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

Abstract

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 ...

Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

“…It has long been proposed that responding during extinction sessions may provide a measure of the incentive-motivational properties of the drug (Markou et al 1993). Recent nicotine studies using an extended (23 h/day) access of self-administration paradigm showed that levels of extinction responding remained higher in rats receiving the highest dose (0.06 mg/kg/infusion) of nicotine compared to rats trained with lower doses (O'Dell et al 2007) and that although the first day extinction responding did not vary as a function of total nicotine infusions/intake, there was a positive correlation of extinction with nicotine infusions earned during the first 2 h of the extended access (Harris et al 2007). Moreover, a cocaine study reported that drug-seeking responding in rats trained to selfadminister higher doses of cocaine were more resistant to extinction than in rats on a lower dose (Valles et al 2006).…”

“…For instance, clinical literature shows that feelings of relief upon smoking are greater in heavy, when compared to light smokers (Parrott 1994(Parrott , 2000Adan et al 2004) and suggests that conditioned responses to drug cues are positively correlated with the degree of alcohol dependence (Glautier and Drummond 1994;George et al 2001). Recent animal studies using the 23 h/day self-administration paradigm showed that lever responding in the first extinction session was positively correlated with nicotine infusions earned during the first 2-h of self-administration (Harris et al 2007) and seemed more resistant to extinction in animals on higher compared to lower doses of nicotine (O'Dell et al 2007). Cue-induced reinstatement of 3,4 methylenedioxymethamphetamine (MDMA; an amphetamine derivative)-seeking in rats was positively correlated to the responses made during prior self-administration training (Ball et al 2007).…”

Sex Differences in Animal Models: Focus on Addiction

“…Rodents will increase intravenous or oral self-administration of drugs with extended access to the drugs and during withdrawal from the dependent state, measured both by an increased amount of drug administration and working exponentially harder to obtain the drug in progressive-ratio schedules of reinforcement. Such increased self-administration in dependent animals has been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed and Koob, 1998;Ahmed et al, 2000;Roberts et al, 2000;Breese et al, 2005;Kitamura et al, 2006;O'Dell et al, 2007).…”

Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

“…That is, unlike the current experimental arrangement, patterns of human tobacco use are not typically continuous but are instead intermittent throughout the waking hours. Thus, further research with methods that may more closely model extended, intermittent human exposure to tobacco (e.g., O'Dell et al, 2007 ) may also be necessary to generalize the current time-related dissipation of the reinforcement enhancement to human behavior. Additionally, the current dose of nicotine delivered via osmotic minipump (3.16 mg/kg/day) reportedly results in plasma levels of 44 ng/ml ( Kenny et al, 2003 ), but other reports have variable estimates of plasma levels from similar doses and route of administration ( Ghosheh, Dwoskin, Miller, & Crooks, 2001 ;LeSage et al, 2002 ;Lockman et al, 2005 ;Nguyen, Rasmussen, & Perry, 2004 ).…”