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Acute Tolerance to the Discriminative Stimulus Effects of Nicotine in Monkeys

Tolerance to the effects of nicotine, a major psychoactive component of tobacco, contributes to escalation in the frequency and quantity of tobacco use. However, mechanisms of tolerance to the effects of nicotine are not well understood. Here, drug discrimination was used to examine the rapid decrease in sensitivity to nicotine (i.e., acute tolerance), including its underlying receptor pharmacology and its relationship to nicotine pharmacokinetics. Rhesus monkeys (n=6) discriminated 0.032 mg/kg of nicotine base administered i.v. under an FR5 schedule of stimulus‐shock termination. Nicotine dose‐dependently increased drug‐lever responding; the ED50 value (95% confidence limits) of nicotine to produce discriminative stimulus effects was 0.012 (0.0077–0.020) mg/kg. The β2‐selective nicotinic acetylcholine receptor (nAChR) antagonist dihydro‐β‐erythroidine produced a 4.8‐fold rightward shift in the nicotine dose‐response function. Methyllycaconitine, an α7‐selective nAChR antagonist, up to 10 mg/kg did not antagonize the nicotine discriminative stimulus. The duration of the nicotine discriminative stimulus was less than 30 min; however, concentrations of nicotine measured in saliva were maximal (45–65 ng/ml) 10–30 min post‐injection. Pretreatment with nicotine (0.032 mg/kg i.v.) 30 min before re‐determination of sensitivity to the effects of nicotine resulted in a 3‐fold rightward shift in the dose‐response function. Firstly, these data suggest that the i.v. nicotine discriminative stimulus is mediated by β2‐containing, not α7‐containing, nAChRs. Secondly, decreased sensitivity to the discriminative stimulus effects of nicotine when preceded by an additional dose of nicotine 30 min earlier provides evidence of acute tolerance. That the peak concentrations of nicotine in saliva persist beyond the offset of its discriminative stimulus effects is also consistent with acute pharmacodynamic tolerance. Collectively, these results demonstrate that tolerance to the discriminative stimulus effects of nicotine can be produced by acute exposure to nicotine and suggest that the mechanism underlying acute tolerance may be related to rapid desensitization of β2‐containing nAChRs.