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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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).

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.

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.

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.

Impact of brief or extended extinction of a taste aversion on inhibitory associations: evidence from summation, retardation, and preference tests.

In five conditioned taste aversion experiments with rats, summation, retardation, and preference tests were used to assess the effects of extinguishing a conditioned saccharin aversion for three or nine trials. In Experiment 1, a summation test showed that saccharin aversion extinguished over nine trials reduced the aversion to a merely conditioned flavor (vinegar), whereas three saccharin extinction trials did not subsequently influence the vinegar aversion. Experiment 2 clarified that result, with unpaired controls equated on flavor exposure prior to testing; the results with those controls suggested that the flavor extinguished for nine trials produced generalization decrement during testing.

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.

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.

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.

Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats.

Rationale: Recent studies have demonstrated that nicotine can enhance operant responding for other nonpharmacological reinforcing stimuli. However, the nature of the reinforcement-enhancing effect of nicotine remains largely unknown.

Objective: The present study determined the dose dependency of the ability of nicotine to increase lever-pressing responses maintained by a compound visual stimulus (VS) in rats and examined its sensitivity to pharmacological antagonism of nicotinic acetylcholine receptors (nAChRs).

The interoceptive Pavlovian stimulus effects of caffeine.

The present research sought to test whether caffeine functioned as a Pavlovian cue in two ways--as a positive drug feature or as a conditional stimulus (CS). As a positive feature (Experiment 1), brief light presentations were followed by sucrose only on sessions in which caffeine (10 mg/kg) was administered. On intermixed saline sessions, light presentations were not followed by sucrose.

The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections.

We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.

Facilitation by drug states does not depend on acquired excitatory strength.

Three experiments examined the effects of drug-extinction when a drug state served as a conditional stimulus (CS) for sucrose delivery or as a positive feature for pairings between a discrete CS (e.g., 15-s light-on) and sucrose.