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Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence.

ABSTRACT: Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hypothesized that the escalation of nicotine intake may only occur when animals are given extended-access (21 h per day) self-administration sessions after repeated periods of abstinence (24-48 h), and after chronic inhibition of monoamine oxidase using phenelzine sulfate. Intermittent access (every 24-48 h) to extended nicotine self-administration produced a robust escalation of nicotine intake, associated with increased responding under fixed- and progressive-ratio schedules of reinforcement, and increased somatic signs of withdrawal. The escalation of nicotine intake was not observed in rats with intermittent access to limited (1 h per day) nicotine self-administration or daily access to extended (21 h per day) nicotine self-administration. Moreover, inhibition of monoamine oxidase with daily administration of phenelzine increased nicotine intake by ? 50%. These results demonstrate that the escalation of nicotine intake only occurs in animals given intermittent periods of abstinence with extended access to nicotine, and that inhibition of monoamine oxidase may contribute to the escalation of smoking, thus validating both an animal model of the escalation of smoking behavior and the contribution of monoamine oxidase inhibition to compulsive nicotine-seeking.

SUBMITTER: Cohen A

PROVIDER: S-EPMC3398720 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence.

Cohen Ami A Koob George F GF George Olivier O

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20120502 9

Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hy ...[more]

PMID: 22549121

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Project description:IntroductionTobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system.MethodsTo investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks).ResultsDuring the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake.ConclusionsA brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence.ImplicationsThese animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes.

Project description:Chronic cocaine exposure influences the density and morphology of dendritic spines on medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a critical brain region for cocaine craving. However, the relationship between spine plasticity and craving remains unclear. To study this relationship, we trained rats to self-administer cocaine using an extended-access regimen (6 h per day, 10 days); controls self-administered saline. Previously, a time-dependent intensification (incubation) of cue-induced cocaine craving has been demonstrated after withdrawal from this regimen; furthermore, Ca2+-permeable AMPA receptors (CP-AMPARs) increase in the NAc core after ~1 month of withdrawal and thereafter mediate the expression of incubated craving. Although neither craving nor CP-AMPAR levels were measured in the present study, we killed rats at four withdrawal day (WD) time-points (WD14, WD25, WD36, or WD60) selected to span the rising phase of incubation and the transition from low to high CP-AMPAR levels. MSNs were iontophoretically filled with Lucifer yellow and spines were analyzed with NeuronStudio software. Compared with saline controls, cocaine rats showed no changes in spine density or morphology in the NAc core on WD14 or WD25. On WD36, approximately the withdrawal time when stable elevation of CP-AMPAR levels is detected, the cocaine group exhibited increased density of thin spines in the NAc core. By WD60, however, this effect had reversed: the density of thin spines was lower in cocaine rats compared with saline rats. In contrast, craving and CP-AMPAR levels remain high on WD60. We also assessed spine density on WD36 in the dorsolateral striatum, a region that is not implicated in incubation of cocaine craving and does not undergo CP-AMPAR plasticity. Here, the cocaine group exhibited a small leftward shift in the distribution of spine densities plotted as a cumulative distribution, opposite to the effect found in the NAc core. Overall, our results demonstrate changes in NAc core spines over 2 months of withdrawal but no simple relationship between the time dependency of these spine changes and the previously demonstrated time course of incubation of cocaine craving. However, they raise the possibility that CP-AMPAR accumulation in the NAc core occurs in a population of thin spines that emerges after ~1 month of withdrawal.

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Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence.

Publications

Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence.

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