Expression and Activity of Nitric Oxide Synthase Isoforms in Methamphetamine-Induced Striatal Dopamine Toxicity

Abstract

Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH: METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline: METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury.

A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity

“…METH and saline injections were conducted as previously described [11]. Briefly, on the treatment day (PND60), rats (4–8 per treatment group) were individually housed in plastic tub cages (Instech Laboratories Inc.).…”

“…DAT immunohistochemistry was performed to evaluate METH-induced DA depletions and was conducted as previously described [11]. Briefly, sections underwent heat-mediated antigen retrieval for 20 min.…”

“…Images were analyzed as previously described [11] and the analysis was conducted by an experimenter blinded to treatment conditions. Briefly, images were digitized and densitometric analysis was performed using the NIH ImageJ software (http://imagej.nih.gov/ij/), yielding background-subtracted, average gray values in striatum.…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…GLP-1: glucagon-like peptide; IRS: insulin receptor substrate; P13K: phosphoinositide 3-kinase; PIP3: phosphatidylinositol 3,4,5-triphosphate; AMPK:5' adenosine monophosphate activated protein kinase; RacI; GTPase; AKT: protein kinase: pro-viral insertion site for moloney leukaemia virus; Enos: endotheliaintric oxide synthase; SirtuinI; NAD-dependent deacetylase silent information regulator; PGC-1 alpha: peroxisome proliferator activated receptor gamma-coativator I apha;ERR alpha: estrogen related receptor alpha; PPAR alpha: peroxisome proliferator activated Ceriello et al, 2004;Hink et al, 2001;O'Sullivan et al, 2014;Cerqueira et al, 2011). While metformin upregulated endothelial nitric oxide synthase (eNOS) mRNA (Kim et al, 2007), methamphetamine had no effect on eNOS mRNA (Friend et al, 2013) which may be at the basis of methamphetamine-induced neurotoxicity. There is deregulation of ceramide production in mitochondrial dysfunction (Novgorodov and Gudz, 2011) and inhibition of sphingomyelinases represent a novel action of nitric oxide (Barsacchi et al, 2007) which might be relevant in anti-apoptosis (Stafstrom, 2003), insulin resistance (Hansen et al,…”

The effects of short term stress on the central and peripheral nitrergic system

“…Many studies have focused on the augmented striatal NO-sGC-cGMP signalling following dopamine depletion, the hallmark feature in the pathogenesis of Parkinson's disease (West and Tseng, 2011;Friend et al, 2013;Schwenkgrub et al, 2013). However, the effect of stress on striatal nitrergic activity is not yet well characterised.…”