The Reference-Dose Place Conditioning Procedure Yields a Graded Dose-Effect Function

A major criticism of the place conditioning procedure for studying conditioned drug reward is that it is relatively insensitive to large quantitative shifts in drug dose (i.e., dose effects are all or none). Experiment 1 demonstrated this lack of sensitivity using a wide range of intravenous (IV) cocaine doses (O.1, 0.3, 0.45, 0.6, 0.9, or 1.2 mg/kg). Rats had cocaine repeatedly paired with one distinct end compartment of a 3 compartment apparatus; vehicle was administered in the other end compartment. In a subsequent drug-free choice test, the 0.45 to 1.2 mg/kg doses of cocaine conditioned a place preference. The magnitude of the effect did not differ. Experiment 2 used a modified version of this standard place conditioning method. In this alternative method termed reference-dose procedure, a fixed dose of cocaine (reference dose) was repeatedly paired with one end compartment (i.e., 0.45 mg/kg); the comparison dose of cocaine was administered in the other end compartment (vehicle, 0.6, or 1.2 mg/kg). Preference for the comparison-dose compartment increased with dose—a graded dose effect curve. In contrast to the standard procedure, the reference-dose procedure revealed that the conditioned rewarding effect of 1.2 mg/kg of cocaine was greater than that of 0.45 mg/kg. This increase in sensitivity to conditioned reward with the reference-dose procedure will likely increase the utility of the place conditioning method as a preclinical model, as well as a procedure for studying processes mediating associatively-motivated choice behavior

Altering the Motivational Function of Nicotine through Conditioning Processes

The collection of chapters in this 55th Nebraska Symposium on Motivation Volume clearly highlights that effective strategies for reducing compulsive tobacco use will require a multifaceted approach in which genetic, neurobiological, individual, and cultural factors are considered. It is difficult, if not impossible, to predict where the next important breakthrough will come from (Bevins & Bardo, 2004; Dethier, 1966; Laidler, 1998). Accordingly, further research that extends and challenges current theory and practice at each of these levels of analysis is needed. The continuing focus of our research program, and the topic of the present chapter, is on the role of Pavlovian conditioning processes involving nicotine. Theoretical and empirical approaches to nicotine dependence that include Pavlovian conditioning processes have lead to important advances in our understanding and treatment of chronic tobacco use (e.g., see Rose, Chapter 8 and Tiffany, Warthen, & Goedecker, Chapter 10 in current Volume). These approaches conceptualize the drug as an unconditioned stimulus (US) or reinforcer. That is, the pharmacological effects of the drug (e.g., reward, analgesia, psychomotor stimulation) enter into an association with stimuli that reliably co-occur with these effects (e.g., paraphernalia, situational cues). Later exposure to these conditioned stimuli (CSs) can evoke conditioned responses (CRs) that increase the chances an individual will seek drug. More recently, we have suggested that the interoceptive stimulus effects of nicotine might also serve as a CS for other appetitive non-drug outcomes (i.e., USs) and/or a stimulus that occasions whether other CS-US associations will or will not occur (i.e., an occasion setter or facilitator; see Bevins & Palmatier, 2004). We have further suggested that such an associative learning history could impact the tenacity of nicotine addiction—e.g., shorten the time between experimentation and dependence, increase the difficulty of quitting, make sustaining abstinence more difficult, etc. At the current time these suggestions are speculative. With this in mind, the present chapter will review the research in this area, as well as highlight some of its historical precursors and suggest some possible future directions for research. In doing so, hopefully the reader will gain an appreciation for how this approach might lead to further insight into how Pavlovian conditioning processes can alter the motivational function of nicotine in a manner that contributes to chronic tobacco use

Individual differences in rat locomotor activity are diminished by nicotine through stimulation of central nicotinic acetylcholine receptors

An increasing body of research has focused on isolating factors that predict or alter individual differences in the behavioral and neural processes mediating the effects of abused drugs. Within this framework, the current report assessed individual differences and the locomotor effect of nicotine. Rats were screened for activity induced by a novel environment. Rats, which were more active to initial environment exposure, remained more active even after seven additional 30-min exposures to the same environment. Treatment with nicotine-di-D tartrate (1 mg/kg, sc) disrupted this effect. This nicotine disruption of individual differences occurred whether nicotine suppressed locomotor activity (initial administration) or stimulated locomotor activity (seventh and eighth administration). Mecamylamine (1 mg/kg), but not hexamethonium (10 mg/kg), completely blocked the suppressant and stimulant effects of nicotine. Further, mecamylamine restored the nicotine-induced disruption of individual differences; hexamethonium had no effect. This data pattern suggests that the disruptive effects of acute and chronic nicotine on individual differences were mediated by neural nicotinic acetylcholine (nACh) receptors

Interoception and Learning: Import to Understanding and Treating Diseases and Psychopathologies

Chemotherapeutic agents nauseate cancer patients. Some individuals with schizophrenia hear voices. Chronic pain can be reduced by analgesics. Nausea, voices, and pain are examples of internal (interoceptive) stimuli closely linked with a disease and/or its treatment. There is evidence that the perception and, hence, role of these internal stimuli can be modified by one’s learning history. There is also increased awareness by researchers and practitioners of the potential import of learning involving internal states to some diseases and psychopathologies. Unfortunately, the science, theory, and practice appear to be trailing behind awareness. In this mini-review, we describe two examples: smoking and panic disorder. While doing so, we discuss the need to develop translationally relevant animal models that will allow investigators to better understand the behavioral and neural mechanisms underlying interoception and learning

Impact of Nicotine Withdrawal on Novelty Reward and Related Behaviors

The authors tested the decreased reward function hypothesis of nicotine withdrawal using a novel-object place conditioning task. A conditioned place preference was evident in controls and in rats that had experienced 4 nicotine withdrawal days, but not in rats that had experienced 1–3 withdrawal days. This implies that the rewarding properties of interacting with novel objects were not readily associated with the environment in which they were paired. Follow-up experiments eliminated other explanations based on withdrawal-induced failures to process object or environment information. Also, expression of conditioning was not affected, indicating that withdrawal likely altered acquisition. Further investigation into the neurochemical and behavioral changes that accompany nicotine withdrawal will lead to a better understanding of the withdrawal syndrome

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, 1 mg/kg), or chlordiazepoxide (CDP, 5 mg/ 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

Interoceptive conditioning in rats: Effects of using a single training dose or a set of 5 different doses of nicotine

Interoceptive conditioning contributes to the tenacity of nicotine dependence. Previous research investigating nicotine as an interoceptive stimulus has typically employed administration of a single training dose of nicotine over an extended time. This approach has allowed for careful study of the nicotine stimulus. In humans, the nicotine stimulus is unlikely to be fixed across learning episodes. Thus, from a translational perspective, systematic variation of nicotine dose in training might better approximate interoceptive conditioning in humans. Notably, training with a class or set of discrete exteroceptive stimuli (e.g., different pictures of cars) produces interesting behavioral differences relative to training with a single stimulus. The present study sought to determine whether similar differences would occur if a set of nicotine stimuli were used in place of a single dose. To investigate this question, one group of male Sprague-Dawley rats was trained on a discriminated goal-tracking task with a set of nicotine doses (0.05, 0.125, 0.2, 0.275, and 0.35 mg/kg). A second group received the standard protocol of training with a single nicotine dose (0.2 mg/kg). On each nicotine session, there was intermittent access to liquid sucrose (26%) in a conditioning chamber. On intermixed saline sessions, sucrose was withheld. We examined acquisition, subsequent extinction, transfer of extinction, nicotine generalization, and mecamylamine blockade. Both groups reliably discriminated between nicotine and saline sessions, were sensitive to non-reinforcement, displayed transfer of extinction, demonstrated dosedependent nicotine generalization, and responding was blocked by mecamylamine. There were no significant differences between the two groups. The unique nature of an interoceptive pharmacological stimulus and the challenges posed for studying the impact of training with a set of interoceptive stimuli are discussed

Forced Abstinence Model of Relapse to Study Pharmacological Treatments of Substance Use Disorder

Understanding and preventing relapse to drug use is one of the most difficult challenges faced by clinicians and practitioners in the struggle to help people remain abstinent. In this paper, we review basic preclinical research on forced abstinence periods that identify the neural substrates involved and neural adaptations that occur after a drug-free period. Our attention focuses on forced abstinence after self-administration because of its promise for translational research in the development of candidate medications to reduce relapse. This model requires subjects (often rats) to initially acquire drug self-administration. However, rather than extinguishing behavior with daily drug-free sessions as in the reinstatement model of drug seeking, subjects are removed from the self-administration situation and do not receive any exposure to the drug. Notably, the integrity of the drug-taking behavior and the drug-associated cues in the drug-taking environment are preserved because they are not experienced in the absence of the drug. Research shows time dependent increases in drug-seeking following forced abstinence periods. More so, neural substrates and adaptations within the mesocorticolimbic system and the nigrostriatal system have been identified that contribute to increased drug seeking following abstinence. From a translational perspective, behavioral and pharmacological treatment of substance use disorder often starts during this initial abstinence period (either forced or voluntary). The forced abstinence model simulates some of the features of this treatment situation and thus allows for the study of potential treatments that alter relapse of drug-seeking behaviors along with the accompanying neurobiological changes

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, 1 mg/kg), or chlordiazepoxide (CDP, 5 mg/ 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

Excitatory conditioning to the interoceptive nicotine stimulus blocks subsequent conditioning to an exteroceptive light stimulus.

Previous research has shown that a nicotine conditional stimulus (CS) can compete with (i.e., overshadow) a brief light CS. Another form of competition, blocking, has not yet been examined with the nicotine CS. Groups of rats were assigned to an element training condition. For the N+ group, during each daily 2-hr element training session, there were ten intravenous nicotine infusions (0.03 mg/kg) followed 30-sec later with 4-s access to sucrose. In the N- group, nicotine and sucrose presentations were explicitly unpaired. The chamber alone group (C alone) had no stimulus presentations. Element training was followed by compound training in all groups. A 30- sec houselight was included during the time between the nicotine infusion and paired sucrose delivery. Non-reinforced element presentations assessed relative control of the goal tracking conditioned response (CR). The N+ group showed a higher proportion of CR control by the nicotine than the light. The opposite pattern was found in the N- and C alone groups indicating that nicotine CS controlled less of the CR than the light. Thus, excitatory conditioning with the nicotine CS blocked later conditioning to the light. This finding adds to literature examining the interaction between interoceptive drug CSs and other environmental stimuli