Comparative effects of NO-synthase inhibitor and NMDA antagonist on generation of nitric oxide and release of amino acids and acetylcholine in the rat brain elicited by amphetamine neurotoxicity.
The aim of this study was to clarify the role of nitric oxide (NO) and lipid peroxidation (LPO) processes as well as the contribution of various neurotransmitters in pathophysiological mechanisms of neurotoxicity induced by amphetamine (AMPH). NO level was determined directly in brain tissues using electron paramagnetic resonance spectroscopy technique. The content of the products of lipid peroxidation (LPO) was measured spectrophotometrically as thiobarbituric acid reactive species (TBARS). The output of neurotransmitter amino acids (glutamate, aspartate, and GABA) and acetylcholine (ACH) was monitored in nucleus accumbens (NAc) by push-pull technique with HPLC detection. Repeated, systemic application of AMPH elevated striatal and cortical NO generation and LPO production. Moreover, administration of AMPH led to a marked and long-lasting increase of ACH release. Surprisingly, while glutamate output was not affected, aspartate release was enhanced 30 to 50 min after each AMPH injection. The release rate of GABA was also elevated. The selective NO-synthase inhibitor 7-nitroindazole (7-NI) was highly effective in abating the rise in the neurotransmitter release induced by the AMPH. The NOS inhibitor also abolished the increase of NO generation produced by AMPH, but did not influence the intensity of LPO elicited by the AMPH administration. Pretreatment with the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) completely prevented increase of NO generation and TBARS formation induced by multiple doses of AMPH. Dizocilpine also abolished the effect of the psychostimulant drug on the release of neurotransmitters ACH, glutamate, aspartate, and GABA in the NAc. Our findings suggest a key role of NO in AMPH-induced transmitter release, but not in the formation of LPO products. It appears that AMPH enhances release of ACH and neurotransmitter amino acids through increased NO synthesis and induces neurotoxicity via NO and also by NO-independent LPO.
Bashkatova
V
V
Institute of Pharmacology, Russian Academy of Medical Sciences, 125315, Moscow, Russia. bashkatovav@yahoo.com
Kraus
M M
MM
Vanin
A
A
Hornick
A
A
Prast
H
H
D000109:Acetylcholine / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000596:Amino Acids; D007191:Indazoles; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D000661:Amphetamine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; C080122:7-nitroindazole