Nicotine analog inhibition of nicotine self-administration in rats

RATIONALE: Partial agonists and antagonists of addictive drugs have been useful in the treatment of dependence. OBJECTIVE: The purpose of this study is to determine whether nicotine analogs with partial agonist or antagonist properties at alpha4beta2 nicotinic acetylcholine receptors (nAChRs) inhibit self-administration of nicotine in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained to self-administer nicotine (unit dose 0.017 mg/kg) intravenously contingent upon the completion of five lever presses. Once stable responding was established, rats were administered test agents, either as a subcutaneous injection before the daily session or co-infused with nicotine. RESULTS: The number of nicotine injections taken per session was reduced to approximately 50% of baseline after either pre-treatment with the broad spectrum nicotinic receptor antagonist, mecamylamine, or by substituting saline for nicotine (extinction). 4'-Trans-methyl-nicotine, a strong partial agonist, inhibited nicotine self-administration and substituted for nicotine to support self-administration. Partial agonists, prepared by substitution at the 1'-N-position with either ethyl or cyclopropylmethyl moieties, potently inhibited self-administration. Antagonists formed by 5'-methyl substitution also inhibited self-administration, with the 5'-trans-methyl enantiomer about ten times more potent than the 5'-cis-methyl enantiomer. In contrast, antagonists formed by aryl substitution at the 5 position of the pyridyl ring of nicotine did not inhibit self-administration. Intravenous co-infusions had similar effects to the pre-injections. In most instances, doses of the analogs that reduced nicotine self-administration had no effect on food intake when measured using a similar FR5 protocol. CONCLUSIONS: Nicotine analogs with alpha4beta2 nAChR partial agonist and antagonist efficacies can inhibit self-administration and may be considered as prototypical smoking-cessation agents.     

The cannabinoid antagonist AM251 attenuates nicotine self-administration and nicotine-seeking behaviour in rats

The cannabinoid receptor subtype (CB1) antagonist rimonabant (SR141716) has been shown to decrease nicotine self-administration and attenuate nicotine-evoked dopamine release in the nucleus accumbens; effects that support recent findings on its clinical efficacy as a smoking cessation aid. The present experiments aim to advance our understanding on the role of CB1 receptors in rodent models of nicotine dependence. AM251, a selective antagonist at CB1 receptors dose-dependently (1, 3 and 10mg/kg IP) suppressed intravenous nicotine (0.03mg/kg per infusion) self-administration in rats during three successive days of pre-treatment. This reduction was short lasting since behaviour was reinstated by suspending AM251 pre-treatment. This was relatively specific to nicotine self-administration since the profile of these reductions produced by AM251 was significantly different from the responses maintained by food pellets. In a model of nicotine-seeking behaviour, rats that had been extinguished by removal of nicotine and associated cues, and presented with a priming dose of nicotine (0.2mg/kg SC) with the cues, showed robustly reinstated responses to nicotine-seeking behaviour. Acute pre-treatment with AM251 (1-10mg/kg IP) dose-dependently attenuated the reinstatement effects produced by nicotine and the contingently presented cues. These preclinical findings support the use of rimonabant as a smoking cessation aid and highlight the CB1 receptor as a viable target to control intake of nicotine and prevent relapse.     

Nornicotine pretreatment decreases intravenous nicotine self-administration in rats

RATIONALE: Nicotine has been shown to be effective as a treatment for reducing tobacco dependence. However, few studies have examined the effect of other nicotinic agonists to determine if they can also decrease nicotine self-administration. OBJECTIVE: The present study determined if nornicotine, a tobacco alkaloid and major nicotine metabolite in brain, could reduce nicotine self-administration in rats. METHODS: Each rat was prepared with an indwelling jugular catheter and trained to self-administer intravenous nicotine (0.03 mg/kg per infusion). After nicotine self-administration stabilized, rats were pretreated with either (-)-nicotine (0, 0.1, 0.3, and 1.0 mg/kg free base) or (+/-)-nornicotine (0, 1, 3, 5.6, and 10.0 mg/kg free base) and assessed for nicotine self-administration. A separate group of rats was maintained on sucrose reinforced responding and pretreated with nornicotine to determine the specificity of the pretreatment effect. In another group of rats, the time course of the pretreatment effect of either (-)-nicotine (0.56 and 1.0 mg/kg) or (+/-)-nornicotine (5.6 and 10.0 mg/kg) was examined. RESULTS: Nicotine and nornicotine each produced a dose-dependent decrease in nicotine self-administration. Furthermore, the decrease in nicotine self-administration in response to the 5.6 mg/kg nornicotine pretreatment was specific to nicotine self-administration, as this dose did not decrease sucrose reinforced responding in tolerant animals. In addition, within the dose range tested, the suppressant effect of nornicotine had a two-fold longer duration than that of nicotine (120 versus 60 min). CONCLUSION: These results suggest that nornicotine may be an effective treatment for tobacco dependence.     

Schedule-induction of nicotine self-administration

Nicotine, although assumed to be an important factor in maintaining the use of tobacco products, has produced equivocal results when tested in drug self-administration studies using standard procedures with laboratory animals. Several recent studies however, have demonstrated nicotine self-administration using a procedure of schedule-induction. Schedule-induced behaviors occur as an adjunct to behavior controlled by an intermittent schedule of reinforcement and are thus not under control of the scheduled contingencies. Using schedule-induction procedures; oral, intravenous and inhaled self-administration of nicotine has been shown in rats, both rats and rhesus monkeys, and humans respectively. Although the self-administration of some doses of nicotine occurred without a concurrent schedule of intermittent reinforcement, schedule-induction results in responding maintained by lower doses of the drug and much more rapid initiation of self-administration. The result of such studies suggest an interaction between environmental factors, such as an intermittent schedule of other reinforcers, and nicotine's pharmacological effects. This interaction may be important in understanding the etiology and maintenance of human tobacco use.     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

Environmental stimuli promote the acquisition of nicotine self-administration in rats

RATIONALE: Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. OBJECTIVES: In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. METHODS: Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. RESULTS: Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. CONCLUSIONS: These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.     

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Rationale. Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives. The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods. Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results. MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions. These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission. Electronic Publication     

Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats

RATIONALE: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission. OBJECTIVES: The present study examined the impact of nicotine treatment on the reinforcement efficacy of self-administered cocaine and non-reinforced responding for cocaine in rats. METHODS: Rats were trained to self-administer cocaine (i.v.) on a progressive ratio (PR) schedule of reinforcement. Self-administration training continued until stable responding was obtained. Acute nicotine pretreatment consisted of a subcutaneous injection (0.15, 0.3 and 0.6 mg/kg) 3 min prior to cocaine access. In the repeated treatment condition, a separate group of animals was given nicotine (0.6 mg/kg, s.c.) 3 min prior to cocaine access for 14 consecutive days. During extinction trials, these animals were injected with nicotine (0.6 mg/kg, s.c.) after 45 min of non-reinforced responding. RESULTS: Acute nicotine treatment produced an inverted U-shaped dose-response function with lower doses increasing and the highest dose decreasing the number of cocaine infusions obtained during a session. Animals treated repeatedly with the highest dose of nicotine showed a significant increase in the number of cocaine infusions by day 8 of nicotine treatment. During extinction sessions when cocaine was not available, injections of nicotine in these animals caused a reinstatement of the previously rewarded lever-press behavior. CONCLUSIONS: These findings indicate that nicotine can facilitate cocaine reinforcement, may contribute to the transition from moderate drug-taking to an escalation of drug intake which is characteristic of addiction, and may trigger relapse.     

Oral self-administration of sweetened nicotine solutions by rats

Oral self-administration of sweetened nicotine solutions in rats was studied in two ways. In the first experiment, one group had continuous access to a water bottle containing a sucrose solution and nicotine (10 μg/ml), while another group had access to an identical sucrose solution without nicotine. All rats had continuous access to water. While consumption of nicotine increased with increasing concentrations of sucrose, consumption of the sucrose + nicotine solution never exceeded the intake of sucrose alone. In subsequent experiments, the delivery of the solutions was made contingent upon an operant response. The sucrose + nicotine solution was found to maintain responding to higher response/reinforcer ratiosthan the sucrose only solution. These data demonstrate that rats will self-administer sweetened nicotine solutions and that sucrose + nicotine solutions are more reinforcing than sucrose solutions alone. Free accessconsumption is not a good predictor of the response maintaining properties of nicotine solutions.     

Effects of continuous nicotine infusion on nicotine self-administration in rats: relationship between continuously infused and self-administered nicotine doses and serum concentrations

Rationale The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. One reason for this limited efficacy may be that typical serum nicotine concentrations provided by NRT do not match the peak arterial nicotine concentrations achieved from smoking.Objective The purpose of the present study was to determine whether continuous nicotine infusion at a rate producing serum nicotine concentrations that match the estimated peak arterial nicotine concentrations associated with nicotine self-administration (NSA) in rats produces greater suppression of NSA than lower infusion rates.Methods The effects of continuous nicotine infusion were studied by intravenously administering nicotine at various rates (1.0, 3.0, and 8.0 mg/kg per day) to rats concurrently self-administering nicotine (0.03 mg/kg per infusion) during 23-h sessions or cocaine (0.17 mg/kg per infusion) during 2-h sessions.Results Continuous nicotine infusion suppressed NSA in a rate-related fashion. NSA was suppressed by 17, 50, and 73% at infusion rates of 1.0, 3.0 and 8.0 mg/kg per day, respectively. The 8.0-mg/kg per day infusion rate, which provided venous serum nicotine concentrations equaling the peak arterial concentrations associated with NSA, suppressed NSA to a greater extent than lower infusion rates. The 8.0-mg/kg per day nicotine infusion rate had no effect on cocaine-maintained responding, demonstrating that its effects were specific for suppression of NSA. This infusion rate provided a mean percentage replacement of nicotine from NSA of more than 700%. Reacquisition of NSA after suppression by the two highest infusion rates was delayed compared with reacquisition after saline extinction.Conclusions Continuous nicotine infusion produced an infusion rate-related suppression of NSA that was greatest when the infusion provided nicotine doses and venous serum concentrations substantially higher than those typically associated with NRT in humans.     

Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

Rationale  The ability of tobacco harm reduction strategies to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon and assessing the feasibility of harm reduction interventions. Objective  The objective of the study was to use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Methods  Rats were trained for NSA during daily 23-h sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Results  Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23-h sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. Conclusions  These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans.     

Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats

Rationale Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine self-administration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior.Objectives This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus.Methods Initially, male and female rats acquired self-administration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg^–1 inf^–1, freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus.Results While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg^–1 inf^–1 on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses. Combining nicotine infusions with the visual stimulus doubled responding compared to nicotine alone at 0.03 and 0.06, but not at 0.15 mg kg^–1 inf^–1: this effect was significantly greater for female rats.Conclusions These data highlight the prominent contribution of nonpharmacological stimuli to nicotine-reinforced behavior across a range of doses in both male and female rats. They also reveal sex differences in operant responding for nicotine under conditions where a nonpharmacological stimulus is either absent, or combined with drug delivery.     

Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

Background

Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.

Methods

Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone + light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug + cues to reinstate nicotine-seeking.

Results

Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.

Conclusions

These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.     

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

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.     

Effects of isoarecolone, a nicotinic receptor agonist in rodent models of nicotine dependence

Rationale The nicotinic receptor agonist, isoarecolone, has ‘nicotine-like’ subjective properties as detected by rats in a discrimination paradigm. However, isoarecolone lacks the intra-accumbens dopamine-releasing effects, a feature akin to most abused substances. In the five-choice serial reaction time task, isoarecolone can enhance attention and thus may be developed as a cognitive enhancer.Objective The present experiments assess the dependence profile of isoarecolone in rodent models of nicotine dependence.Method and results Tests for cross-substitution in which isoarecolone is substituted for nicotine [0.3 mg/kg/infusion (inf)] self-administration suggest isoarecolone to have nominal reinforcing properties (0.3 or 1.0 mg/kg/inf); intake of isoarecolone declined over three test sessions in which responding was no different from saline extinction, and behaviour was reinstated by re-presenting nicotine. In a model of nicotine-seeking behaviour, rats having been extinguished by removal of nicotine (0.03 mg/kg/inf) and associated cues, the presentation of priming doses of nicotine (0.1–0.4 mg/kg s.c.) with the cues robustly reinstated responding of nicotine-seeking behaviour. Tests with priming doses of isoarecolone (1–20 mg/kg s.c.) shown previously to generalise to nicotine in discrimination tests produced significant levels of reinstatement but the responses were significantly less compared to nicotine-induced reinstatement.Conclusion Overall, these results suggest that isoarecolone with its unique profile of behavioural activity should be further examined for treating chronic diseases that are characterised by attentional dysfunction.     

Tranylcypromine enhancement of nicotine self-administration

Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.     

Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats

Rationale Immunization of rats against nicotine using a nicotine conjugate vaccine reduces the distribution of nicotine to brain in rats and attenuates some of nicotine's physiological and behavioral effects. It is not known whether such a vaccine can attenuate nicotine's reinforcing effects. Objective The present experiment was conducted to determine whether a nicotine conjugate vaccine could interfere with the acquisition and maintenance of nicotine self-administration (NSA) in rats given 23 h day⁻¹ access to nicotine. Methods To examine acquisition of NSA, rats were vaccinated with nicotine or control immunogen prior to being given access to a 0.01 mg kg⁻¹ infusion⁻¹ nicotine under a fixed-ratio(FR) 1 schedule for week 1, FR 2 for week 2, and FR 3 for week 3. Acquisition of cocaine self-administration (CSA) was similarly examined to determine the specificity of vaccination effects. To examine maintenance of NSA, rats were initially trained to self-administer nicotine under an FR 3 schedule, and then vaccinated with nicotine or control immunogen while NSA continued to be monitored. Results NSA was significantly lower in vaccinated rats compared to controls during the acquisition protocol, with a 38% decrease in the number of infusions during the last week of training. The percentage of rats meeting acquisition criteria in the vaccinated group was lower (36%) than that in the control group (70%), but this difference was not statistically significant. Vaccination did not affect acquisition of CSA, demonstrating its specificity for nicotine. Maintenance of NSA was significantly reduced in vaccinated rats as compared to controls after the final vaccine injection, with a mean reduction of 57%. There was no evidence in either protocol that vaccinated rats attempted to compensate for altered nicotine distribution by increasing nicotine intake. Conclusion These data suggest that vaccination against nicotine can reduce the reinforcing effects of nicotine in rats and may have therapeutic potential for the treatment of tobacco dependence.     

Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement

Rationale Current conceptualizations of drug reinforcement assume that drug-taking behavior is a consequence of the contingent, temporal relationship between the behavior and drug reward. However, stimulant drugs also potentiate the rewarding effects of other reinforcers when administered noncontingently. Objectives These studies were designed to determine whether noncontingent nicotine enhances the reinforcing properties of a nonpharmacological reinforcer and whether this direct effect facilitates operant behavior within the context of a nicotine self-administration procedure. Methods Rats self-administered nicotine or food, or received noncontingent nicotine, saline, or food either with or without a response-contingent, unconditioned reinforcing visual stimulus (VS). Results Noncontingent nicotine, whether delivered as discrete injections based on a pattern of self-administered nicotine or as a continuous infusion, increased response rates maintained by the VS. There were no significant differences in responding by animals that received contingent compared with noncontingent nicotine when a VS was available. This increase was not observed in the absence of the VS or as a consequence of noncontingent food delivery. Operant behavior was equally attenuated and reinstated by the removal and subsequent replacement of contingent and noncontingent nicotine. Nicotine supported self-administration in the absence of response-contingent, nicotine-paired stimuli; however, response rates were drastically reduced compared with nicotine self-administration with the VS. Conclusions Nicotine influences operant behavior in two ways: by acting as a primary reinforcer when it is contingent upon behavior, and by directly potentiating the reinforcing properties of other stimuli through a nonassociative mechanism. Nicotine self-administration and smoking may be largely dependent upon this later action. This work was supported by National Institute on Drug Abuse research grants, DA-10464 and DA-12655. "Principles of laboratory animal care" (NIH No. 85-23, revised 1985) were followed throughout all experiments. This research was approved by the University of Pittsburgh Institutional Animal Care and Use Committee, Assurance Number A3187-01     

Norepinephrine release in amygdala of rats during chronic nicotine self-administration: an in vivo microdialysis study

The essential role of the amygdala in learning and memory, including cue-associated learning, is influenced by local release of norepinephrine (NE). The current study investigated changes in amygdaloid NE secretion in rats learning to self-administer nicotine in an unlimited access model (23 h/day). In vivo microdialysis of NE was performed for 9 h intervals during three phases of nicotine self-administration: acquisition (day 1); early maintenance, when self-administration rates first stabilized (day 8.4+/-0.7); and later, during fully stable maintenance (day 17.6+/-1.0). On day 1, a greater number of self-administration episodes (SAEs) were associated with elevated NE levels in rats bar-pressing for nicotine (88% vs. 39% with saline). By early maintenance, such episodes increased threefold and overall NE levels were greater. During later maintenance, however, bar-pressing behavior was similar and NE was elevated by the first SAE of the day, but total daily NE levels were no longer elevated. In all the three phases, the enhanced NE release during the first daily SAE did not occur in the last SAE 9 h later. Thus, in an animal model of unlimited nicotine self-administration that approximates the human pattern of nicotine consumption via smoking, the amygdaloid NE response to nicotine diminishes over each day and with the stabilization of self-administration. The decline of amygdaloid NE secretion after long-term nicotine self-administration likely reflects desensitization to the pharmacological effects of nicotine. In addition, amygdaloid NE release, which enhances the consolidation of amygdala-dependent memory, may no longer be necessary once self-administration behavior has been established.     

Nicotine reinstatement of nicotine self-administration after long-term extinction

The effect of non-contingent priming injections of nicotine on the reinstatement of drug-seeking behaviour was studied in rats following the long-term extinction of nicotine self-administration. Male rats were trained to lever press for 0.03 mg/kg per infusion of intravenous nicotine. Nicotine maintained a robust self-administration behaviour (11.5±1.2; mean±SEM infusions/1-h session). When nicotine availability was discontinued, and only a non-contingent saline infusion was presented to the experimental subjects at the beginning of each daily session, responding for the drug-paired lever decreased to low values. After 4–13 sessions, responding extinguished. During this “extinction” period, non-contingent priming infusions of nicotine 0.001, 0.003, 0.01 or 0.03 mg/kg per infusion induced reinstatement of responsing for the drug-paired lever. The increased responding, compared with the corresponding previous day on saline, was observed at all four nicotine doses but was not statistically significant for the higher priming dose (0.03 mg/kg per infusion). These preliminary results indicate that nicotine priming is able to induce reinstatement of drug-seeking behaviour in rats similarly to other reinforcing drugs. The present findings show analogies with similar phenomena described in ex-smokers and support the addictive role of nicotine in tobacco smoking.