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Nicotine abstinence following chronic exposure is associated with impairments in memory and variety of cognitive functions. Daily nicotine (2mg/kg, sc, four times daily) administration for 14days and its abrupt withdrawal significantly impaired avoidance learning in inhibitory avoidance task as indicated by a significant decrease in the step through latency. Animals injected with agmatine (10–40μg/rat, icv) from day 7 to 14 before the first daily dose of nicotine (2mg/kg, sc) showed increased step through latencies during retrieval test. Similarly Intracerebroventricular injection of l-arginine (25–100μg/rat), a biosynthetic precursor of agmatine and arcaine (50μg −100μg/rat), an agmatinase inhibitor, also increased the step through latency during retrieval test in nicotine withdrawn animals. In separate experiments, α2-adrenoceptor agonist, clonidine (0.5–1μg/rat, icv) not only demonstrated significant increase in the step through latency as in nicotine withdrawn rats but also potentiated the pharmacological effect of agmatine. In contrast, pre-treatment of α2-adrenoceptor antagonist, yohimbine (0.5μg/rat, icv) antagonized the memory enhancing effect of agmatine (20μg/rat, icv) in nicotine withdrawn rats. In addition, brain agmatine analysis carried out at 72h time point of nicotine withdrawal showed marked decrease in basal brain agmatine content as compared to control. Overall, the data indicate that agmatine attenuates nicotine withdrawal induced memory impairment through modulation of α2adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of cognitive deficits following nicotine withdrawal.Nicotine withdrawal impaired the avoidance response in rats.Agmatine treatment during dependence ameliorated the memory impairment in nicotine withdrawn animals.Agmatinergic agents increased the step through latency in withdrawn rats.Clonidine synergized the effect of agmatine on avoidance response following nicotine withdrawal.Impaired avoidance in nicotine withdrawn rats was correlated with decreased brain agmatine.