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

Nitric oxide synthesis contributes to opiate tolerance and dependence, Nico tine 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 syndr ome. 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 w ith 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 mecamylami ne-precipitated abstinence signs (mean +/- SEM), while those receiving IS o r 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 po st-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 effec tive 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 observa tion; 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 f unction of L-NNA dose. Once again, this effect was attenuated significantly more by co-administration of L-arginine than by D-arginine. The overall pa ttern of results suggests that nitric oxide synthesis is critical to the ex pression of nicotine abstinence syndrome.