Nicotine modulates nitric oxide in rat brain

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Abstract

Nicotine exerts its central actions by regulating cationic fluxes through nicotinic acetylcholine receptors (nAChRs). By this effect, the drug likely also modifies events occurring beyond the nAChR, including the regulation of nitric oxide (NO) synthesis. The present study was undertaken to assess the effects of acute and chronic nicotine administration (0.4 mg/kg, s.c.) on levels of NO2+NO3, stable metabolites of NO, in brain regions of male and female rats. Nicotine increased levels of the metabolites, and therefore presumably of NO, with sex differences in the degree of stimulation, the brain regions affected, and the variance between the effects of acute and chronic administration. Prior inhibition of NO synthase eliminated the effect of nicotine in all regions studied. While nicotine appeared to increase NO indirectly via glutamate receptors in the cortex and hippocampus, this was not true of the corpus striatum, where blocking NMDA-type glutamate receptors with MK-801 had no effect. The findings support the view that NO is likely involved in some of the central effects of nicotine.

Introduction

Nicotine is a drug of abuse, and the use of tobacco causes disease and death. Nonetheless, nicotine also has positive, cognition-enhancing properties (Heishman et al., 1994), which may be a factor that impedes smoking cessation. Nicotinic acetylcholine receptors (nAChRs) are present, both pre- and post-synaptically, in brain regions critical for cognitive function and addiction: cortex, striatum and ventral tegmental area (Levin, 1992). The neurochemical and behavioral effects of nicotine involve interactions of the drug with nAChRs on neurons that use acetylcholine, dopamine, norepinephrine, serotonin, glutamate and GABA as transmitters (Kaiser and Wonnacott, 1999). Although it is well established that activation of nAChRs can lead to entry of Na+ into the cell, evidence also supports the view that activation of some nAChRs leads to enhanced entry of Ca2+ (Rosecrans and Karan, 1993). Increase in intracellular Ca2+, in addition to triggering neurotransmitter release, may influence a variety of neuronal functions, such as regulation of nitric oxide (NO) synthesis, which may affect nicotine dependence and cognitive enhancement.

NO is a gaseous biological messenger molecule in the CNS; and it is enzymatically formed from l-arginine by NO synthase (NOS), a Ca2+-calmodulin requiring enzyme, with citrulline as the co-product. Ca2+ influx causes activation of NOS. It has been proposed that NO mediates the neurotoxic actions of glutamate, to promote long-term potentiation and long-term depression and to modulate neurotransmitter release and uptake (Pogun and Kuhar, 1994).

Previous evidence has linked NO synthesis to the effects of nicotine in the vascular system. In this regard, nicotine induces relaxation in peripheral (Hui et al., 1997; Uchiyama et al., 1997; Zhang et al., 1998) and cerebral arteries (Alcayaga et al., 1997; Okamura et al., 1997; Toda et al., 1997) through a mechanism that involves NO. In canine cerebral artery strips, flunarizine, an antimigraine agent that blocks Ca2+ entry across cell membranes, attenuates nicotine-induced and NO-mediated relaxation (Ayajiki et al., 1997), suggesting that the effects of nicotine involve Ca2+-induced increase in NO production. Intravenous injections of nicotine increase cortical cerebral blood flow in urethane-anaesthetized rats, independent of mean arterial pressure (Uchida et al., 1997). This response is abolished after blocking nAChRs in the brain parenchyma, implying the activation of nAChRs in nicotine-induced cortical vasodilatation.

Interactions between nicotine and NO synthesis have also been observed in skeletal muscle and in the gastrointestinal and reproductive systems. Muscle cell degeneration induced by nicotinic cholinergic agonists has been shown to involve elevated intracellular Ca2+ levels followed by enhanced NO production (El-Dada and Quik, 1997). In the gastrointestinal system, nicotine liberates NO from non-adrenergic, non-cholinergic nerves involved in the relaxation of the sphincter of Oddi, where neurons containing NADPH-diaphorase (NO synthesizing cells) have been demonstrated (Tanobe et al., 1995). In rats chronically exposed to cigarette smoke, penile NOS activity and neuronal NOS content are decreased while erectile responses and endothelial NO synthase levels are not affected (Xie et al., 1997).

There are few studies on the possible mediation of the biobehavioral effects of nicotine by NO. Relevant to these studies is the observation that stable metabolites of NO (NO2+NO3) show sexual dimorphism in rat brain; in cortical regions, females have lower levels than males (Taskiran et al., 1997). In a water maze study, male rats demonstrated that they used navigational rather than visual cues while female rats relied on visual cues for the solution of a place learning problem. However, nicotine-treated females changed their strategy and behaved in the same manner as males (Kanit et al., 1998). In a follow-up study the male-type strategy was positively correlated with NO2+NO3 levels in the cortex (Kanit et al., 2000). In addition, we have recently shown that nicotine-induced enhancement of active avoidance learning in rats is abolished by prior NOS inhibition (Yilmaz et al., 2000). In view of these studies, the observed effect of nicotine on the behavior of female rats may be mediated through increased cortical levels NO.

Table 1 summarizes the similarities or relationships between some effects of nicotine and NO.

The aim of the current study was to see if nicotine modulates brain NO following acute and chronic application. After finding that nicotine does increase brain NO2+NO3 levels, we carried out subsequent studies to delineate the mechanism of action of nicotine-induced NO release.

Section snippets

Animals

Sexually mature male and female Sprague–Dawley rats (3 months, 220–250 g) were obtained from Ege University Animal Care Center. The rats were kept under standard colony conditions (three to four per cage, 20–22°C, 12-h light/dark cycle) with food and water provided ad libitum. The protocol employed was approved by the institutional Ethical Committee.

Drugs

(−)-Nicotine hydrogen tartrate was dissolved in isotonic saline (0.9% NaCl). The pH of the nicotine solution was adjusted to 7 with dilute NaOH;

Time-course of nicotine effect

A multifactorial ANOVA with Sex (male, female) and Time (10, 30, 60, 120 min and control) as the between subjects, and Brain region (cortex, hippocampus, corpus striatum, cerebellum) as the within subjects factors and total NO2+NO3 levels as the dependent variable revealed the following main effects and interactions:

Sex:F(1,52)=49.68, P<0.0001
Time:F(4,52)=44.31, P<0.0001
Brain region:F(3,156)=22.72, P<0.0001
Brain region×Sex:F(3,156)=5,66, P<0.001
Brain region×Time:F(12,156)=9.27, P<0.0001
Brain

Discussion

The present study demonstrates that nicotine, given by acute and/or chronic administration, increases the stable metabolites of NO. This effect is region-specific and shows sexual dimorphism. As nicotine can enhance Ca2+ influx into a cell (Rosecrans and Karan, 1993), the acute effects of nicotine may involve the stimulation of NOS by this mechanism, or by another direct effect on NOS-containing interneurons. Inhibition of neuronal NOS abolishes the effect of nicotine in all regions, suggesting

Acknowledgements

This study was supported by grants SBAG-U/15-1 and 15-3 from The Scientific and Technical Research Council of Turkey (TUBITAK).

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