Acute Tolerance To Nicotine Research Articles

Rapid nicotine tolerance and cross-tolerance to varenicline in rhesus monkeys: Drug discrimination.

Acute tolerance to effects of nicotine plays an important role in nicotine dependence, but the mechanism underlying these effects is unclear. Drug discrimination was used in the current study to examine the impact of nicotine pretreatment on sensitivity to the discriminative stimulus effects of nicotine and the FDA-approved smoking cessation pharmacotherapy varenicline. Rhesus monkeys (n = 4) discriminated 0.032 mg/kg nicotine base iv from saline under an FR5 schedule of stimulus-shock termination. Both nicotine and varenicline increased drug-appropriate responding; ED50 values (95% confidence limits) were 0.0087 [0.0025, 0.030] and 0.028 [0.0096, 0.082] mg/kg, respectively. Additional pretreatment injections of the training dose of nicotine (0.032 mg/kg, iv) produced tolerance to its discriminative stimulus effects and the magnitude of this effect was related to the number of pretreatment injections administered. Two pretreatment injections of the training dose of nicotine (0.032 mg/kg, iv) produced a 5.4-fold rightward shift in the nicotine dose-response function and a sevenfold rightward shift in the varenicline dose-response function. The duration of tolerance under these conditions was less than 60 min. These results demonstrate that tolerance to the discriminative stimulus effects of nicotine can be produced by acute nicotine exposure. Acute cross-tolerance from nicotine to varenicline is consistent with similar actions at nAChRs, and suggests that conditions resulting in acute nicotine tolerance could impact sensitivity to other nAChR agonists. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System

Rapid tolerance develops to many of nicotine's behavioral and autonomic effects. A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naïve, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption.

Acute behavioral tolerance to nicotine in the conditioned taste aversion paradigm

AbstractAcute behavioral tolerance to nicotine is a well‐established phenomenon in animals, although previous drug discrimination studies have suggested that subpopulations of rats may exist that fail to exhibit acute tolerance to nicotine. The present study sought to determine whether these findings might extend to the conditioned taste aversion (CTA) paradigm. In experiment 1, rats were administered 0.8 mg/kg s.c. nicotine or vehicle before a pairing session with saccharin, and then administered either 0.4 mg/kg nicotine or vehicle immediately afterward. Rats treated with vehicle pre‐session and then nicotine post‐session developed a significant CTA to nicotine, whereas rats treated with 0.8 mg/kg nicotine s.c. pre‐session failed to develop a CTA to nicotine. In experiment 2, rats were identified as exhibiting or failing to exhibit acute tolerance to nicotine in a drug discrimination paradigm. Rats that produced acute nicotine tolerance failed to develop a CTA after 24 h, but did so after 48 h, while rats that did not produce nicotine tolerance exhibited CTA after 24 h, but not after 48 h. These findings indicate that acute behavioral tolerance to nicotine extends to its aversion effects. Drug Dev Res 68:522–528, 2007. © 2008 Wiley‐Liss, Inc.

Acute tolerance to the cardiovascular effects of nicotine

Acute tolerance to cardiovascular effects of nicotine was examined by presenting to male smokers a single administration of each of three different doses of nicotine (0.5, 1.0, 2.0 mg) or a placebo (0 mg) in a brief series of nasal spray boluses to mimic nicotine intake via smoking. Each dose was presented on a separate occasion. Changes in heart rate, systolic and diastolic blood pressure, finger pulse amplitude (peripheral vasoconstriction) and, in a subsample, plasma nicotine concentration were assessed during and after dose administration. Acute tolerance to nicotine was determined by comparing responses at ascending plasma nicotine concentrations during dose administration with the responses at comparable descending plasma concentrations following administration. For each nicotine dose, there was substantial acute tolerance to blood pressure, but less tolerance to heart rate (except for 0.5 mg), and little tolerance to pulse amplitude responses. These findings indicate that cardiovascular adaptation to nicotine during cigarette smoking may be rapid but variable in magnitude depending on the response being measured.

Non-smokers show acute tolerance to subcutaneous nicotine

Plasma nicotine concentrations following subcutaneous (SC) injection were measured in six subjects who included three life-long nonsmokers. On average, a peak plasma level of 8.5 ng/ml (SD = 3.1) was reached 15 min after the mean dose of 13.25 micrograms/kg nicotine base. Subjective effects were reported by five subjects. The peak heart rate response (mean boost 11 beats per min at 10 min) preceded and was already declining by the time plasma nicotine concentrations peaked. Hysteresis plots showed clear evidence of acute nicotine tolerance in subjects who had never smoked, indicating that acute tolerance is not an acquired phenomenon. The acquisition by smokers of chronic tolerance to nicotine has not yet been systematically demonstrated. Reliable dose-response studies in smokers and nonsmokers are needed, and use of the SC route for this purpose is discussed.

Loss of acute nicotine tolerance and severity of cigarette withdrawal.

Twenty-one smokers underwent 24-h abstinence from cigarettes. Both prior to, and after, the abstinence period cardiovascular and subjective effects of smoking a cigarette were measured. Withdrawal symptoms found during abstinence were: irritability, depression, hunger, difficulty concentrating, restlessness and urges to smoke. In addition, the subjects reported feeling physically less well. Withdrawal discomfort was positively correlated with the strength of the subjective effects (e.g. dizziness, nausea) of smoking the post-abstinence cigarette after taking account of estimated nicotine boost from that cigarette. A similar, though only marginally significant association was found between withdrawal severity and heart rate boost from the post-abstinence cigarette. Our results suggest that the severity of withdrawal may be related to loss of acute tolerance to nicotine. It is not clear whether this is due to more rapid nicotine clearance, constitutional differences in sensitivity to nicotine in the absence of acute tolerance, or other factors. There was no evidence to support the view that higher chronic tolerance to nicotine's heart-rate effects was associated with more severe withdrawal. If anything, the reverse appeared to be the case.