The nitric oxide synthesis inhibitor nitro- L -arginine ( L -NNA) attenuates nicotine abstinence syndrome in the rat

Abstract

Nitric oxide synthesis contributes to opiate tolerance and dependence. Nicotine dependence and abstinence syndrome in the rat appear to involve opiate mechanisms. Therefore, it was postulated that nitric oxide synthase (NOS) activity might be essential for the expression of nicotine abstinence syndrome. Twenty-one rats were rendered dependent by SC infusion of 9 mg/kg per day nicotine tartrate via Alzet osmotic minipump. Rats were pretreated SC with vehicle alone, or with 18 or 30 mg/kg of the NOS inhibitor L-NNA (nitro-L-arginine). Thirty minutes later, rats were challenged by 1 mg/kg of the nicotinic antagonist mecamylamine SC and observed for 30 additional minutes. Rats pretreated with vehicle displayed a total of 68.7+/-8.0 mecamylamine-precipitated abstinence signs (mean+/-SEM), while those receiving 18 or 30 mg/kg L-NNA had 12.7+/-2.0 and 5.1+/-1.7 signs, respectively. All three groups differed significantly from one another according to Dunn's post-hoc procedure. Rats pretreated with L-NNA combined with an excess of the NOS substrate L-arginine had significantly more mecamylamine-precipitated abstinence signs than rats receiving L-NNA combined with D-arginine. Also, D-NNA, which does not selectively bind to NOS, was significantly less effective than L-NNA in preventing mecamylamine-precipitated abstinence syndrome. Additional studies determined the effect of L-NNA on spontaneous nicotine abstinence syndrome. Rats were assessed for abstinence signs at 17 and 20 h after termination of nicotine infusion. They received injections of 9, 18, or 30 mg/kg L-NNA SC or vehicle alone immediately before the 20-h observation; all rats were observed for 30 min. Signs at 20 h (post-injection) as a percentage of signs at 17 h (pre-injection) declined significantly as a function of L-NNA dose. Once again, this effect was attenuated significantly more by co-administration of L-arginine than by D-arginine. The overall pattern of results suggests that nitric oxide synthesis is critical to the expression of nicotine abstinence syndrome.

Rodent Models of Nicotine Withdrawal Syndrome

“…In contrast, genetic deletion of the β4 subunit eliminated somatically expressed nicotine withdrawal behaviors in the mouse (Salas et al 2004). Centrally administered hexamethonium, a noncompetitive nicotinic receptor antagonist with relative specificity for α3β4 receptors, precipitated somatically expressed nicotine withdrawal signs with enormous potency (Malin et al 1997), particularly as compared with DHβE (Malin et al 1998b). One speculative possibility is that α4β2 receptors, with their close connection to reinforcement mechanisms, might be responsible for withdrawal-induced changes in those mechanisms, while α3β4 receptors might be involved in the heightened irritability leading to somatically expressed nicotine withdrawal signs.…”

“…Chronic nicotine exposure increases nitric oxide metabolites in multiple brain regions (Pogun et al 2000), and there is persistently increased hypothalamic nitric oxide response to food deprivation following nicotine withdrawal (Mannucci et al 2005). Several inhibitors of nitric oxide synthase prevent mecamylamine-precipitated nicotine withdrawal syndrome and reverse spontaneous withdrawal syndrome, as indicated by somatically expressed behaviors (Adams and Cicero 1998;Malin et al 1998b). Finally, ion channel events are also likely to participate in the expression of nicotine withdrawal syndrome.…”

“…The competitive nicotinic receptor antagonist DHβE has relative specificity for this class of receptor. Peripherally administered DHβE precipitated nicotine withdrawal, as indicated by raised ICSS thresholds, while centrally administered DHβE precipitated nicotine withdrawal, as indicated by somatically expressed behavioral signs (Epping-Jordan et al 1998;Malin et al 1998b). However, knockout mice devoid of β2 subunits still demonstrated somatically expressed nicotine withdrawal behaviors (Besson et al 2006;Salas et al 2004).…”

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice

“…It is considered to play an important role in the neurobiology of addiction (Uzbay and Oglesby 2001). For instance, Malin et al (1998) reported that Nnitro-L-arginine (L-NNA), a NOS inhibitory agent, suppressed the severity of all signs of nicotine abstinence; and, this suppressive effect of L-NNA was reversed by Larginine, a NO precursor, suggesting an effect specific to NOS. Also, previous studies indicated that preventing NO formation by several NOS inhibitors could reverse both the acute locomotor activity enhancing effect of psychostimulant agents (Przegalinski and Filip 1997;Çelik et al 1999) and development of locomotor sensitization (Pudiak and Bozarth 1993;Ohno and Watanabe 1995).…”

eNOS and XRCC4 VNTR variants contribute to formation of nicotine dependence and/or schizophrenia

“…Some studies reported that the high concentration of NO in cigarette smoke interferes with the action of enzyme NOS or lowers the level of NOS (5). In rats, NOS inhibitors can alleviate symptoms of the nicotine abstinence syndrome, and co-administration of L-arginine is likely to diminish the attenuating effect of the the NOS inhibitor (6). NOS has three distinct isoforms; neuronal (nNOS/NOS1), inducible (iNOS/NOS2) and endothelial (eNOS/NOS3) (7).…”