Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity

Abstract

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.

Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats

“…Probes for reverse microdialysis were constructed as previously described (Halpin et al, 2014). Briefly, probes were made of PE 20 tubing (Becton Dickinson), silica tubing (OD, 150 μm; Polymicro Technologies), 26 ga stainless steel hypodermic tubing (Small parts), Hollow Fiber Microdialysis Membrane ( active membrane, 1.7 mm; 13,000 molecular cutoff; 216 μm outer diameter; Spectrum Laboratories), 2 ton waterproof epoxy and tygon microbore tubing.…”

“…Surgeries for the probe placement were performed a day before the microdialysis experiment. The microdialysis procedure on next day of probe placement has been shown to provide stable baseline glutamate concentration (Halpin et al, 2014 ). The probes were stereotaxically placed into the NAc (AP+1.8, ML+1.5, DV-6.5/-7mm).…”

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

“…MA also causes alterations in brain structure including gray matter loss, neuronal damage and microgliosis in various regions of the brain [8–10]. These changes in the brain have been attributed to oxidative stress [11], alteration in blood-brain barrier (BBB) integrity [12], mitochondrial dysfunction [13] and increased excitotoxicity [14]. Recently, the data from our laboratory have also reported increase in proinflammatory cytokines and involvement of cytochrome P450 in MA-mediated oxidative stress as other possible mechanisms for MA-mediated neurotoxicity.…”

Effect of the environmental enrichment on the severity of psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats

“…Recent findings have shown that chronic METH use alters synaptic plasticity in the brain, which may contribute to its adverse effects [35], include dependence, withdrawal syndrome and drug craving [9,17,34]. The METH use causes neurotoxicity in multiple neurotransmitter systems [13,18,41]. METH-induced alterations in dopamine levels in mesolimbic, nigrostriatal systems and prefrontal cortex involve in craving and rewarding effects of drug [16,28].…”