A low dose of nicotine is sufficient to produce nicotine withdrawal in mice

Abstract

The objective of our study was to investigate whether the chronic administration of a low dose of nicotine can be followed by a withdrawal syndrome at cessation of nicotine delivery. Previous studies showed various results, depending in the doses of nicotine, species, ways of administration and behavioural paradigms, but all emphasized a withdrawal effect on some or all of the following spontaneous behaviours: grooming, rearing, body shake or tremor, body scratching, abdominal constriction, jumping. However, it is not clear which behaviour is exactly altered, as a global behavioural index is most frequently used. This is not clear either if anxiety modulates the behavioral expression of withdrawal or which factors contribute to its locomotors effect, if any. To distant-angle these processes, we scored each of these behaviours individually before nicotine exposure, during continuous nicotine delivery and at cessation of nicotine delivery after precipitated withdrawal by mecamylamine injection. We also measured locomotor activity and anxiety levels in the same animals. We used a low dose of nicotine (2.4 mg/kg/day as free base) that has been previously shown to produce nicotinic receptors up-regulation, both in the brain and in blood cells. With such a low dose, nicotine withdrawal didn't affect locomotion nor anxiety levels but increased the number of rearing, jumping, and marginally, body-scratching. Other behaviours, classically considered to contribute to withdrawal syndrome, were unaffected, e.g., grooming, body or forelimb shakes. Our results show that anxiety may be dissociated from the behavioural withdrawal syndrome. Also, the severity of the syndrome produced by nicotine withdrawal is qualitatively and quantitatively different from the one induced by other drugs of abuse and also by the one produced by nicotine at higher doses.

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“…Regarding possible NTX-induced alterations involving overall locomotion and jumping activity, no conclusions can be drawn because our observation chambers were unsuited for a reliable evaluation of these behaviors, which were not taken into account in our study. Moreover, more accurate information regarding the effect of NTX on rearing (and, possibly, information on other anxiety-sensitive related behaviors) could have probably been obtained by additionally subjecting the rats to an open field test [47], but this was not performed in our study.…”

“…Indeed, the latter condition is commonly associated with behaviors that, besides ptosis, also include (among others) increased rearing and distinct occurrence of teeth chatters and wet dog shakes [48][49][50][51]. A possible explanation for these differences is that the specific set of behavioral manifestations involved in a withdrawal syndrome may vary qualitatively and/or quantitatively not only among species (or strains) but also within the same species (and strain) depending on the nature and intensity of the withdrawal and the related state of dependence (e.g., withdrawal from exogenous opioids versus withdrawal from endogenous opioids; the specific type of opioid causing addiction; withdrawal precipitated by antagonist administration versus withdrawal precipitated by abrupt discontinuation of the drug of abuse) [19,47,48,52].…”