Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats

Paterson, Neil E.; Markou, Athina

doi:10.1007/s00213-003-1692-7

Cited by 88 publications

(102 citation statements)

References 40 publications

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“…Thus, it is possible that access to nicotine self-administration for durations longer than the 20 days reported here may induce further adaptations in brain reward systems similar to those observed in rats treated with nicotine via mini-pumps, and in cocaine self-administering rats. Nevertheless, repeated 1 or 6 h daily access to nicotine self-administration was recently shown to induce 'physical' dependence on nicotine, such that a spontaneous somatic withdrawal syndrome was observed 23 h after cessation of nicotine intake (Paterson and Markou, 2004). Thus, although somatic signs of spontaneous withdrawal were not investigated in the present study, it is likely that 'physical' dependence on nicotine developed in parallel with the reward hypersensitivity reported here.…”

Section: Discussionmentioning

confidence: 64%

Nicotine Self-Administration Acutely Activates Brain Reward Systems and Induces a Long-Lasting Increase in Reward Sensitivity

Kenny

Markou

2005

Neuropsychopharmacol

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Nicotine is a major component of tobacco smoke contributing to the initiation and persistence of the harmful tobacco habit in human smokers. The reinforcing effects of nicotine likely arise through its ability to stimulate brain circuitry mediating the detection and experiencing of natural rewards. Nevertheless, remarkably little is known concerning the acute or long-lasting actions of nicotine on brain reward systems in vivo. Here, we investigated the effects of intravenously self-administered nicotine (0.03 mg/kg/infusion, free base) on the sensitivity of brain reward systems, reflected in alterations of intracranial self-stimulation (ICSS) thresholds in rats. Rats selfadministered nicotine during 1 or 12 h daily sessions, with reward thresholds assessed 1 h before and 15 min after each self-administration session. Control rats remained nicotine naïve throughout. Nicotine self-administration increased the sensitivity of brain reward systems, detected by post-nicotine lowering of reward thresholds in 1 and 12 h rats. This nicotine-enhanced sensitivity of reward systems was reversed by the high-affinity nicotinic receptor antagonist dihydro-b-erythroidine (DHbE; 3 mg/kg). Surprisingly, nicotine-induced excitation of reward systems persisted for at least 36 days after nicotine self-administration had ceased. Overall, these data demonstrate that rats can voluntarily consume quantities of nicotine sufficient to increase the sensitivity of brain reward systems, an action likely crucial in establishing and maintaining the nicotine habit. Moreover, self-administered nicotine resets the sensitivity of reward systems to a new increased level, thereby imprinting an indelible 'memory' of its effects in reward systems, an action that so far appears unique to nicotine among drugs of abuse.

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Section: Discussionmentioning

confidence: 64%

Nicotine Self-Administration Acutely Activates Brain Reward Systems and Induces a Long-Lasting Increase in Reward Sensitivity

Kenny

Markou

2005

Neuropsychopharmacol

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241

204

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“…These rats also display a compensatory increase in nicotine IVSA when the dose is lowered (0.03 to 0.003 mg/kg) and a decrease in nicotine-seeking behavior when nicotine is replaced with saline. Moreover, male rats display nicotine IVSA in extended access models (6 -23 h) using low nicotine doses (0.00375 mg/kg/injection), and the level of nicotine intake approximates that of human smokers (Valentine et al, 1997;Paterson and Markou, 2004;Kenny and Markou, 2006). The 23-h access model of nicotine IVSA seems to be sensitive to genetic differences, since nicotine intake is more quickly acquired and persistently maintained in Lewis versus Holtzman and Fisher strains of male rats (Brower et al, 2002).…”

Section: Introductionmentioning

confidence: 94%

“…All drugs were dissolved in 0.9% sterile saline, and mecamylamine was administered in a volume of 1 ml/kg. The drug doses were selected based on previous work in our laboratory (Watkins et al, 1999;Paterson and Markou, 2004) and that of others using extended access to nicotine IVSA (Valentine et al, 1997;Fu et al, 2001;Lesage et al, 2002Lesage et al, , 2003.…”

Section: Drugsmentioning

confidence: 99%

Extended Access to Nicotine Self-Administration Leads to Dependence: Circadian Measures, Withdrawal Measures, and Extinction Behavior in Rats

O’Dell¹,

Chen²,

Smith³

et al. 2006

J Pharmacol Exp Ther

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120

112

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The present study characterized nicotine intake, circadian patterns of food and water intake, precipitated somatic signs of withdrawal, and extinction of nicotine-seeking behavior in rats with 23-h access to intravenous self-administration (IVSA). Separate groups of animals were allowed access to nicotine IVSA (0.015, n ϭ 9; 0.03, n ϭ 14; 0.06, n ϭ 16; mg/kg/0.1 ml infusion/s; fixed ratio 1) and trained to nosepoke for food and water 23 h/day for 40 consecutive days. Somatic signs of nicotine withdrawal were examined following saline or mecamylamine administration (1.5 mg/kg i.p.), and extinction of nicotine-seeking behavior was assessed. A dose-dependent decrease in lever responding and an increase in nicotine intake were observed, with the highest nicotine dose producing the lowest amount of lever responding and the highest amount of nicotine intake. Nicotine acutely reduced diurnal and nocturnal food intake, producing smaller and fewer meals, and an increased rate of eating. Differences in rate of nicotine intake between the light and dark phase decreased significantly, especially in rats receiving higher unit nicotine doses (0.03 and 0.06 mg/kg), along with long-term decreases in the circadian profile and amplitude of feeding. Mecamylamine precipitated robust withdrawal signs, the magnitude of which was positively correlated with the total amount of self-administered nicotine. Extinction of nicotine-seeking behavior was observed and was facilitated by removal of nicotine-associated cues. The results demonstrate that rats will self-administer nicotine to the point of producing dependence, as measured by somatic signs, resistance to extinction, and measures of food intake.To more closely model tobacco use in humans, recent studies have examined extended access to nicotine intravenous self-administration (IVSA) in rats. For example, female rats display increased nicotine IVSA during the active phase of the light cycle during 3 weeks of continuous nicotine access (Cox et al., 1984). These rats also display a compensatory increase in nicotine IVSA when the dose is lowered (0.03 to 0.003 mg/kg) and a decrease in nicotine-seeking behavior when nicotine is replaced with saline. Moreover, male rats display nicotine IVSA in extended access models (6 -23 h) using low nicotine doses (0.00375 mg/kg/injection), and the level of nicotine intake approximates that of human smokers (Valentine et al., 1997;Paterson and Markou, 2004;Kenny and Markou, 2006). The 23-h access model of nicotine IVSA seems to be sensitive to genetic differences, since nicotine intake is more quickly acquired and persistently maintained in Lewis versus Holtzman and Fisher strains of male rats (Brower et al., 2002). Furthermore, the 23-h model of nicotine IVSA is sensitive to passive nicotine administration. Nicotine intake decreased following implantation of a minipump that delivers doses of nicotine that are equal to, or higher than, peak levels associated with simulated nicotine intake (LeSage et al., 2002). In addition, nicotine intake in ...

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“…The escalation of drug intake with prolonged or extended access is not exclusive for cocaine and ethanol. In both operant self-administration and oral ingestion setups, escalation of drug intake has been observed for other drugs of abuse, including the psychostimulants methamphetamine, amphetamine and methylphenidate (e.g., Kitamura et al, 2006), the opiates heroin and etonitazene (Wolffgramm and Heyne, 1995;Heyne, 1996;Ahmed et al, 2000) but, remarkably, much less so for nicotine (Paterson and Markou, 2004;Kenny and Markou, 2006). Consistent with the notion that escalation of drug intake is an important step in the development of compulsive drug use, it has been shown that, after escalated cocaine or alcohol self-administration, other behavioral characteristics of addictive behavior can also be observed.…”

Section: Escalation Of Drug Usementioning

confidence: 99%

Compulsive drug use and its neural substrates

Lesscher

Vanderschuren²

2012

Reviews in the Neurosciences

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Drug addiction is a chronic relapsing brain disease, characterized by compulsive drug use. Despite the fact that drug addiction affects millions of people worldwide, treatments for this disorder are limited in number and efficacy. In our opinion, understanding the neural underpinnings of drug addiction would open new avenues for the development of innovative treatments for this disorder. Based on an awareness that drug use and drug reward do not equal drug addiction, there has been increasing interest in developing animal models of addiction that mimick the loss of control over drug use more closely than existing models aimed at studying drug reward. The present review provides an overview of animal studies of compulsive drug use and the neural mechanisms involved. First, the employed models are summarized, with a particular emphasis on models of escalation of drug use and resistance to punishment. Next, we discuss mechanisms within the (ventral and dorsal) striatum and (central) amygdala that have recently been implicated in the compulsive seeking and taking of alcohol and cocaine. The studies discussed here provide a promising line of research that will advance our knowledge of the neural circuits involved in the self-destructive behavior that characterizes drug addiction.

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Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats

Cited by 88 publications

References 40 publications

Nicotine Self-Administration Acutely Activates Brain Reward Systems and Induces a Long-Lasting Increase in Reward Sensitivity

Nicotine Self-Administration Acutely Activates Brain Reward Systems and Induces a Long-Lasting Increase in Reward Sensitivity

Extended Access to Nicotine Self-Administration Leads to Dependence: Circadian Measures, Withdrawal Measures, and Extinction Behavior in Rats

Compulsive drug use and its neural substrates

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