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RATIONALE: When people with drug addiction encounter cues associated with drug use, this can trigger cravings and relapse. These cues can include conditioned stimuli (CSs) signaling drug delivery and discriminative stimuli (DSs) signaling drug availability. Compared to CS effects, DS effects are less explored in preclinical studies on cue-induced relapse. OBJECTIVE: We compared CS and DS effects on reward seeking following abstinence from intermittent-access cocaine (or sucrose) self-administration. METHODS: During 15-20 intermittent-access sessions, rats self-administered i.v. cocaine or sucrose pellets paired with a light-tone CS. Cocaine/sucrose was available for 5-min (signalled by a light; DS+) and unavailable for 25 min (signalled by different lighting conditions; DS-), and this cycled for 4 h/session. Following abstinence, we measured cocaine/sucrose seeking under extinction triggered by CS and DS presentation, and instrumental responding reinforced by these cues. RESULTS: Across intermittent-access sessions, rats increased lever pressing for cocaine or sucrose during DS+ periods and decreased responding during DS- periods. On days 2 and 21 of abstinence, only presentation of the DS+ or DS+ and CS combined elicited increased cocaine/sucrose-seeking behaviour (i.e., increased active lever presses). Presenting the DS- alongside the DS+ suppressed the increased cocaine-seeking behaviour otherwise produced by the DS+ . Finally, on day 21 of abstinence, rats showed equivalent levels of lever pressing reinforced by the DS+ , CS and by the DS+ and CS combined, suggesting comparable conditioned reinforcing value. CONCLUSIONS: After intermittent self-administration, cocaine-associated DSs and CSs acquire similar conditioned reinforcing properties, but DSs more effectively trigger increases in drug seeking.

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RATIONALE: It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question. OBJECTIVES: Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans. METHODS: Rats were trained to discriminate between ten, 10 s puffs of aerosol generated from 3 mg/ml nicotine e-liquid and nicotine-free e-liquid using a food-reinforced operant procedure. Following acquisition, tests were conducted to determine the specificity of the nicotine aerosol stimulus as well as the impact to the stimulus effects of nicotine resulting from the addition of menthol to e-liquid. RESULTS: Rats learned the nicotine aerosol puff vs vehicle puff discrimination in a mean of 25 training sessions. Injected nicotine fully substituted for the stimulus effects of nicotine aerosol. The stimulus effects of nicotine aerosol were blocked by the nicotinic receptor antagonist mecamylamine. The nicotinic receptor partial agonist, varenicline as well as the stimulant d-amphetamine substituted more robustly for nicotine aerosol puffs than did the NMDA antagonist, ketamine. Menthol enhanced the stimulus effects of nicotine aerosol without altering nicotine blood plasma levels. CONCLUSIONS: Nicotine aerosol puffs can function as a training stimulus in rats. The stimulus effects were CNS-mediated and receptor specific. Menthol appears to enhance the stimulus effects of nicotine aerosol through a pharmacodynamic rather than pharmacokinetic mechanism.

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Goal-directed and habitual actions are clearly defined by their associative relations. Whereas goal-directed control can be confirmed via tests of outcome devaluation and contingency-degradation sensitivity, a comparable criterion for positively detecting habits has not been established. To confirm habitual responding, a test of control by the stimulus-response association is required while also ruling out goal-directed control. Here we describe an approach to developing such a test in rats using two discriminative stimuli that set the occasion for two different responses that then earn the same outcome. Performance was insensitive to outcome devaluation and showed stimulus-response specificity, indicative of stimulus-controlled behavior. The reliance of stimulus-response associations was further supported by a lack of sensitivity during the single extinction test session used here. These results demonstrate that two concurrently trained responses can come under habitual control when they share a common outcome. By reducing the ability of one stimulus to signal its corresponding response-outcome association, we found evidence for goal-directed control that can be dissociated from habits. Overall, these experiments provide evidence that tests assessing specific stimulus-response associations can be used to investigate habits.

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For abuse potential assessment, U.S. Food and Drug Administration (FDA) requests that new, brain-penetrating drugs are ideally compared with approved drugs that share the mechanism of action and are judged to have abuse liability by the Drug Enforcement Agency. For development of the dual orexin receptor antagonist (DORA) daridorexant, the FDA recommended conducting a rat drug discrimination paradigm against the approved, schedule IV, DORA suvorexant. Surprisingly, at suvorexant plasma levels up to three-fold the maximum concentration at the highest approved human dose, rats did not learn to discriminate the suvorexant stimulus from vehicle.

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As the natural science of behavior evolves, the use of precise terminology is critical to maintain its conceptual and terminological integrity. The current state of terminology in stimulus control is well developed with respect to reinforcement and incomplete with respect to punishment. In this paper, we aim to make the case that the current conceptualization for discriminative stimulus control in relation to punishment would be enhanced by modifying the definition of the discriminative stimulus for punishment (SDp) and by adding a new term to the current taxonomy that denotes when a punishment contingency is inactive.

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The influence of Pavlovian Conditioned Stimuli (CS) on ethanol self-administration and choice between ethanol and an alternative are potentially important. Ethanol-paired CS might increase ethanol self-administration, especially when it has been reduced during recovery, though the selectivity of these increases has been questioned. To date, one study examined the effects of an ethanol-paired CS on ethanol choice and found that the CS increased ethanol-responding more than food-responding when both were in extinction. However, it remains unclear whether ethanol-paired CS increase ethanol-choice that is not in extinction. Here, we examine the effects of an ethanol-paired CS on ethanol-choice when both food- and ethanol-responding are reinforced. Sixteen adult male Lewis rats were trained on a concurrent schedule to respond for ethanol on one lever and for food on the other lever. Ethanol was available under an FR 5 schedule, and food was available under an FR schedule that was adjusted for each rat to earn an equal number of food and ethanol deliveries. Then, 2-min light presentations were paired with an RT 25-sec schedule of ethanol delivery for 10 sessions in the absence of both levers. After this, subjects were placed back on the concurrent schedule for one session, then five sessions with the CS being present or absent on each trial of the concurrent schedule occurred. Rats learned to respond on one lever for ethanol and on the other for food and earned similar numbers of ethanol and food deliveries. During Pavlovian Conditioning, the number of head entries into the head-entry detector was higher in the presence of the CS than in its absence. In the test sessions, rats made more ethanol responses in the presence of the CS than in its absence. However, this effect was small and did not increase the amount of ethanol earned. Thus, ethanol-paired CS could increase ethanol-responding under a choice procedure but did not increase ethanol consumption meaningfully under the studied conditions.

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Human behavioral pharmacology methods have been used to rigorously evaluate the effects of a range of centrally acting drugs in humans under controlled conditions for decades. Methods like drug self-administration and drug discrimination have been adapted from nonhuman laboratory animal models. Because humans have the capacity to communicate verbally, self-report methods are also commonly used to understand drug effects. This perspective article provides an overview of these traditional human behavioral pharmacology methods and introduces some novel methodologies that have more recently been adapted for use in the field. Design (e.g., using placebo controls, testing multiple doses) and ethical (e.g., avoiding enrollment of individuals seeking treatment, determining capacity to consent) considerations that must be addressed when conducting these types of studies are also described.

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Stimulant use disorders present an enduring public health concern. Chronic stimulant use is associated with a range of health problems, with notable increases in stimulant overdose that disproportionately affect marginalized populations. With these persistent problems, it is important to understand the behavioral and pharmacological factors that contribute to stimulant use in humans. The purpose of this chapter is to provide an update and narrative review on recent human laboratory research that has evaluated the behavioral pharmacology of stimulant drugs. We focus on two prototypic stimulants: cocaine as a prototype monoamine reuptake inhibitor and d-amphetamine as a prototype monoamine releaser. As such, placebo controlled human laboratory studies that involved administration of doses of cocaine or d-amphetamine and were published in peer reviewed journals within the last 10 years (i.e., since 2011) are reviewed. Primary outcomes from these studies are subjective effects, reinforcing effects, cognitive/behavioral effects, and discriminative stimulus effects. Both cocaine and d-amphetamine produce classical stimulant-like behavioral effects (e.g., increase positive subjective effects, function as reinforcers), but there are notable gaps in the literature including understanding sex differences in response to stimulant drugs, cognitive-behavioral effects of stimulants, and influence of use history (e.g., relatively drug naïve vs drug experienced) on stimulant effects.

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Relapse within the context of a substance use disorder can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken this association between drug-associated cues and drug-taking behavior and may reduce the probability of relapse. This study evaluated a regimen of extinction training on cocaine and heroin self-administration in rhesus monkeys under a drug-vs-food choice procedure. Behavior was initially maintained under a concurrent schedule of food (1-g food pellets; fixed-ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection; fixed-ratio 10) (n = 4 males) or heroin injections (0-0.01 mg/kg/injection; fixed-ratio 10) (n = 3 females and 1 male) during daily 2-hr choice sessions. Subsequently, choice sessions were supplemented by daily 20-hr saline self-administration sessions for 14 consecutive days. During saline self-administration sessions, only drug-associated discriminative stimuli were presented and responding produced saline injections. Drug continued to be available during choice sessions. Prior to extinction training, both cocaine and heroin maintained dose-dependent increases in drug-vs-food choice. Exposure to 14 saline self-administration sessions failed to significantly decrease drug choice and increase food choice. These preclinical results do not support the effectiveness of extinguishing drug-associated discriminative stimuli as a nonpharmacological treatment strategy for reducing drug choice.

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Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.

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Resurgence is an increase in a previously reinforced behavior following a worsening of conditions for a more recently reinforced behavior. Discrimination training is incorporated into treatment for problem behavior to prevent treatment adherence failures that may result in resurgence. There is evidence that resurgence may be reduced when a stimulus that signals alternative-response extinction is present compared with absent; however, the generality of this effect is unknown given the limited testing conditions. The goal of the present experiments was to further examine the effects of such stimuli in a reverse-translational evaluation using rats. Target responding was reinforced in baseline and then placed on extinction in the following discrimination-training phase. An alternative response was differentially reinforced in a two-component multiple schedule where one stimulus (i.e., SD) signaled alternative-response reinforcement and the other (i.e., SΔ) signaled extinction. Experiment 1 assessed resurgence in both the SΔ and SD when alternative reinforcement was removed. Experiment 2 evaluated resurgence under conditions that better approximated those used in the clinic in which the alternative-response SΔ was present or absent. The SΔ failed to suppress target responding during resurgence testing in both experiments. These findings suggest that the conditions under which an alternative-response SΔ will successfully mitigate resurgence may be limited and require further research.

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Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.

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Polydrug abuse is common among drug abusers. In particular, psychostimulants are often taken with ethanol, and the combination of 3,4-methylenedioxymethamphetamine (MDMA) and alcohol is one of the most common forms of polydrug abuse. However, the mechanism by which these drugs influence behavior remains unclear. The present study was designed to delineate the mechanisms that underlie the effects of the interaction between MDMA and ethanol on behavior in rodents. The combination of MDMA with ethanol enhanced their locomotor-increasing, rewarding, and discriminative stimulus effects without enhancing their effects on the release of dopamine from the nucleus accumbens in rodents. In addition, ethanol potently enhanced locomotor activity produced by the dopamine receptor agonist apomorphine in mice. In antagonism tests, the dopamine D1 -receptor antagonist SCH23390, but not the D2 -receptor antagonist haloperidol, completely suppressed hyperlocomotion induced by MDMA. However, hyperlocomotion induced by the co-administration of MDMA and ethanol was potently suppressed by haloperidol. These results suggest that the synergistic effects of MDMA and ethanol are mediated through dopamine transmission, especially through postsynaptical regulation of D2 -receptor-mediated functions.

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INTRODUCTION: Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and cocaine have historically created concern for its potential as a drug of abuse. In September 2019, the FDA published a docket requesting comments for the development of abuse deterrent formulations for CNS stimulants, emphasizing the abuse of methylphenidate as a public health concern. AREAS COVERED: We conducted a narrative review of research on the clinical pharmacology, therapeutic efficacy, and abuse potential of methylphenidate. EXPERT OPINION: Several studies indicate that methylphenidate has at least some abuse potential. Methylphenidate, amphetamine, methamphetamine, and cocaine overlap in their subjective, reinforcing, and discriminative stimulus effects. Regardless, methylphenidate remains an efficacious treatment for ADHD in children and adults when properly adhered to, especially when paired with non-pharmacological treatments. The development of abuse deterrent formulations of methylphenidate is warranted.

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Midbrain dopamine (DA) neurons are involved in the processing of rewards and reward-predicting stimuli, possibly analogous to reinforcement learning reward prediction errors. Here we studied the activity of putative DA neurons (n = 37) recorded in the ventral tegmental area of rats (n = 6) performing a behavioural task involving occasion setting. In this task an occasion setter (OS) indicated that the relationship between a discriminative stimulus (DS) and reinforcement is in effect, so that reinforcement of bar pressing occurred only after the OS (tone or houselight) was followed by the DS (houselight or tone). We found that responses of putative DA cells to the DS were enhanced when preceded by the OS, as were behavioural responses to obtain rewards. Surprisingly though, we did not find a homogeneous increase in the mean activity of the population of putative DA neurons to the OS, contrary to predictions of standard temporal-difference models of DA neurons. Instead, putative DA neurons exhibited a heterogeneous response on a single unit level, so that some units increased and others decreased their activity as a response to the OS. Similarly, putative non-DA cells did not show a homogeneous response to the DS on a population level, but also had heterogeneous responses on a single unit level. The heterogeneity in the responses of neurons in the ventral tegmental area may reflect how DA neurons encode context and point to local differences in DA signalling.

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In tests of the derivation of complex relations such as transitivity, extant cues might fail to evoke effective responding, necessitating the construction of supplemental stimuli prior to their solution. The significance of this process was investigated by within-subject manipulation of an instructional variable designed to produce different levels of construction of supplemental stimulation concerning relationships among stimulus elements of concatenated conditional discriminations. In two experimental sessions, serial training of three 5-member stimulus classes occurred, either with the instruction to simply name the component stimuli or to both name them and generate a tale serially linking the stimuli named; such constructed stimuli might be spontaneously reconstructed by precurrent acts in subsequent tests of "emergent" relations. Participants whose supplemental stimulus construction at the first session was limited to name-giving derived significantly more relations when, in training at session two, they generated tales linking stimulus elements; this same near-errorless derivation was obtained at the first session whenever relational stimuli beyond bidirectional naming were constructed. In some cases the uninstructed construction of supplementary relational stimuli occurred at the first session, to equivalent effect; such construction might constitute a typically unobserved component of the derivation of relations among stimulus elements entailed in multiple conditional discriminations.

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The study and use of punishment in behavioral treatments has been constrained by ethical concerns. However, there remains a need to reduce harmful behavior unable to be reduced by differential-reinforcement procedures. We investigated whether response-contingent presentation of a negative discriminative stimulus previously correlated with an absence of reinforcers would punish behavior maintained by positive reinforcers. Across four conditions, pigeons were trained to discriminate between a positive discriminative stimulus (S+) signaling the presence of food, and a negative discriminative stimulus (S-) signaling the absence of food. Once learned, every five responses on average to the S+ produced S- for a duration of 1.5 s. S+ response rate decreased for a majority of pigeons when responses produced S-, compared to when they did not, or when a neutral control stimulus was presented. In Condition 5, choice between two concurrently presented S+ alternatives shifted away from the alternative producing S-, despite a 1:1 reinforcer ratio. Therefore, presenting contingent S- stimuli punishes operant behavior maintained on simple schedules and in choice situations. Development of negative discriminative stimuli as punishers of operant behavior could provide an effective approach to behavioral treatments for problem behavior and subverting suboptimal choices involved in addictions.

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Research on the stimulus properties of drugs began with studies on state dependent learning during the first half of the twentieth century. From that research, an entirely new approach evolved called drug discrimination. Animals (including humans) could discriminate the presence or absence of a drug; once learned, the drug could serve as a discriminative stimulus, signaling the availability or nonavailability of reinforcement. Early drug discrimination research involved the use of a T-maze task, which evolved in the 1970s into a two-lever operant drug discrimination task that is still used today. A number of important concepts and principles of drug discrimination are discussed. (1) The discriminative stimulus properties of drugs are believed in large part to reflect the subjective effects of drugs. While it has been impossible to directly measure subjective effects in nonhuman animals, drug discrimination studies in human subjects have generally supported the belief that discriminative stimulus properties of drugs in nonhuman animals correlate highly with subjective effects of drugs in humans. In addition to the ability of the drug discrimination procedure to measure the subjective effects of drugs, it has a number of other strengths that help make it a valuable preclinical assay. (2) Drug discrimination can be used for classification of drugs based on shared discriminative stimulus properties. (3) The phenomena of tolerance and cross-tolerance can be studied with drug discrimination. (4) Discriminative stimulus properties of drugs typically have been found to be stereospecific, if a drug is comprised of enantiomers. (5) Discriminative stimulus properties of drugs reflect specific CNS activity at neurotransmitter receptors. (6) Both human and nonhuman subjects display individual differences in their sensitivity to discriminative stimuli and drugs. (7) The drug discrimination procedure has been used extensively as a preclinical assay in drug development. This chapter is the first in the volume The Behavioural Neuroscience of Drug Discrimination, which includes chapters concerning the discriminative stimulus properties of various classes of psychoactive drugs as well as sections on the applications and approaches for using this procedure.

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In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence.

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Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

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