Nicotine modulates nitric oxide in rat brain
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 (NO−2+NO−3) 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 NO−2+NO−3 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 NO−2+NO−3 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 NO−2+NO−3 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).
References (60)
- et al.
Cat carotid body chemosensory responses to non-hypoxic stimuli are inhibited by sodium nitroprusside in situ and in vitro
Brain Res.
(1997) - et al.
Flunarizine, an anti-migraine agent, impairs nitroxidergic nerve function in cerebral arteries
Eur. J. Pharmacol.
(1997) - et al.
Nicotine increases intracellular calcium in rat hippocampal neurons via voltage-gated calcium channels
Neurosci. Lett.
(1995) Transmitter-induced calcium signalling in cultured neurons of the insect brain
J. Neurosci. Methods
(1996)- et al.
Possible involvement of nitric oxide in long-term potentiation
Eur. J. Pharmacol.
(1991) - et al.
NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the l-arginine-nitric oxide pathway
Neurosci. Lett.
(1991) - et al.
Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids
Anal. Biochem.
(1982) - et al.
Effects of chronic nicotine ingestion on pressor response to N-omega-nitro-l-arginine methyl ester and ex vivo concentration and relaxation response of aorta to l-arginine
Pharmacol. Res.
(1997) - et al.
Chronic nicotine treatment counteracts nigral cell loss induced by a partial mezodiensefelic hemitransection an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat
Neuroscience
(1993) - et al.
Nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via alpha7-neuronal receptors and neuronal CNS receptors
Brain. Res.
(1997)
Nicotine interacts with sex in affecting rat choice between ‘look-out’ and ‘navigational’ strategies in the Morris water maze place learning task
Brain. Res. Bull.
Inhibition of neuronal NO synthase potentiates the dimethylphenylpiperazinium-evoked carrier-mediated release of norepinephrine from rat hippocampal slices
Neurosci. Lett.
Effect of NO production on the redox modulatory site of the NMDA receptor-channel complex
Neuron
Nicotine-dizolcipine interactions and working and reference memory performance of rats in the radial-arm maze
Pharmacol. Biochem. Behav.
Nitric oxide induces neurotransmitter release from hippocampal slices
Eur. J. Pharmacol.
Nitric oxide stimulates Ca (2+)-independent synaptic vesicle release
Neuron
NO inhibits [3H]dopamine uptake
Brain. Res.
Neurobehavioral mechanisms of nicotine action: role in the initiation and maintenance of tobacco dependence
J. Subst. Abuse Treat.
Nicotine-evoked NO release in the rat hippocampal slice
Neurosci. Lett.
Effect of Ca2+/calmodulin-dependent protein kinase II inhibitors on the neurogenic cerebroarterial relaxation
Eur. J. Pharmacol.
Effect of stimulation of nicotinic cholinergic receptors on cortical cerebral blood flow and changes in the effect during aging in anesthetized rats
Neurosci. Lett.
Analysis of the vasodilator nerve function by nicotine in isolated dog-skin artery
Eur. J. Pharmacol.
Effect of long-term passive smoking on erectile function and penile NO synthase in the rat
J. Urol.
Inhibition of NO synthase disrupts inhibitory gating in rat hippocampus
J. Pharmacol. Exp. Ther.
The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity
Br. J. Pharmacol.
Nitrate determination in biological fluids by an enzymatic one-step assay with nitrate reductase
Clin. Chem.
Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures
Proc. Natl. Acad. Sci. USA
Involvement of NO in nicotinic receptor-mediated myopathy
J. Pharmacol. Exp. Ther.
Cited by (43)
Better antidepressant efficacy of mecamylamine in combination with L-NAME than with L-arginine
2020, Behavioural Brain ResearchTransmitters and Receptors in Nicotine Withdrawal Syndrome
2017, Negative Affective States and Cognitive Impairments in Nicotine DependenceStriatal NOS1 has dimorphic expression and activity under stress and nicotine sensitization
2015, European NeuropsychopharmacologyEffects of chronic nicotine administration on body weight, food intake and nitric oxide concentration in female and male rats
2014, PathophysiologyCitation Excerpt :The present study also revealed significant increase in serum NO concentrations in all nicotine treated groups compared to control in males only but not in females. Acute or chronically administered nicotine has been demonstrated to increase NO formation in nervous system as well as in systemic organs [9,11]. Studies have reported that NO is important for synaptic plasticity and long-term potentiation (LTP) as well various cognitive and non-cognitive effects [8].