Effects of continuous nicotine infusion on nicotine self-administration in rats: relationship between continuously infused and self-administered nicotine doses and serum concentrations (original) (raw)
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An analysis of response to nicotine infusion using an automated radiotelemetry system
Psychopharmacology, 1994
Previous studies from our laboratory have demonstrated that chronic nicotine infusion evokes tolerance to nicotine injected IP several hours after withdrawal from chronic infusion. This method may introduce problems related to withdrawal reactions and to stress associated with handling of the animals. The studies reported here measured tolerance to nicotine in mice using an automated radiotelemetry system. DBA/2 mice were infused intravenously with saline for 4 days followed by infusion of a 4 mg/kg per h dose of nicotine for 7 days. After the nicotine treatment, the mice were infused with saline for 7 days. The nicotine was infused continuously or in four 1 mg/kg pulses, two 2 mg/kg pulses or one 4 mg/kg pulse each hour. Home cage activity and body temperature were measured throughout the treatment periods using a radiotelemetry system. Nicotine infusion produced an abrupt decrease in body temperature and activity, but this effect was totally reversed within 12 h in the continuously infused and four infusions/h treatment groups. Mice that received one or two infusions/h also showed a rapid response to nicotine that was reversed as treatment proceeded, but nicotine continued to produce a measurable effect for several days. After nicotine withdrawal, temperature and activity returned to predrug infusion values in all of the groups except those infused once per hour. This group showed depressed activity for a minimum of 3 days after nicotine treatment stopped. Thus, the kinetics of nicotine administration affected the intensity of response during continued treatment as well as activity after cessation of chronic treatment.
PLOS ONE, 2015
Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addictionrelated research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotineinfused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models, including evaluation of more clinically relevant nicotine dosing regimens and other measures of nicotine withdrawal (e.g., anxiety-like behavior, somatic signs), may be useful for understanding the development of the nicotine withdrawal syndrome.
Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice
Pharmacology Biochemistry and Behavior, 1998
The nicotinic compounds (Ϫ)-cytisine, (Ϫ)-lobeline, (Ϯ)-epibatidine, (S)-3methyl-5-(1-methyl-2-pyrrolidinyl)isoaxzole (ABT-418) , (Ϫ)-nicotine, and cocaine were compared in an acute self-administration model using drug-naive mice that could self-administer intravenous infusions contingent on nose poking (fixed ratio 1 with no time out). Although the nose pokes of yoked control mice were unaffected by unit dose, inverted U-shaped unit dose-response curves were seen with cocaine (up to 0.26 mg/kg/infusion), nicotine (up to 0.175 mg/kg/infusion), cytisine (up to 0.125 mg/kg/infusion), and lobeline (up to 1.25 mg/kg/infusion) in mice receiving infusions contingent upon nose poke responses. Epibatidine (up to 1.25 g/kg/infusion) and ABT-418 (up to 0.125 mg/kg/infusion) failed to exhibit inverted U-shaped unit dose-response curves. The present studies demonstrate that cytisine and lobeline, but not ABT-418 or epibatidine, were self-administered by drug-naive mice in a manner similar to cocaine and nicotine. These findings are discussed in terms of potency and selectivity at the ␣ 4  2 nicotinic acetylcholine receptor subunit combination.
Reinforcing Effects of Nicotinic Compounds
Pharmacol Biochem Behav, 1998
The nicotinic compounds (Ϫ)-cytisine, (Ϫ)-lobeline, (Ϯ)-epibatidine, (S)-3methyl-5-(1-methyl-2-pyrrolidinyl)isoaxzole (ABT-418) , (Ϫ)-nicotine, and cocaine were compared in an acute self-administration model using drug-naive mice that could self-administer intravenous infusions contingent on nose poking (fixed ratio 1 with no time out). Although the nose pokes of yoked control mice were unaffected by unit dose, inverted U-shaped unit dose-response curves were seen with cocaine (up to 0.26 mg/kg/infusion), nicotine (up to 0.175 mg/kg/infusion), cytisine (up to 0.125 mg/kg/infusion), and lobeline (up to 1.25 mg/kg/infusion) in mice receiving infusions contingent upon nose poke responses. Epibatidine (up to 1.25 g/kg/infusion) and ABT-418 (up to 0.125 mg/kg/infusion) failed to exhibit inverted U-shaped unit dose-response curves. The present studies demonstrate that cytisine and lobeline, but not ABT-418 or epibatidine, were self-administered by drug-naive mice in a manner similar to cocaine and nicotine. These findings are discussed in terms of potency and selectivity at the ␣ 4  2 nicotinic acetylcholine receptor subunit combination.
A clinical pharmacological study of subcutaneous nicotine
Eur J Clin Pharmacol, 1993
The stable isotope-labeled compound 3',-3'dideuteronicotine (nicotine-da) was used to investigate the disposition kinetics and effects of nicotine administered subcutaneously to 6 smokers. Plasma nicotine-d2 concentrations were measured for 8 h after subcutaneous injection of 4 doses (0.4, 0.8, 1.2, and 2.4 mg). Peak plasma nicotine concentration correlated well with the dose, averaging 2.8 to 14.8 ng/ml, 19 to 25 min after injection of the 0.4 mg and 2.4 mg doses, respectively. The plasma clearance over bioavailability ratio (CL/f) averaged 12 to 13 ml. rain-~. kg 1, similar to the clearance reported previously for intravenously administered nicotine. Thus, bioavailability appears to be approximately 100 %. The heart rate response was more sensitive to the nicotine dose than the blood pressure response. Subjective effects showed large interindividual variability. The results reported herein may be useful in planning future studies. Administration of nicotine by the subcutaneous route appears to be a practical and safe method for studying the human pharmacology of nicotine.
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2015
Cigarette smoking is largely driven by the reinforcing properties of nicotine. Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration procedures in humans and nonhuman primates. The body of literature using nonhuman primate subjects indicates nicotine functions as a positive reinforcer when available for self-administration via IV catheters. However, it can also be difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects acquire the behavior. Although the body of literature using human subjects is limited, the evidence indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarett...
Nicotine addiction and its Pharmacological effects: A
Journal of Applied Pharmaceutical …, 2011
Despite the known health risks of nicotine addiction, numerous people still smoke cigarettes and use other forms of tobacco, and many have difficulty quitting. Nicotine is readily absorbed from tobacco, resulting in an almost immediate response from the ...
Importance of nonpharmacological factors in nicotine self-administration
Physiology & Behavior, 2002
There is mounting evidence that nonpharmacological factors critically modulate the effects of several drugs of abuse both in humans and experimental animals. This paper reviews research from this laboratory on one factor that influences the degree to which nicotine is selfadministered: environmental stimuli that form the context within which nicotine is taken. The results suggest that the direct, pharmacological actions of nicotine are necessary but not sufficient to explain either the high rates of self-administration exhibited by laboratory animals or cigarette smoking by humans, and that future investigations on the neurophysiological effects of nicotine that underlie smoking behavior must take into account the environmental context within which the behavior occurs. D
Reinforcing effects of nicotine and non-nicotine components of cigarette smoke
Psychopharmacology, 2010
Rationale Nicotine and non-nicotine components of cigarette smoke contribute to its reinforcing effects; however, the specific role of each component in maintaining behavior has not yet been elucidated. Objectives To assess the reinforcing effects of nicotine and non-nicotine components of cigarette smoke by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized ("denic") cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. Methods Sixteen smokers participated in seven sessions: 1) a baseline smoking assessment, used to tailor the nicotine dose per infusion; 2) two sessions for training discrimination of IV nicotine vs. saline infusions and denic smoke vs. sham puffs; and 3) four sessions assessing choice behavior after different satiation conditions. Results Denic smoke was self-administered more than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was inversely correlated with subjective ratings of "comfort" associated with nicotine. Smoke satiation reduced the number of denic puffs taken during choice periods, while prior nicotine administration did not affect puffing behavior. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke. Conclusions In established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors.
Psychopharmacology, 2004
Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence.