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Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity

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Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity Neuropsychopharmacology (2014) 39, 1031–1038 & 2014 American College of Neuropsychopharmacology. All rights reserved 0893-133X/14 www.neuropsychopharmacology.org Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity 1 1 ,1 Laura E Halpin , Nicole A Northrop and Bryan K Yamamoto* 1 Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA Ammonia has been identified to have a significant role in the long-term damage to dopamine and serotonin terminals produced by methamphetamine (METH), but how ammonia contributes to this damage is unknown. Experiments were conducted to identify whether increases in brain ammonia affect METH-induced increases in glutamate and subsequent excitotoxicity. Increases in striatal glutamate were measured using in vivo microdialysis. To examine the role of ammonia in mediating changes in extracellular glutamate after METH exposure, lactulose was used to decrease plasma and brain ammonia. Lactulose is a non-absorbable disaccharide, which alters the intestinal lumen through multiple mechanisms that lead to the increased peripheral excretion of ammonia. METH caused a significant increase in extracellular glutamate that was prevented by lactulose. Lactulose had no effect on METH-induced hyperthermia. To determine if ammonia contributed to excitotoxicity, the effect of METH and lactulose treatment on calpain-mediated spectrin proteolysis was measured. METH significantly increased calpain-specific spectrin breakdown products, and this increase was prevented with lactulose treatment. To examine if ammonia-induced increases in extracellular glutamate were mediated by excitatory amino-acid transporters, the reverse dialysis of ammonia, the glutamate transporter inhibitor, DL-threo-b-benzyloxyaspartic acid (TBOA), or the combination of the two directly into the striatum of awake, freely moving rats was conducted. TBOA blocked the increases in extracellular glutamate produced by the reverse dialysis of ammonia. These findings demonstrate that ammonia mediates METH-induced increases in extracellular glutamate through an excitatory amino-acid transporter to cause excitotoxicity. Neuropsychopharmacology (2014) 39, 1031–1038; doi:10.1038/npp.2013.306; published online 20 November 2013 Keywords: methamphetamine; glutamate; excitotoxicity; glutamate transporter; ammonia INTRODUCTION neuronal damage and the mechanisms that mediate the neurotoxic effects of METH remain unknown. Methamphetamine (METH) is an abused psychostimulant METH has been shown to significantly increase extra- that causes persistent damage to dopamine and serotonin cellular glutamate within the striatum (Nash and Yamamoto, terminals in the striatum, prefrontal cortex, and hippocam- 1992), a region known to contain calcium-permeable AMPA pus (Ricaurte et al, 1980; Seiden et al, 1988; Wagner et al, receptors that are located presynaptically on dopamine 1980). The long-term dopamine and serotonin terminal and serotonin terminals (Betarbet and Greenamyre, 1999; damage is associated with numerous cognitive deficits Hernandez et al, 2003; Keefe et al, 1993; Nash and exhibited by METH users and has more recently been Yamamoto, 1992). Blockade of METH-induced increases shown to correlate with the potential for relapse of drug use in glutamate, activation of AMPA or NMDA receptors, or (Clark et al, 2006; Johanson et al, 2006; Rogers et al, 1999; NOS-derived peroxynitrite protect against the mitochon- Simon et al, 2002; Volkow et al, 2001; Wang et al, 2012). drial and neuronal damage produced by the drug and Numerous convergent mechanisms have been identified provide evidence for activation of calcium-dependent to have a role in the persistent dopamine and serotonin proteases such as calpain in mediating the long-term terminal damage produced by METH and include metabolic damage to dopamine and serotonin terminals elicited by compromise, oxidative stress, and excitotoxicity (Yamamoto METH (Farfel et al, 1992; Staszewski and Yamamoto, 2006; and Raudensky, 2008). Recently, acute liver damage and Tata and Yamamoto, 2007). Calpain is a calcium-activated increases in ammonia have also been implicated (Halpin protease that is activated in the context of excitotoxicity and Yamamoto, 2012), but how ammonia contributes to this in response to significant increases in intracellular calcium. Calpain causes proteolysis of numerous essential cytoskeletal components including non-erythroid spectrin *Correspondence: Dr BK Yamamoto, Department of Neurosciences, University of Toledo College of Medicine, 3000 Arlington Ave., Toledo, (Gerencser et al, 2009; Goll et al, 2003; Pike et al, 2001; OH 43614, USA, Tel: +1 4193834109, Fax: +1 4193833346, Saggu et al, 2010; Siman et al, 1989). E-mail: [email protected] Although METH increases corticostriatal glutamate Received 30 July 2013; revised 4 October 2013; accepted 23 October release through a polysynaptic, D1-receptor-mediated dis- 2013; accepted article preview online 29 October 2013 inhibition of corticostriatal projections (Mark et al, 2004), Methamphetamine, ammonia and excitotoxicity LE Halpin et al 1032 synaptic glutamate is also regulated by amino-acid trans- ammonia and neurological symptoms of hepatic encephalo- porters (EAAT) that are located primarily on astrocytes and pathy (Al Sibae and McGuire, 2009; Jia and Zhang, 2005; transport extracellular glutamate from the synapse into Nicaise et al, 2008). In lactulose experiments, rats received astrocytes. A potential modulator of extracellular glutamate lactulose (5.3 g/kg) or vehicle via oral gavage every 12 h for 2 and glutamate uptake by astrocytes is ammonia (Chan et al, days before METH treatment until the day before rats were 2000; Gorg et al, 2010; Gorg et al, 2007; Norenberg, 1987). killed (Halpin and Yamamoto, 2012). This drug treatment is This is particularly relevant in the context of the pharma- known to fully block the increases in both plasma and brain cological actions of METH because ammonia has been ammonia concentrations produced by METH. All rats were identified recently as a novel, peripherally derived mediator killed by live decapitation 5 days after the METH or saline of METH neurotoxicity (Halpin and Yamamoto, 2012). treatment. Despite this association, the specific mechanism by which Subcutaneous temperature transponders were implanted ammonia contributes to METH neurotoxicity is unknown, into the rats 2 days before the beginning of each experiment although ammonia at high micromolar to millimolar to allow for remote monitoring of temperature and to concentrations caused by hepatotoxicity is known to reduce stress that would otherwise be produced by rectal contribute to global neuronal damage through excitotoxic, measures. The transponders used were 2.2 Â 14 mm and oxidative, metabolic, and neuroinflammatory processes weighed 120 mg (IPTT-300 transponder, BMDS). (Cauli et al, 2007; Chan et al, 2000; Hawkins et al, 1973; All treatments were carried out in accordance with the Kosenko et al, 1997; Kosenko et al, 2003). National Institute of Health Guide for Care and Use of rats. The objective of the current study is to examine the All treatments are approved by the University of Toledo contribution of peripherally derived ammonia to METH- Institutional Animal Care and Use Committee. induced elevations in extracellular glutamate and excito- toxicity in the striatum. It is hypothesized that ammonia In Vivo Microdialysis increases extracellular striatal glutamate through an altera- tion in glutamate transporter function, the result of which is Intracranial probes were constructed using PE 20 tubing calpain-mediated spectrin proteolysis indicative of calcium- (Becton Dickinson), silica tubing (OD of 150 mm, Polymicro dependent excitotoxicity (Siman et al, 1989). To evaluate Technologies), 26-ga stainless steel hypodermic tubing the role of ammonia, we used the non-absorbable (Small Parts), hollow fiber microdialysis membrane (4 mm disaccharide lactulose, which is a primary treatment for of active membrane, MWCO 13 000, 216 mm, Spectrum hepatic encephalopathy and is used to lower elevated Labs), 2-ton waterproof epoxy and tygon microbore tubing. plasma ammonia resulting from hepatotoxicity (Al Sibae Surgeries were performed the day before drug treatment. and McGuire, 2009; Jia and Zhang, 2005; Nicaise et al, 2008). Rats were anesthetized using xylazine (5 mg/kg) and Subsequent to oral administration, lactulose remains in the ketamine (75 mg/kg) and the probe was stereotaxically gut and increases the fecal excretion of ammonia through lowered into the striatum (AP þ 1.2, ML þ 3.0, DV À 6.5 numerous mechanisms including acidifying the intestinal mm). One day later and after a 1-h equilibration period, þ lumen to trap enterohepatically cycling NH4 , functioning baseline samples were collected every hour for 3 h at a flow as a laxative to increase intestinal motility and decrease rate of 1.5 ml/min. Samples were collected every hour during protein absorption, which is the sole dietary source of METH or saline treatment until 2 h after the last drug ammonia, and through increasing ammonia metabolism by injection. Artificial cerebrospinal fluid (aCSF), ammonia intestinal bacteria (Mortensen, 1992; Panesar and Kumari, (200 mM), the EAAT antagonist DL-threo-b-benzyloxyas- 2011). To examine a mechanism by which peripheral partic acid (TBOA; 500 mM), or the combination of ammonia contributes to increases in glutamate at the ammonia and TBOA were reverse dialyzed into the striatum concentrations
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