Development of a nicotine aerosol self-administration model in rats and the effects of e-liquid flavors.

Electronic nicotine delivery system (ENDS) use is maintained by the positive reinforcement associated with preferred flavors. These flavors become conditioned reinforcers through pairings with primary reinforcers. This study sought to extend prior research with intravenous nicotine self-administration and develop a more ecologically valid preclinical model of aerosol self-administration in rats that incorporated flavors paired with sucrose. Rats were first trained to respond for oral sucrose with or without raspberry flavor to establish the flavor as a conditioned reinforcer for some groups. Rats were then exposed to aerosol self-administration. All groups responded for raspberry-flavored aerosol with or without nicotine. Rats responded more for raspberry flavored sucrose than unflavored sucrose. Despite raspberry increasing responding for sucrose, the flavor did not function as a conditioned reinforcer during aerosol self-administration and did not increase responding for nicotine. Throughout the aerosol self-administration phase, most groups responded more on the active than inactive lever, and some groups increased their response when the fixed ratio value was increased. At the end of the study, rats in nicotine groups earned similar or fewer aerosol deliveries than rats in vehicle groups. Aerosolized nicotine did not function as a reinforcer in this study, whereas aerosolized raspberry flavor may have maintained self-administration. Further preclinical investigation is needed to articulate the impact of flavors on ENDS use and whether they offset some aversive effects of nicotine or maintain responding on their own. If flavors reduce some aversive effects of self-administered nicotine, then policies to regulate flavors in e-liquids are prudent.

Nicotine Self-Administration With Tobacco Flavor Additives in Male Rats.

INTRODUCTION: Nicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs. METHODS: Menthol (160 or 320 µM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR. RESULTS: In experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 µg/kg/infusion (Neutral group) to 3.25 µg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 µg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 µg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent. CONCLUSION: Tobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low. IMPLICATIONS: Tobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence.

Intravenous and oral caffeine self-administration in rats.

Caffeine is widely consumed for its psychoactive effects worldwide. No pre-clinical study has established reliable caffeine self-administration, but we found that caffeine can enhance the reinforcing effects of non-drug rewards. The goal of the present studies was to determine if this effect of caffeine could result in reliable caffeine self-administration. In 2 experiments rats could make an operant response for caffeine delivered in conjunction with an oral 'vehicle' including saccharin (0.2% w/v) as a primary reinforcer. In Experiment 1, intravenous (IV) caffeine infusions were delivered in conjunction with oral saccharin for meeting the schedule of reinforcement. In control conditions, oral saccharin alone or presentations of IV caffeine alone served as the reinforcer. In Experiment 2, access to caffeine was provided in an oral vehicle containing water, decaffeinated instant coffee (0.5% w/v), or decaffeinated coffee and saccharin (0.2%). The concentration of oral caffeine was then manipulated across testing sessions. Oral and IV caffeine robustly increased responding for saccharin in a manner that was repeatable, reliable, and systematically related to unit IV dose. However, the relationship between oral caffeine dose and operant behavior was less systematic; the rats appeared to titrate their caffeine intake by reducing the consummatory response (drinking) rather than the appetitive response (lever pressing). These studies establish reliable volitional caffeine self-administration in rats. The reinforcement enhancing effects of caffeine may help to explain widespread caffeine use by humans, who ingest caffeine in complex vehicles with reinforcing properties.

Orbitofrontal participation in sign- and goal-tracking conditioned responses: Effects of nicotine.

Pavlovian conditioned stimuli can acquire incentive motivational properties, and this phenomenon can be measured in animals using Pavlovian conditioned approach behavior. Drugs of abuse can influence the expression of this behavior, and nicotine in particular exhibits incentive amplifying effects. Both conditioned approach behavior and drug abuse rely on overlapping corticolimbic circuitry. We hypothesize that the orbitofrontal cortex (OFC) regulates conditioned approach, and that one site of nicotine action is in the OFC where it reduces cortical output. To test this, we repeatedly exposed rats to 0.4 mg/kg nicotine (s.c.) during training and then pharmacologically inactivated the lateral OFC or performed in vivo electrophysiological recordings of lateral OFC neurons in the presence or absence of nicotine. In Experiment 1, animals were trained in a Pavlovian conditioning paradigm and behavior was evaluated after inactivation of the OFC by microinfusion of the GABA agonists baclofen and muscimol. In Experiment 2, we monitored phasic firing of OFC neurons during Pavlovian conditioning sessions. Nicotine reliably enhanced conditioned responding to the conditioned cue, and inactivation of the OFC reduced conditioned responding, especially the sign-tracking response. OFC neurons exhibited phasic excitations to cue presentation and during goal tracking, and nicotine acutely blunted this phasic neuronal firing. When nicotine was withheld, both conditioned responding and phasic firing in the OFC returned to the level of controls. These results suggest that the OFC is recruited for the expression of conditioned responses, and that nicotine acutely influences this behavior by reducing phasic firing in the OFC.

Differentiating the primary reinforcing and reinforcement-enhancing effects of varenicline.

RATIONALE: Varenicline (VAR), a smoking cessation aid that is a partial agonist at nicotinic receptors, mimics the reinforcement-enhancing effects of nicotine. Varenicline, when accompanied by non-drug cues, is self-administered by rats, though it is unclear whether this results from varenicline acting as a primary reinforcer or a reinforcement enhancer of the cues. OBJECTIVES: This study sought to disentangle these two potential actions. METHODS: Rats were allowed to self-administer intravenous nicotine, saline, or varenicline during 1-h sessions in operant chambers equipped with two levers. Five groups had concurrent access to drug infusions and a moderately reinforcing visual stimulus (VS) for responding on separate levers. Meeting the reinforcement schedule on one lever was reinforced with VAR (0.01, 0.06, 0.1 mg/kg/infusion), nicotine (0.06 mg/kg/infusion), or saline, while meeting the same schedule on the other lever delivered the VS. Additional groups were reinforced for pressing a single "active" lever and received VAR paired with the VS, the VS with response-independent infusions of VAR, or VAR alone (0.1 mg/kg/infusion). RESULTS: Rats readily responded for VAR paired with VS on a single lever. However, when VAR was the only reinforcer contingent on a response, rats did not respond more than for saline. CONCLUSIONS: These findings show that VAR does not serve as a primary reinforcer in rats at doses that increase responding for non-drug reinforcers. These data are consistent with research showing that the primary reinforcing effects of VAR are weak, at best, and that the primary reinforcing and reinforcement-enhancing actions of nicotinic drugs are pharmacologically distinct.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by nicotine and they implicate dopaminergic systems both in conditioned approach as well as the incentive-promoting effects of nicotine.

Sex differences in adolescent methylphenidate sensitization: effects on glial cell-derived neurotrophic factor and brain-derived neurotrophic factor.

This study analyzed sex differences in methylphenidate (MPH) sensitization and corresponding changes in glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotprhic factor protein (BDNF) in adolescent male and female rats. After habituation to a locomotor arena, animals were sensitized to MPH (5mg/kg) or saline from postnatal day (P) 33-49, tested every second day. On P50, one group of animals were injected with saline and behavior assessed for conditioned hyperactivity. Brain tissue was harvested on P51 and analyzed for GDNF protein. A second group of animals was also sensitized to MPH from P33 to 49, and expression of behavioral sensitization was analyzed on a challenge given at P60, and BDNF protein analyzed at P61. Females demonstrated more robust sensitization to MPH than males, but only females given MPH during sensitization demonstrated conditioned hyperactivity. Interestingly, MPH resulted in a significant increase in striatal and accumbal GDNF with no sex differences revealed. Results of the challenge revealed that females sensitized and challenged with MPH demonstrated increased activity compared to all other groups. Regarding BDNF, only males given MPH demonstrated an increase in dorsal striatum, whereas MPH increased accumbal BDNF with no sex differences revealed. A hierarchical regression analysis revealed that behavioral sensitization and the conditioned hyperactivity test were reliable predictors of striatal and accumbal GDNF, whereas sensitization and activity on the challenge were reliable predictors of accumbal BDNF, but had no relationship to striatal BDNF. These data have implications for the role of MPH in addiction and dopamine system plasticity.

Effects of nicotine on olfactogustatory incentives: preference, palatability, and operant choice tests.

INTRODUCTION: The use of additives in tobacco may capitalize on the incentive motivational properties of tastes and scents such as mint (menthol), vanilla, and strawberry. These incentives are intended to increase tobacco experimentation, but their salience may also be enhanced by the incentive amplifying effects of nicotine (NIC). The goal of the present studies was to investigate the potential interaction between the incentive amplifying effects of NIC and gustatory incentives. METHODS: One of two discriminable tastes (grape or cherry Kool-Aid®; 0.05% wt/vol; unsweetened) was paired with sucrose (20% wt/vol; conditioned stimulus [CS+]) in deionized water, whereas the other taste (CS-) was presented in deionized water. Experiment 1 investigated the effects of NIC pretreatment on preference for the CS+ versus CS- in 2-bottle choice tests. Experiment 2 investigated the effects of NIC on palatability of the CS+ and CS- using orofacial taste reactions. Experiment 3 investigated the effects of NIC on reinforcement by the CS+ and CS- using a concurrent choice operant task. RESULTS: NIC pretreatment robustly increased operant responding for the CS+ but did not alter responding for the CS- in the operant choice task (Experiment 3). However, NIC pretreatment did not alter intake or palatability of the CS+ or CS- (Experiments 1 and 2). CONCLUSIONS: NIC increases the reinforcing effects of gustatory incentive stimuli, even though these stimuli were not paired with NIC administration. The findings suggest that adding taste incentives to tobacco products may increase the attractiveness of these products to consumers and the probability of repeated use.

The effect of nicotine on sign-tracking and goal-tracking in a Pavlovian conditioned approach paradigm in rats.

RATIONALE: Nicotine (NIC) potently increases operant responding for non-NIC reinforcers, and this effect may depend on drug-mediated increases in incentive motivation. According to this hypothesis, NIC should also potently increase approach to Pavlovian-conditioned stimuli associated with rewards. OBJECTIVE: The present studies explored the effects of NIC on Pavlovian-conditioned approach responses. METHOD: To do so, liquid dippers were used to deliver an unconditioned stimulus (US; 0.1 ml sucrose) after presentation of a conditioned stimulus (CS; 30 s illumination of a stimulus light)-both the CS and US were presented in receptacles equipped to monitor head entries. RESULTS: In experiment 1, the CS and US were presented in the same receptacle, but NIC pretreatment (0.4 mg/kg base) did not increase conditioned approach responses. Delivery of the sucrose US was then shifted to receptacle in a different location. All rats learned to approach the new US location (goal-tracking) at similar rates. Approach to the CS receptacle (sign-tracking) declined for saline-pretreated rats, but NIC pretreatment increased sign-tracking. In experiment 2, NIC pretreatment increased sign-tracking when the CS and US were spatially separated during acquisition. In experiment 3, NIC pretreatments were replaced with saline, but the effect of NIC persisted for an additional 24 test sessions. CONCLUSION: The findings suggest that NIC increases incentive motivation and that this effect is long-lasting, persisting beyond the pharmacological effects of NIC.

Caffeine increases the motivation to obtain non-drug reinforcers in rats.

BACKGROUND: Caffeine is widely considered to be a reinforcer in humans, but this effect is difficult to measure in non-human animals. We hypothesized that caffeine may have dual reinforcing effects comparable to nicotine--limited primary reinforcing effects, but potent reinforcement enhancing effects. The present studies tested this hypothesis by investigating the effect of caffeine on responding for non-drug rewards. METHODS: In two experiments, rats were shaped to respond on a progressive ratio (PR) schedule for sucrose solution (20%, w/v; experiment 1) or a fixed ratio 2 (FR2) schedule for a moderately reinforcing visual stimulus (VS; experiment 2). Pretreatment with various doses of caffeine (0-50 mg/kg, intraperitoneal injection) were administered prior to tests over successive week days (M-F). In experiment 1, acute administration of low-moderate caffeine doses (6.25-25 mg/kg) increased responding for sucrose under the PR schedule. This effect of caffeine declined over the initial 15 test days. In experiment 2, only acute pretreatment with 12.5mg/kg caffeine increased responding for the visual stimulus and complete tolerance to this effect of caffeine was observed over the 15 days of testing. In follow up tests we found that abstinence periods of 4 and 8 days resulted in incomplete recovery of the enhancing effects of caffeine. CONCLUSION: The findings suggest that caffeine enhances the reinforcing effects of non-drug stimuli, but that the pharmacological profile of these effects may differ from other psychomotor stimulants.

Varenicline dose dependently enhances responding for nonpharmacological reinforcers and attenuates the reinforcement-enhancing effects of nicotine.

INTRODUCTION: Varenicline (VAR), a partial nicotinic agonist, is one of the most effective smoking cessation pharmacotherapies. The therapeutic efficacy of VAR could be partly the result of substituting for and/or blocking the reinforcement-enhancing effects of nicotine (NIC). We assessed the effects of VAR alone and in combination with NIC (0.4 mg/kg) while rats pressed the lever for a moderately reinforcing visual stimulus (VS). METHODS: Rats were injected with placebo (0.9% saline), NIC, VAR (0.1-1 mg/kg), or NIC + VAR. A follow-up study was conducted with a broader dose range of VAR-alone dosages (0.01-3.0 mg/kg). All drug manipulations were conducted in a between-subjects design to prevent confounding effects of repeated exposure. RESULTS: There was a dose-dependent effect of VAR alone. Moderate doses of VAR (0.1 and 1.0 mg/kg) increased the number of VS presentations earned, while lower and higher VAR doses (0.01 and 3.0 mg/kg) did not change responding for the VS. VAR dose dependently attenuated the reinforcement-enhancing effects of NIC, with the highest dose (1.0 mg/kg) exhibiting the greatest antagonist effect. CONCLUSIONS: The results of these studies support the assertion that the therapeutic efficacy of VAR may be due to the partial agonist characteristics of the drug, specifically, its ability to partially replace the reinforcement-enhancing effects of NIC as well as antagonize these effects.

The role of conditioning history and reinforcer strength in the reinforcement enhancing effects of nicotine in rats.

RATIONALE: Nicotine (NIC) administration can increase behaviors that result in delivery of non-drug reinforcers (e.g., salient sensory stimuli). However, little is known about the circumstances under which NIC increases these behaviors. OBJECTIVE: The present studies sought to extend the reinforcement enhancing effects of NIC to sucrose rewards for which intensity could be systematically manipulated. METHOD: In Experiment 1, rats were trained to respond for sucrose (30% w/v) on a progressive ratio (PR) schedule of reinforcement and were pretreated with NIC (0.4 mg/kg free-base) or physiological saline (SAL). The intensity of the sucrose reward was manipulated over subsequent testing sessions (0-60% w/v). Similar procedures were used in Experiment 2; however, each subject received only one sucrose concentration (0-20%) to control for conditioning history. In Experiment 3, a fixed ratio 3 (FR3) schedule of reinforcement was used to investigate putative activating effects of NIC. Experiment 4 investigated whether NIC pretreatment would reduce sucrose intake in limited-access drinks. RESULTS: In Experiment 1, NIC increased the motivation to obtain all sucrose concentrations, including water. However, when conditioning history was controlled (Experiment 2) the reinforcement enhancing effects of NIC were systematically related to the strength of the reinforcer. In Experiment 3, NIC neither increased nor decreased responding for sucrose. In Experiment 4, NIC reduced sucrose intake, but only at concentrations that resulted in peak drink volumes (5-20%). CONCLUSION: The results suggest that the reinforcement enhancing effects of NIC depend on conditioning history and do not appear to be the result of simple behavioral activation.

Differential rearing conditions and alcohol-preferring rats: consumption of and operant responding for ethanol.

Exposing rats to differential rearing conditions during early postweaning development has been shown to produce changes in a number of behaviors displayed during adulthood. The purpose of the present studies was to investigate whether rearing alcohol-preferring (P) and nonpreferring (NP) rats in an environmental enrichment condition (EC), a social condition (SC), or an impoverished condition (IC) would differentially affect self-administration of 10% ethanol. In Experiment 1, rats were tested for consumption of 10% ethanol in limited- and free-access tests. For Experiment 2, rats were trained to respond in an operant chamber for ethanol and then provided concurrent access to 10% ethanol and water. Each solution was presented in a separate liquid dipper after meeting the schedule of reinforcement on distinct levers. After concurrent access tests, the water lever/dipper was inactivated and a progressive ratio (PR) schedule was initiated. Three successive solutions (10% ethanol, 15% ethanol, and 10% sucrose) were tested under the PR. For P rats, rearing in an EC reduced ethanol consumption, preference, and motivation to obtain ethanol, relative to P rats reared in an IC. Thus, exposure to a novel environment immediately after weaning acted to decrease the reinforcing properties of ethanol in an animal model for alcoholism.

Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats.

RATIONALE: Nicotine serves as a primary reinforcer but also potently enhances responding for nonnicotine stimuli with reinforcing properties. One of the most successful pharmacotherapies for smoking cessation, bupropion, also increases responding for nondrug reinforcers such as food and brain stimulation rewards. OBJECTIVE: The present studies investigated whether treatment with bupropion and nicotine had similar effects on responding for a reinforcing visual stimulus (VS). They also investigated whether the effects of bupropion and nicotine depended on common pharmacological substrates. RESULTS: Nicotine (0.4 mg/kg base) enhanced responding for the VS, and this enhancing effect increased across testing sessions, replicating our previous findings. Bupropion (3, 10, and 30 mg/kg salt) dose-dependently increased responding for the VS. Treatment with 10 and 30 mg/kg bupropion resulted in a profile similar to nicotine; operant responding increased over repeated drug treatments. The reinforcement enhancing effect of nicotine, but not bupropion, was blocked by pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine. In contrast, the reinforcement enhancing effect of bupropion, but not nicotine, was blocked by pretreatment with the alpha noradrenergic antagonist prazosin. CONCLUSION: The reinforcement enhancing effects of nicotine and bupropion increased over time and repeated treatments suggesting a shared mechanism of action. However, the reinforcement enhancing effects of nicotine are mediated by nicotinic acetylcholine receptors, whereas the reinforcement enhancing effects of bupropion were mediated by alpha noradrenergic receptors.

The role of nicotine in smoking: a dual-reinforcement model.

Models of intravenous nicotine self-administration in laboratory animals are being used to investigate the behavioral and neurobiological consequences of nicotine reinforcement, and to aid in the development of novel pharmacotherapies for smoking cessation. Central to these models is the principle of primary reinforcement, which posits that response-contingent presentation of a primary reinforcer, nicotine, engenders robust operant behavior, whereas response-independent drug delivery does not. This dictum of nicotine as a primary reinforcer has been widely used to explain why people smoke tobacco-smoking results in the rapid delivery of nicotine to the brain, setting up a cascade of neurobiological processes that strengthen subsequent smoking behavior. However, there is mounting evidence that the primary reinforcement model of nicotine self-administration fails to fully explain existing data from both the animal self-administration and human smoking literatures. We have recently proposed a "dual reinforcement" model to more fully capture the relationship between nicotine and self-administration, including smoking. Briefly, the "dual reinforcement" model posits that nicotine acts as both a primary reinforcer and a reinforcement enhancer. The latter action of nicotine had originally been uncovered by showing that a reinforcing VS, which accompanies nicotine delivery, synergizes with nicotine in the acquisition and maintenance of self-administration, and that this synergism can be reproduced by combining operant responding for the reinforcing stimulus with non-contingent (response-independent) nicotine. Thus, self-administration (and smoking) is sustained by three actions: (1) nicotine, acting as a primary reinforcer, can sustain behavior that leads to its delivery; (2) nicotine, acting as a primary reinforcer, can establish neutral environmental stimuli as conditioned reinforcers through Pavlovian associations; and (3) nicotine, acting as a reinforcement enhancer, can magnify the incentive value of accompanying stimuli, be they conditioned or unconditioned reinforcers.

Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats.

RATIONALE: Opioid neurotransmission has been implicated in reinforcement-related processes for several drugs of abuse, including opiates, stimulants, and alcohol. However, less is known about its role in the motivational effects of nicotine and nicotine-associated environmental cues. OBJECTIVE: This study investigated whether pretreatment with naltrexone, an opioid receptor antagonist, alters conditioned incentive salience of nicotine cues under two conditions: cue-induced reinstatement of nicotine-seeking after extinction and cue-maintained responding during extinction. The effect of naltrexone on nicotine self-administration during the maintenance phase was also examined. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to self-administer nicotine (0.03 mg/kg/infusion, i.v.) on a fixed-ratio 5 schedule and associate a conditioned stimulus (CS) with each nicotine delivery. Once responding was extinguished by saline substitution for nicotine and omission of the CS, the reinstatement tests were conducted following subcutaneous administration of naltrexone (0, 0.25, 1, 2 mg/kg). In separate groups of rats, naltrexone (0, 2 mg/kg) was chronically given before each extinction sessions, where responses on the active lever resulted in presentations of the CS without nicotine infusion (saline substitution). Self-administration/naltrexone tests were conducted in different groups of rats receiving similar nicotine self-administration training. RESULTS: Naltrexone significantly attenuated the CS-reinstated responding on the active, previously nicotine-reinforced lever in the reinstatement tests and the CS-maintained active lever responding during the extinction tests. In contrast, neither acute nor chronic naltrexone produced an effect on nicotine self-administration behavior. CONCLUSIONS: These results indicate that activation of opioid receptors is implicated in mediation of the conditioned incentive properties of nicotine cues but not in the maintenance of nicotine self-administration. Therefore, these findings suggest that opioid receptor antagonists might have clinical potential for prevention of smoking relapse associated with exposure to environmental cues.

Occasion setting by drug states: Functional equivalence following similar training history.

Three experiments examined whether a drug state serving as a positive feature for pairings between a discrete conditional stimulus (CS, 15-s light or 15-s noise) and sucrose could transfer facilitative control to a CS with which it had never been presented. To do so, a CS was paired with a sucrose reward in the nicotine (0.4 mg/kg), amphetamine (AMP, 1mg/kg), or chlordiazepoxide (CDP, 5mg/kg) drug state; in separate saline sessions the CS was presented but was not followed by any reward. All three drug states facilitated responding to a discrete CS; previous studies found that this facilitation did not depend on direct associations between the drug state and sucrose. When a second discrimination was trained (e.g., CDP: light-sucrose and nicotine: noise-sucrose) the drug states facilitated responding to the CS trained in that state (nicotine: noise) as well as the CS normally presented in the other drug state (e.g., nicotine: light). A novel drug state (e.g., amphetamine) did not affect responding to either CS, indicating that the originally trained drug states had acquired functional similarity based on learning history. Also, a novel or ambiguous CS did not evoke responding in the previously trained drug state, indicating that both the features (drug states) and target conditional stimuli had to be trained in discriminations before transfer could occur.

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

RATIONALE: The motivational effects of nicotine-associated cues have been demonstrated in animal studies. However, it is unknown whether the effectiveness of nicotine cues in reinstating nicotine-seeking varies with the extent of prior nicotine self-administration. In addition, the issue of whether bupropion (an FDA-approved smoking cessation medication) interferes with the conditioned incentive of nicotine cues remains to be addressed. OBJECTIVE: This study determined the relationship of cue-reinstated nicotine-seeking and the levels of prior self-administration and examined the effect of bupropion on cue-induced reinstatement of nicotine-seeking in comparison with that on self-administration. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine at different doses (0, 0.015, 0.03, 0.06 mg/kg/infusion) and to associate an auditory/visual cue with each nicotine delivery. After extinction, three reinstatement tests at 15 day intervals were conducted with re-presentation of the cue without nicotine delivery. In separate groups of rats trained with 0.03 mg/kg/infusion nicotine, bupropion (0, 10, 20, 40 mg/kg) was intraperitoneally administered to different groups before the reinstatement and in a within-subject design before the self-administration tests. RESULTS: Cue-induced reinstatement of active lever responses was observed at all nicotine doses in the first reinstatement test, but at only the two highest doses during the second and third tests. The magnitude of reinstatement was positively correlated with level of prior responding for nicotine. Bupropion pretreatment decreased nicotine self-administration but enhanced cue-reinstated nicotine-seeking. CONCLUSIONS: These results demonstrate the positive correlation of cue-reinstated nicotine-seeking with prior responding for nicotine self-administration and the persistence of the cue effect after taking higher doses of nicotine. The results of pharmacological tests suggest that although it is able to help achieve smoking cessation, bupropion may have little clinical benefit for the prevention of relapse associated with exposure to environmental smoking cues.

Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine.

Nicotine self-administration models typically evaluate the effects of smoking cessation aides on 'primary reinforcement' engendered by nicotine. However, the more recently described reinforcement enhancing effects of the drug are not always included in experimental analyses of potential therapeutics. We evaluated the effects of pretreatment with noncompetitive antagonists of the metabotropic glutamate 5 receptor (mGluR5) on each reinforcement-related effect of nicotine using a model in which a reinforcing visual stimulus (VS) and nicotine infusions were concurrently available. Five groups (2-lever, VS-only, NIC+VS, NIC-only, or SAL-only) were instrumented for self-administration. The 2-lever group could earn a nicotine infusion (0.06 mg/kg per infusion free base) for meeting the schedule on one lever (eg right), or VS for meeting the schedule on the other lever (eg left). The VS-only group could earn VS or saline under similar contingencies. Remaining rats could press one lever to earn both reinforcers (NIC+VS), nicotine infusions (NIC-only), or saline infusions (SAL-only); the other lever was 'inactive'. Responding on the VS lever in the 2-lever group was greater than that of the VS-only group, reflecting the reinforcement-enhancing effect of nicotine. Pretreatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) decreased nicotine intake as well as the enhanced responding for the concurrently available VS. In follow-up studies, replacing nicotine via experimenter-administered infusions sustained the drugs reinforcement enhancing effect; neither MPEP nor MTEP decreased the enhancing effects of nicotine. These findings are consistent with other studies suggesting that mGlu5 receptors mediate nicotine seeking, but do not alter the reinforcement enhancing effects of nicotine.

Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine.

RATIONALE: Nicotine is widely assumed to convey reinforcing properties upon tobacco-related stimuli through associative learning. We have proposed that the reinforcement derived from these conditional stimuli can be inflated by a nonassociative "reinforcement-enhancing" effect of nicotine. OBJECTIVES: Experiment 1 investigated whether nicotine could establish a stimulus as a conditioned reinforcer. Using the same subjects, Experiment 2 examined whether responding for a nicotine-associated stimulus was enhanced by response-independent administration of nicotine. MATERIALS AND METHODS: Self-administered nicotine (Paired group, 0.03 mg kg(1) infusion(-1)) or saline (conditional stimulus or CS-Only group) was paired with a stimulus light (CS). An Unpaired group, yoked to the Paired group, received equal exposure to nicotine and the CS, but each event was temporally separated. To test for conditioning, the CS was then made contingent upon a novel lever-pressing response. In Experiment 2, a subset of the paired rats (self-administering) continued to lever press while receiving contingent nicotine and the CS. To determine whether nicotine enhanced responding for the CS, two remaining subsets of the Paired group responded for the CS while receiving nicotine (YNIC) or saline (YSAL) yoked to the self-administering rats. All remaining control groups received response-contingent CS presentations, together with yoked nicotine or saline. RESULTS: Pairing self-administered nicotine with the CS promoted the acquisition of a novel response for the CS. In Experiment 2, the Paired YNIC group responded at higher rates than control groups receiving YNIC or YSAL. CONCLUSIONS: Nicotine can establish stimuli as conditioned reinforcers for which noncontingent nicotine can enhance responding.