tool to analyze metabolite concentrations in physiological and biological states. It is therefore applied to explore biomarkers for disease diagnosis [1][2][3][4] and to assess drug responses and toxicity [5][6][7][8]. Various metabolomic approaches are used, and among these, lipidomics includes the comprehensive analysis of lipid metabolites [9,10].…”

What Have Mass Spectrometry-Based Proteomics and Metabolomics (Not) Taught Us about Psychiatric Disorders?

“…Besides energy metabolism and oxidative stress, alterations in other mitochondrion-related mechanisms and functions have been reported [21,40,41,42]. The majority of these studies have used proteomics approaches, as mitochondrion-specific metabolomics in psychiatry is just beginning to be applied [43]. These studies have revealed alterations in mitochondrial import, transport and structural elements in high versus low trait anxiety mice [21,40], in mitochondrion-orchestrated apoptosis in a mouse model of schizophrenia-like symptoms [41] and in structural mitochondrial components in a methamphetamine-induced behavioral sensitization mouse model of schizophrenia-related symptoms [42].…”