Nadia Chaudhri

Cue dependency of nicotine self-administration and smoking

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

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

RationaleCurrent 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.ObjectivesThese 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.MethodsRats self-administered nicotine or food, or received noncontingent nicotine, saline, or food either with or without a response-contingent, unconditioned reinforcing visual stimulus (VS).ResultsNoncontingent 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.ConclusionsNicotine 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.

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.

Importance of nonpharmacological factors in nicotine self-administration.

There is mounting evidence that nonpharmacological factors critically modulate the effects of several drugs of abuse both in humans and experimental animals. This paper reviews research from this laboratory on one factor that influences the degree to which nicotine is self-administered: environmental stimuli that form the context within which nicotine is taken. The results suggest that the direct, pharmacological actions of nicotine are necessary but not sufficient to explain either the high rates of self-administration exhibited by laboratory animals or cigarette smoking by humans, and that future investigations on the neurophysiological effects of nicotine that underlie smoking behavior must take into account the environmental context within which the behavior occurs.

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.

Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior.

Addiction is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. The NMDA receptor (NMDAR), which is a major target of alcohol, is implicated in striatal-based habit learning. We found that, in the dorsal striatum, alcohol (ethanol) exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol-mediated long-term facilitation (LTF) of the activity of NR2B-containing NMDARs (NR2B-NMDARs) in the dorsal striatum. This LTF is Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior.

Separable Roles of the Nucleus Accumbens Core and Shell in Context- and Cue-Induced Alcohol-Seeking

Conditioned responding to drug-predictive discrete cues can be strongly modulated by drug-associated contexts. We tested the hypothesis that differential recruitment of the nucleus accumbens (NAc) core and shell mediates responding to drug cues in a drug vs non-drug context. Rats were trained to discriminate between two 10-s auditory stimuli: one stimulus (CS+) was paired with ethanol (10% v/v; 0.2 ml; oral) whereas the other (CS−) was not. Training occurred in operant conditioning chambers distinguished by contextual stimuli, and resulted in increased entries into the ethanol delivery port during the CS+ when compared with the CS−. In experiment 1, port entries were then extinguished in a second context by withholding ethanol, after which context-induced renewal of ethanol-seeking was tested by presenting both stimuli without ethanol in the previous training context. This manipulation stimulated strong responding to the CS+ in rats pretreated with saline in the core (n=9) or shell (n=10), which was attenuated by pharmacologically inactivating (muscimol/baclofen; 0.1/1.0 mM; 0.3 μl/side) either subregion pretest. In experiment 2, after discrimination, training rats were habituated to a different context in which ethanol and both stimuli were withheld. Cue-induced ethanol-seeking was then elicited by presenting the CS+ and CS− without ethanol in the different context. Saline-pretreated rats responded more to the CS+ than the CS− (core n=8; shell n=9), and inactivating the core but not shell attenuated this effect. These data highlight an important role for the core in cue-induced ethanol-seeking, and suggest that the shell is required to mediate the influence of contexts on conditioned ethanol-seeking.

Reinstated ethanol‐seeking in rats is modulated by environmental context and requires the nucleus accumbens core

The reinstatement of ethanol (EtOH)‐seeking induced by an EtOH‐predictive light‐tone stimulus is enhanced in an environment associated with prior EtOH self‐administration (SA) compared with a context associated with EtOH unavailability ( Tsiang & Janak, 2006 ). Here we hypothesized that EtOH‐seeking would be elicited by the conditioned sensory stimulus properties of EtOH and that this reinstatement would be similarly modulated by context. We also determined whether pharmacologically inactivating the nucleus accumbens (NAc), a key structure in relapse circuitry, would attenuate reinstated EtOH‐seeking. Rats lever‐pressed for oral EtOH (10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory and tactile stimuli. Responding was then extinguished by withholding EtOH in a different context. EtOH‐seeking, expressed as elevated responding without EtOH delivery, was subsequently tested by presenting an oral EtOH prime (two aliquots of 0.1 mL EtOH) in either the extinction or the prior EtOH‐SA context. Rats received a microinfusion (0.3 μL/hemisphere) of saline or GABA agonists (muscimol/baclofen) into the NAc core or shell immediately before the reinstatement test. Robust EtOH‐seeking was observed in the prior EtOH‐SA but not the extinction context in saline‐pretreated rats. This effect was significantly attenuated by inactivating the NAc core but not shell. Conversely, NAc shell inactivation significantly elevated lever‐pressing in the extinction context. These data suggest that the sensory stimulus properties of oral EtOH can reinstate EtOH‐seeking when experienced in the appropriate context and that functional activity in the NAc core is required for this effect. In contrast, the shell may normally inhibit incorrect behavioral responses.

Context-induced relapse of conditioned behavioral responding to ethanol cues in rats.

BACKGROUND The environmental context in which drug-conditioned cues are encountered could modulate the capacity of such cues to trigger relapse in abstinent addicts. We explored this hypothesis using a behavioral animal model. METHODS Rats were trained to discriminate between two auditory stimuli; the first (CS+) was paired with 10% ethanol and the second (CS-) was presented without ethanol. Training occurred in operant conditioning chambers equipped with distinct contextual stimuli, and entries into the ethanol delivery port during the stimuli were measured. Behavior was then extinguished by presenting both stimuli without ethanol in a second, different context. Context-dependent renewal of port entries was tested by presenting the CS+ and CS- without ethanol in the original training context. RESULTS At test, port entries during the CS+ increased compared with extinction levels, while responding during the CS- remained unchanged (n = 11). This effect was attenuated after multiple extinction sessions in three distinct contexts (n = 18), compared with an equivalent number of extinction sessions in a single unique context (n = 16). Context-dependent renewal of port entries was also observed to a CS+ paired with 14% sucrose (n = 7) but not to a CS+ paired with 2% sucrose (n = 8). CONCLUSIONS Environmental contexts can trigger the relapse of behavioral responding to ethanol- and sucrose-predictive cues in rats. For ethanol, this effect can be reduced by extinguishing responses to the ethanol cue in multiple distinct contexts, a manipulation that could increase the efficacy of cue-reactivity treatments for addiction.

The Potent Effect of Environmental Context on Relapse to Alcohol-Seeking After Extinction

Environments in which the pharmacological effects of alcohol have been experienced become potent triggers for relapse in abstinent humans. Animal models developed to study the effect of environmental contexts on relapse to alcohol-seeking behavior demonstrate that alcohol-seeking is renewed by exposure to an alcohol-associated context, following the extinction of alcohol-seeking in a different context. Hence, contexts in which alcohol conditioning and extinction learning occur can be critical determinants for whether or not alcohol-seeking behavior is observed. This review summarizes preclinical research to date examining the role of alcohol contexts on the reinstatement of extinguished responding for alcohol. Behavioral studies have elucidated factors that are important for eliciting context-dependent relapse, and have uncovered novel interactions between alcohol-seeking driven by discrete alcohol cues in different contexts. Neuropharmacological studies provide substantial evidence for a role of dopaminergic systems in context-dependent reinstatement, and growing support for opioidergic mechanisms as well. Several key limbic brain regions have been identified in the modulation of alcohol-seeking by context, supporting a proposed neural circuit that includes the hippocampus, nucleus accumbens, basolateral amygdala, lateral hypothalamus, and the paraventricular thalamus.