Matthew I. Palmatier

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

RationaleAlthough considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed at reducing smoking remain deficient.ObjectivesThis review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented.ConclusionsAnimal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper—that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers—provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.

Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers

RationaleNicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers.ObjectivesThe present study sought to dissociate these two effects of nicotine on reinforcement.MethodsFor one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever. Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine infusions (NIC only) or VS presentations (VS only) for pressing the active lever.ResultsNicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC + VS).ConclusionsThese data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.

Novel-object place conditioning: behavioral and dopaminergic processes in expression of novelty reward.

In a choice situation, rats given repeated access to novel objects in one of two distinct environments display an increase in preference for the novelty-paired environment. The experiments in this present report extend the generality of this effect to new procedures. Further, this shift in preference depends on object novelty; no systematic shift in preference was observed if the environment was paired with a familiar object. Experiments in the present report also provided evidence against non-associative accounts that rely on mechanisms that leave the paired environment more novel than the unpaired environment (e.g. object interaction interfering with environmental familiarization). Consistent with a conditioning account is the loss of place conditioning when access time with the novel objects was shortened from 10 min to 5 or 2.5 min. Interestingly, although a decrease in time with objects prevented place conditioning, these groups showed a novelty-conditioned increase in activity. Finally, treatment with the dopamine D(1) antagonist SCH-23390 (0.03 mg/kg) or the dopamine D(2)/D(3) antagonist eticlopride (0.1 mg/kg) before the post-conditioning preference test blocked expression of the novel-object place conditioning. Taken together, these experiments establish that the increased preference produced by object-environment pairings reflects a conditioned association between environmental cues and the appetitive effects of receiving access to novel stimuli.

Immunization to nicotine with a peptide-based vaccine composed of a conformationally biased agonist of C5a as a molecular adjuvant.

This paper describes the synthesis of a nicotine hapten (Nic) that possesses a carboxyl sidearm functional group allowing for conjugation to a peptide via amide bond formation. Nic was attached to the N-terminal amino group of a 19-residue peptide composed of a conformationally biased agonist of human C5a (YSFKPMPLaR), which is used as a molecular adjuvant and a B cell epitope of human MUC1 glycoprotein (YKQGGFLGL) to yield a peptide-based nicotine vaccine, NicYKQGGFLGLYSFKPMPLaR. Rats immunized with this vaccine were significantly less sensitive to behavioral effects (a Pavlovian discrimination task) induced by their exposure to high concentrations of nicotine (0.4 mg/kg) relative to their non-vaccinated counterparts. The attenuation of these nicotine-induced behavioral effects emanated from the presence of nicotine-specific antibodies (Abs) that were present in the sera of vaccinated rats even after their repeated exposure to high concentrations of nicotine during the time required to perform the behavioral assays. These results suggest that immunization with NicYKQGGFLGLYSFKPMPLaR in the absence of adjuvant is an effective means of inducing a nicotine-specific Ab response, which is capable of attenuating nicotine-induced behavioral/psychoactive effects.

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.

The Role of Nicotinic Acetylcholine Receptors in the Primary Reinforcing and Reinforcement-Enhancing Effects of Nicotine

The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose–response relationships (0, 30, 60, or 90 μg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose–response relationship for active lever responding in the NIC+VS group. The dose–response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and chronic profiles.

Nicotine-conditioned locomotor sensitization in rats: assessment of the US-preexposure effect

In rats, stimulus-nicotine associations can be altered by preexposure to the nicotine US (unconditioned stimulus). This alteration differs with the conditioning preparation. In a conditioned taste avoidance preparation, preexposure to nicotine weakens conditioning. In contrast, nicotine preexposure enhances acquisition of a nicotine-conditioned place preference. No one has examined the effects of US preexposure on nicotine locomotor conditioning. In three separate experiments, we assessed the effects of nicotine preexposure on the subsequent expression of conditioned hyperactivity produced by a nicotine US. We found evidence for nicotine-conditioned locomotor sensitization in non-preexposed rats that received repeated pairings of a distinct context with the psychomotor effects of a 0.42 mg/kg dose of nicotine (free base). Conditioning was not observed at lower nicotine doses (0.18 and 0.11 mg/kg) in non-preexposed rats. Preexposure to the 0.42 and 0.18 mg/kg doses of nicotine (3 or 9 days) attenuated acute locomotor suppression and enhanced the development of locomotor sensitization to that same dose. Despite similar qualitative shifts in the locomotor profile induced by preexposure to the nicotine US, conditioned hyperactivity was only altered after 3 or 9 days of preexposure at the 0.18 mg/kg dose. Thus, similar to place conditioning, nicotine preexposure can enhance the subsequent effectiveness of the nicotine US in a locomotor conditioning preparation.

Stimulus Properties of Nicotine, Amphetamine, and Chlordiazepoxide as Positive Features in a Pavlovian Appetitive Discrimination Task in Rats

Recent experiments from our laboratory have demonstrated that drug states can signal when environmental cues will be followed by rewarding outcomes (ie Pavlovian conditioning). However, little is known about the generality of this approach and whether it can be used for studying the pharmacological properties of drug states. Accordingly, the present experiments tested the pharmacological specificity of nicotine (0.4 mg/kg), amphetamine (1 mg/kg), and chlordiazepoxide (CDP, 5 mg/kg) in this Pavlovian drug discrimination procedure. Following drug administration, presentation of a conditional stimulus (CS) was followed by brief access to sucrose. When saline was administered, the same CS was presented but sucrose was withheld. In substitution tests, rats in each condition received varying doses of all training drugs and caffeine. Anticipatory food seeking developed during the CS on drug sessions but not on saline sessions for all drug features (ie drug state-specific conditional response (CR)). In generalization tests, this CR decreased as a function of decreases in the training dose. Median effective doses (ED50s) were calculated for nicotine (0.054 mg/kg), amphetamine (0.26 mg/kg), and CDP (2.48 mg/kg). No compound tested substituted for the CDP training drug. Partial substitution was evident between nicotine and amphetamine; CDP did not substitute for either of these drug features. Caffeine fully substituted for nicotine (ED50=15.45 mg/kg) and amphetamine (ED50=3.70 mg/kg), but not for CDP. These results are consistent with the hypothesis that drug states can occasion appetitive Pavlovian CRs in a pharmacologically specific manner.

The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose

Stimuli associated with nicotine (NIC) can acquire new meaning via Pavlovian conditioning. If a stimulus is associated with the primary reinforcing effects of NIC, the new conditional properties of the stimulus should make it a more valuable reinforcer (i.e., increase the motivation to obtain the stimulus), and this value should be based, in part, on the strength or intensity of the primary reinforcer (i.e., NIC dose). The purpose of the present study was to investigate whether NIC-conditioned reinforcement increased motivation to obtain non-NIC stimuli, as reflected by performance on a progressive ratio (PR) reinforcement schedule, and whether this increased motivation was systematically related to NIC dose. Two Paired groups were allowed to nose-poke for NIC (0.03 or 0.09mg/kg/infusion, IV) accompanied by 15-s illumination of a stimulus light (conditional stimulus or CS). Two Unpaired groups (0.03 or 0.09mg/kg/infusion) could also make a nose-poke response for the CS; however their NIC infusions were controlled by the Paired group (i.e., yoked design). A fifth group (CS-Only) was allowed to nose-poke for CS presentations and saline infusions. After 29 conditioning sessions the nose-poke operant was prevented by obscuring the receptacle and the CS (accompanied by saline infusion for all groups) was made contingent upon a novel operant response (lever press). During the acquisition of this novel response, each CS/saline infusion earned increased the number of responses required to earn the next CS/saline infusion. Pairings with the primary reinforcing effects of NIC resulted the acquisition of a novel response for the CS. Motivation to obtain the CS depended on salience (dose) of the primary reinforcement (NIC).

Examination of GABAergic and Dopaminergic Compounds in the Acquisition of Nicotine-Conditioned Hyperactivity in Rats

In rats, a distinct environment repeatedly paired with nicotine (0.421 mg/kg base, s.c.) comes to evoke an increase in activity in the absence of any drug. This hyperactivity indicates a Pavlovian-conditioned association between the environment and nicotine. We investigated whether a dopamine D1 receptor antagonist (SCH-23390), a D2/D3 antagonist (eticlopride) or a GABAB agonist (baclofen) would prevent the acquisition of nicotine-conditioned hyperactivity. In saline-pretreated rats, acute nicotine suppressed activity during the conditioning phase (i.e. environment-nicotine pairings); chronic nicotine stimulated activity. Pretreatment with SCH-23390 (0.01 mg/kg, i.p.) attenuated the activating effects of nicotine without affecting controls. Eticlopride (0.03–0.07 mg/kg, i.p.) and baclofen (0.625 and 1.25 mg/kg, i.p.) did not affect nicotine-induced activity in a selective manner. Regardless of the pretreatment drug, rats acquired the environment-nicotine association as indexed in a drug-free test. The inability of SCH-23390 to block the acquisition of nicotine-conditioned locomotor activity is notable because in past research SCH-23390 blocked expression of the learned association.