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Purpose Nicotine and alcohol-containing products are some of the most commonly used substances of abuse and are both leading causes of preventable death. These substances also have significant interactions that have additive and, in some cases, multiplicative effects on the health consequences of their use. Thus, to reduce these negative consequences, it is important to understand the abuse liability of nicotine and alcohol in combination, especially in the most relevant use cases among those who are most vulnerable. Specifically, as tobacco cigarette use is continually decreasing, vaping is quickly replacing cigarettes as the primary mode of nicotine use. This pattern is especially true in adolescent populations in which vaping has grown considerably. Particularly concerning is that adolescents are more vulnerable than adults to the negative consequences of substance use. It is therefore imperative to revisit the literature as it relates to the rising state of co-use of vaping products with alcohol. Here, we review the clinical outcomes of nicotine and alcohol co-use as they relate to the abuse liability of each individually. Special attention is paid to adolescent findings, where available, as well as investigations that use nontobacco nicotine products as these may more accurately reflect the more recent trends of co-use. Implications Though nicotine alone has previously been considered a proxy for tobacco and tobacco cigarette use, combustible routes of administration have been decreasing. They are, instead, being replaced by e-cigarettes that do not involve other tobacco constituents and contain additional nonnicotine constituents of their own. Unfortunately, the literature remains limited with regard to e-cigarettes and their interactions with other substances, especially their prevalent co-use with alcohol. This review attempts to discuss the current literature on nicotine and alcohol co-use in the context of the vaping epidemic, predominantly focusing on addiction-related outcomes and why e-cigarette use may be unique.

The use of cannabis is rapidly gaining legal status across North America. Such dramatic legislative shifts have prompted an urgency in elucidating the stimulus effects of cannabis consumption. Cannabis use, though relatively safe compared to other drugs of abuse, has been associated with greater risk of mental health disorders, possibly via its primary psychoactive constituent, Δ-9-tetrahydrocannabinol (THC). In this review, we discuss endocannabinoid activation and cannabis constituents from the perspective of subjective interoceptive (internally-perceived) states and how that relates to anxiety. Human studies have examined these subjective effects through use of self-report questionnaires. However, non-human studies use proxy methods of assessing anxiety states, such as elevated plus maze and fear conditioning paradigms. So far, this body of research has demonstrated that both endogenous and exogenous cannabinoid activation generally elicits biphasic effects on expression of the subjective state, with lower doses appearing to have anxiolytic properties and higher doses perceived as anxiogenic. Unfortunately, research with these compounds has been historically limited due to excessively tight regulatory control. Therefore, much work remains regarding the investigation of interactions between cannabinoid receptor activity and cannabis constituents on anxiety. Ongoing changes in legal status will hopefully mitigate the challenges faced by researchers attempting to access cannabis and THC that is inherently built in by federal and international classifications.

The current study investigated whether the stimulus effects of morphine can function as a positive and negative feature in a Pavlovian occasion setting drug discrimination preparation in male and female rats. Sprague-Dawley rats were assigned to a feature positive (FP) or feature negative (FN) training group and all received intermixed morphine (3.2 mg/kg, IP) or saline injections 15 min before 20-min daily training sessions. For FP rats, on morphine sessions, each of eight 15-s white noise (WN) presentations was followed by 4-s access to sucrose (0.01 ml, 26% w/v); on saline sessions, sucrose was withheld. FN rats learned the reverse contingency. FP discrimination was acquired somewhat sooner than FN discrimination, and females, but not males, became sensitized to the locomotor effects of morphine, which did not influence conditioned responding. Rats then entered dose generalization testing. There was no sex difference in dose generalization for FN groups (ED50 1.26 for males and 1.57 for females). Yet for FP rats, the dose response curve for females was shifted to the right compared to males (ED50 0.54 for males and 1.94 for females). FP females exhibited enhanced responding at a dose higher than that of their original training. These findings reveal the need to reassess our notions of drug stimuli that guide appropriate associative behaviours from the perspective of sex differences.

RATIONALE: Over the past decade, adolescent cigarette smoking has been declining. However, adolescent nicotine consumption via electronic cigarettes is rapidly gaining popularity. Earlier onset nicotine use is associated with increased risk of dependence. A bidirectional relationship between nicotine and stress exists; perceived stress is a predictor for nicotine use, and stress reduction is a commonly reported reason for using nicotine. OBJECTIVES: We assessed the prolonged impact of adolescent high-dose nicotine and/or footshock exposure on adult nicotine self-administration, anxiety-like behaviour, and hormonal responsivity. METHODS: During adolescence (postnatal day [P]28–56) male Sprague-Dawley rats were assigned to one of five groups: saline (SALPRE: 1ml/kg, SC, every day), nicotine (NICPRE: 1mg/kg, SC, alternating daily with saline; 14 total nicotine injections), footshock (SHOCKPRE: 8 of 0.5sec, 0.8mA alternating sessions; saline every day), or combination nicotine and footshock (NIC+SHOCK: concurrent and alternating daily with saline, or NIC—SHOCK: alternating with saline on shock sessions). On P70, one cohort underwent spontaneous intravenous nicotine self-administration (0.03mg/kg/infusion); another cohort was assessed for open-field behaviour (P71), then corticosterone (CORT) response to nicotine or footshock in adulthood (P72–73). RESULTS: Intermittent adolescent nicotine or footshock alone (NICPRE and SHOCKPRE) did not potentiate adult spontaneous nicotine intake compared to SALPRE. However, both combination groups (NIC+SHOCK, NIC—SHOCK) showed increased adult nicotine consumption without associated differences in baseline anxiety-like behaviour or CORT response. CONCLUSIONS: Adolescent nicotine and footshock stressors have a synergistic effect on adult nicotine consumption, enhancing nicotine intake. Avenues toward reducing stress in adolescent nicotine users may provide opportunities to reduce vulnerability to adult nicotine consumption.

Women are more sensitive to cocaine craving elicited by stimuli associated with relapse. Ovarian hormones modulate cocaine craving and may therefore function as risk factors or therapeutic agents for the development and treatment of cocaine use disorder, respectively. We review herein the neuropharmacological effects of the steroid hormones 17ß-estradiol, progesterone, and allopregnanolone, a progesterone metabolite, in relation to their effects on cocaine-induced locomotion, behavioural sensitization, conditioned place preference, and reinstatement of cocaine seeking. In general, the literature suggests that female rats are more sensitive to these cocaine-induced behaviours than males and that 17ß-estradiol facilitates the expression of these sex differences. Alternatively, in females, exogenous progesterone attenuates cocaine conditioned place preference, reinstatement, and possibly behavioural sensitization, either on its own or after conversion to allopregnanolone. These opposing effects of 17ß-estradiol and progesterone/allopregnanolone involve endocannabinoid, γ-aminobutyric acid, dopamine, and glutamate transmission in the medial prefrontal cortex and striatum. We conclude that 17ß-estradiol may be a risk factor for various components of cocaine use disorder in women, whereas progesterone and allopregnanolone may be potential treatment options.

With the signing of H.R. 1256, the Family Smoking Prevention and Tobacco Control Act, the United States Food and Drug Administration (FDA) gained regulatory authority over the tobacco industry. A notable clause in this Act permits the FDA to regulate nicotine yields. However, they cannot completely remove this addictive constituent from tobacco products. This restriction has prompted the FDA to seek research on the threshold dose of nicotine that does not support dependence. This idea of threshold dose has led to an interesting reframing of scientific questions. For example, some researchers studying nicotine from this regulatory perspective translated the notion of an addiction threshold to a construct thought to play a role in addiction but which can be more readily operationalized. Examples include reinforcement threshold, discrimination threshold, and reinforcer-enhancement threshold. In this Perspective Paper, we highlight the importance of behavioral pharmacology and, specifically, the experimental analysis of behavior to help establish a scientific basis for policy decisions regarding nicotine yields. Recent research, including exemplars provided herein, note vast individual differences in the effects of nicotine at a known dose. Unfortunately, the behavioral and biological factors that contribute to such individual variations remain to be understood. We believe that behavior analysts are uniquely well-positioned to contribute to this understanding.

The HIV-1 transgenic (Tg) rat model is valuable for understanding HIV-associated neurocognitive disorders (HAND) and accompanying substance use and misuse. Tg and F344/NHsd wildtype (WT) rats were allowed to self-administer intrajugular cocaine. For the first seven sessions, neither genotype self-administered cocaine (0.1 mg/kg/infusion) on a fixed ratio 1 schedule. We thus implemented a lever–cocaine “autoshaping” session followed by a series of manipulations changing dose and reinforcement schedule. Tg rats self-administered much less cocaine than WT rats throughout the study. Five of eight Tg rats modestly increased self-administration from sessions 36–50. Of those, only three showed a lever discrimination. Eight of ten WT rats acquired robust self-administration by session 19; all WT rats self-administered cocaine by the end of the study. WT and Tg rats had similar baseline locomotor activity in the self-administration chamber suggesting that the low levels of cocaine intake in the Tg rats did not reflect a non-specific motor impairment in this rat strain. Concomitant measurement of activity with self-administration revealed activity increases that followed increased cocaine intake. That relation held in Tg rats. Therefore, the present study provides evidence that HIV-1 Tg rats are less sensitive to the reinforcing effects of cocaine than their F344 WT counterparts.

Nicotine and varenicline (Chantix®; the leading non-nicotine cessation pharmacotherapy) can come to control appetitive behaviors such as goal-tracking. We tested rats (N = 48) in a drug-discriminated goal-tracking (DGT) task where each rat received daily subcutaneous injections of either nicotine (0.4 mg/kg) or saline (0.9% [w/v]) interspersed across the acquisition phase (Phase 1). On saline days, sucrose was intermittently available. On nicotine days, sucrose was withheld. All rats acquired the discrimination with increased goal-tracking rates on saline days relative to nicotine days. Following acquisition, rats were separated into four groups to assess drug-substitution and discrimination reversal in Phase 2. The first group maintained the stimulus-reinforcer relation from acquisition (NIC-). The reversal group was now given access to sucrose on nicotine days (NIC+). The substitution group replaced nicotine with varenicline (1 mg/kg) while maintaining the acquisition stimulus-reinforcer relation (VAR-). The substitution and reversal group had nicotine replaced by varenicline and the stimulus-reinforcer relation reversed (VAR+). Rats in all groups learned or maintained their Phase 1 discriminations. For Phase 2, the reversal groups (+ conditions) acquired their discriminations within 10 sessions. The VAR- group displayed a pattern of disrupted discrimination at the outset of Phase 2 but was reestablished after continued training. In substitution testing, VAR groups received nicotine and NIC groups received varenicline. The NIC- and VAR- groups displayed full substitution of the test stimulus whereas the NIC+ and VAR+ groups displayed partial substitution of the test stimulus. Rats underwent nicotine extinction in Phase 3. Initial responding for each group mimicked Phase 2 training (i.e., higher responding by the reversal groups). All rats maintained similarly low levels of responding after six sessions. In conclusion, initial learning history with nicotine (i.e., + or −) influenced drug-stimulus substitution and the rate at which new learning (e.g., reversal) occurs with the varenicline and nicotine interoceptive stimuli.

Introduction While cigarette smoking rates have been steadily decreasing over the past decade, there has been a dramatic increase in nicotine use via e-cigarettes, especially during adolescence. Adolescent e-cigarette use is associated with a greater risk of future cigarette smoking, and increased rates of cigarette smoking in individuals who may have otherwise never tried cigarettes. In humans and rodents, early initiation of nicotine use has been associated with greater consumption, dependence, and persistent nicotine use. The present study sought to investigate the long-lasting effect of daily high-dose nicotine exposure during adolescence on nicotine consumption in adulthood. Method Male Sprague-Dawley rats were exposed daily to nicotine (1.0 mg/kg, subcutaneous), or vehicle (1 mL/kg saline, subcutaneous) during adolescence (post-natal day [P] 28–41). Adult nicotine self-administration (0.02 mg/kg/infusion, intravenous) was assessed beginning on P75 on fixed-ratio 1 (FR1), fixed-interval 1 min (FI1), and progressive ratio (PR) schedules of reinforcement. Results Adolescent nicotine pre-exposure did not affect adult nicotine self-administration on the simple FR1 schedule, however increased intake and responding for nicotine was observed when a short delay was implemented on an FI1 schedule of reinforcement. Conclusions Adolescence is a critical period when the brain is especially vulnerable to the effects of nicotine. Nicotine exposure in adolescence enhances susceptibility to increased nicotine intake in adulthood on a reinforcement schedule more reflective of human nicotine intake patterns, and this effect can extend into adulthood even after termination of nicotine exposure during adolescence.

There has been an increasing interest in the role of interoception in drug addiction. Work in this area has largely come from two different directions. The first direction being from altered neural activity in individuals with substance use disorders that impairs emotional processing. Thus, physiological changes caused by drugs or drug-associated stimuli are interpreted in ways that evoke drug cravings, thereby driving enhanced drug seeking. The second direction being from the study of operant and Pavlovian conditioning processes. Here, drug effects are conceptualized as interoceptive stimuli that acquire control over behavior. Such learned alterations involving drug stimuli come to guide drug-related behaviors that affect risk and abuse liability. This chapter delves into the point at which these approaches appear to be converging, and discusses where we are in our understanding today and how this research may inform improved therapeutic techniques.

Background Smoking constitutes a significant public health risk. Alcohol and methamphetamine use disorders are also highly co-morbid with smoking, further increasing negative health outcomes. An important question in determining the underlying neurobiology of nicotine poly-drug use is understanding whether having a positive history with nicotine effects alters later drug-taking behavior. Methods The current experiments sought to elucidate whether having an appetitive nicotine conditioning history would affect later alcohol or methamphetamine self-administration. Adult male and female Long-Evans rats were first trained on a discriminated goal-tracking task in which the interoceptive effects of nicotine predicted sucrose reinforcement. As a control, pseudo-conditioned groups were included that had equated nicotine and sucrose experience. Rats were then shifted to either alcohol self-administration or methamphetamine self-administration. Results Nicotine conditioning history had no effect on acquisition or maintenance of alcohol self-administration in males or females. In contrast, an appetitive nicotine conditioning history decreased methamphetamine self-administration in female rats, but not males. Conclusions In female, but not male, rats, an appetitive conditioning history with nicotine decreases methamphetamine, but not alcohol, self-administration. This dissociation suggests that the effects may be due to a specific increase in the reinforcing value of methamphetamine. This may have implications for better understanding the progression of drug use from nicotine to methamphetamine.

The alarming increase in heroin overdoses in the USA is a reminder of the need for efficacious and novel treatments for opiate addiction. This may reflect the relatively poor understanding of the neural basis of heroin, as compared to cocaine, seeking behaviour. While cocaine reinforcement depends on the mesolimbic system, well‐established cocaine seeking is dependent on dorsolateral striatum (aDLS) dopamine‐dependent mechanisms which are disrupted by N‐acetylcysteine, through normalisation of corticostriatal glutamate homeostasis. However, it is unknown whether a functional recruitment of aDLS dopamine‐dependent control over instrumental responding also occurs for heroin seeking, even though heroin reinforcement does not depend on the mesolimbic dopamine system. Lister Hooded rats acquired heroin self‐administration and were subsequently trained to seek heroin daily over prolonged periods of time under the control of drug‐paired cues, as measured under a second‐order schedule of reinforcement. At different stages of training, that is, early on and when heroin seeking behaviour was well established, we measured the sensitivity of drug‐seeking responses to either bilateral aDLS infusions of the dopamine receptor antagonist α‐flupenthixol (5, 10 and 15 μg/side) or systemic administration of N‐acetylcysteine (30, 60 and 90 mg/kg). The results demonstrate that control over heroin seeking behaviour devolves to aDLS dopamine‐dependent mechanisms after extended training. Further aDLS‐dependent well‐established, cue‐controlled heroin seeking was disrupted by N‐acetylcysteine. Comparison with previous data on cocaine suggests that the development of drug seeking habits and the alteration of corticostriatal glutamate homeostasis, which is restored by N‐acetylcysteine, are quantitatively similar between heroin and cocaine.

With the signing of H.R. 1256, the Family Smoking Prevention and Tobacco Control Act, the United States Food and Drug Administration (FDA) gained regulatory authority over the tobacco industry. A notable clause in this Act permits the FDA to regulate nicotine yields. However, they cannot completely remove this addictive constituent from tobacco products. This restriction has prompted the FDA to seek research on the threshold dose of nicotine that does not support dependence. This idea of threshold dose has led to an interesting reframing of scientific questions. For example, some researchers studying nicotine from this regulatory perspective translated the notion of an addiction threshold to a construct thought to play a role in addiction but which can be more readily operationalized. Examples include reinforcement threshold, discrimination threshold, and reinforcer-enhancement threshold. In this Perspective Paper, we highlight the importance of behavioral pharmacology and, specifically, the experimental analysis of behavior to help establish a scientific basis for policy decisions regarding nicotine yields. Recent research, including exemplars provided herein, note vast individual differences in the effects of nicotine at a known dose. Unfortunately, the behavioral and biological factors that contribute to such individual variations remain to be understood. We believe that behavior analysts are uniquely well-positioned to contribute to this understanding.

Everyone should care deeply about statistical power and effect size given that the current estimates of wasted nonreproducible and exaggerated research findings range from 50 to 85%, combined with the mandates from the National Institutes of Health (NIH) that proposal reviewers focus on scientific rigor and investigators consider sex as a biological variable. In this Viewpoint, we provide recommendations and resources regarding power analyses aimed at enhancing rigor, and hence decreasing waste, when designing experiments. As part of this effort, we also make recommendations for reporting key statistics that will aid others in estimating sample size based on published research.

Background Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopamine-dependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown. Methods High- and low-impulsive rats identified in the five-choice serial reaction-time task were trained to self-administer cocaine (.25 mg/infusion) with infusions occurring in the presence of a cue-light conditioned stimulus. Dopamine transmission was blocked in the DLS after three stages of training: early, transition, and late-stage, by bilateral intracranial infusions of α-flupenthixol (0, 5, 10, or 15 μg/side) during 15-min cocaine-seeking test sessions in which each response was reinforced by a cocaine-associated conditioned stimulus presentation. Results In early-stage tests, neither group was affected by DLS dopamine receptor blockade. In transition-stage tests, low-impulsive rats showed a significant dose-dependent reduction in cocaine seeking, whereas high-impulsive rats were still unaffected by α-flupenthixol infusions. In the final, late-stage seeking test, both groups showed dose-dependent sensitivity to dopamine receptor blockade. Conclusions The results demonstrate that high impulsivity is associated with a delayed transition to DLS-dopamine-dependent control over cocaine seeking. This suggests that, if impulsivity confers an increased propensity to addiction, it is not simply through a more rapid development of habits but instead through interacting corticostriatal and striato-striatal processes that result ultimately in maladaptive drug-seeking habits.

Drug addiction may be associated with a loss of executive control over maladaptive incentive habits. We hypothesize that these incentive habits result from a pathological coupling of drug-influenced motivational states and a rigid stimulus-response habit system by which drug-associated stimuli through automatic processes elicit and maintain drug seeking. Neurally, incentive habits may depend upon an interaction between the basolateral amygdala and nucleus accumbens core, together with the progressive development of a ventral-to-dorsolateral striatum functional coupling through the recruitment of striato-nigro-striatal dopamine-dependent loop circuitry. Recent evidence suggests that both ventral striatal and central nucleus pathways from the amygdala may be required for the recruitment of DLS-dependent control over habitual behavior.

Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top-down inhibitory control over limbic–striatal mechanisms of drug-seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self-administer cocaine under a seeking–taking chained schedule. Intermittent mild footshock punishment of the cocaine-seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine-seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7-day abstinence period, rats were re-exposed to the drug-seeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self-administering cocaine, but further implicates subregions of the prefrontal cortex in relapse.

The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early- and late-stage performance of cocaine-seeking behavior. Rats were trained to self-administer cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of α-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule [FI15(FR10:S)] so that cocaine-seeking performance became well established. At this stage, intra-aDLS, but not pDMS, α-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. α-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of cocaine-seeking behavior, supporting the theory of dynamic shifts in the striatal control over cocaine seeking between goal-directed and habitual performance.

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.

N-acetylcysteine (NAC) has been suggested to have therapeutic potential in the treatment of drug addiction through its effects on brain glutamate homeostasis. Here we show that NAC treatment resulted in dose-dependent reductions in cocaine seeking at both early and late stages of acquisition and maintenance of cocaine-seeking behavior, while confirming it had no effect on cocaine reinforcement. The results indicate that NAC is able to significantly diminish the propensity to seek cocaine early and late in the development of addiction and, taken together with previous work, indicates significant potential in relapse prevention.

Environmental stimuli that co-occur with tobacco use come to evoke drug-related conditioned responses (CRs) that appear involved in continued use of nicotine-containing products. In rats, nicotine can serve as a conditional stimulus (CS) for non-drug unconditioned stimuli (USs), prompting the question of whether the nicotine CS can compete with, or overshadow, a non-drug environmental stimulus for control of a CR. In Experiment 1, male Sprague-Dawley rats were assigned to a group [0, 0.01, 0.03, 0.045, or 0.06 mg nicotine (base)/kg/infusion]. During each session, there were 10 intravenous infusions followed by a 30-second houselight to form a compound CS. At light offset there was 4-second access to sucrose. For Experiment 2, groups were nicotine (0.03 mg/kg/infusion) + light compound paired, nicotine + light compound unpaired, nicotine paired and light unpaired, and nicotine unpaired and light paired. Paired stimuli were presented with sucrose similar to Experiment 1. Unpaired stimuli were temporally separated from sucrose. Following acquisition, tests of nicotine and light alone were conducted by intermixing non-reinforced trails into training sessions. Nicotine dose-dependently overshadowed the light CS as shown by reduced light control of conditioned responding with higher doses. The nicotine, light, and nicotine + light compound had to be paired with sucrose to evoke a CR. These results demonstrate nicotine overshadows an exteroceptive visual stimulus. Because exteroceptive stimuli are often the focus of cue-exposure therapy, such competition may help begin to explain the marginal effectiveness of these therapies.

Research using a drug discriminated goal-tracking (DGT) task showed that the N-methyl-D: -aspartate (NMDA) channel blocker MK-801 (dizocilpine) reduced the nicotine-evoked conditioned response (CR).Given the unknown mechanism of the effect, Experiment 1 replicated the MK-801 results and included tests with NMDA receptor ligands. Experiments 2a and 2b tested whether MK-801 pretreatment blocked DGT via a state-dependency effect.In Experiment 1, adult male Sprague-Dawley rats received intermittent access to liquid sucrose following nicotine (0.4 mg base/kg); no sucrose was delivered on intermixed saline sessions. Conditioning was indicated by increased anticipatory dipper entries (goal-tracking) on nicotine compared to saline sessions. Antagonism and/or substitution tests were conducted with MK-801, phencyclidine, CGP 39551, d-CPPene (SDZ EAA 494), Ro 25,6981, L-701,324, ACPC, and NMDA. In Experiment 2a, rats received nicotine and sucrose on every session-no intermixed saline sessions without sucrose. Tests combined MK-801 or the non-competitive nicotinic acetylcholine receptor antagonist, mecamylamine with either nicotine or saline. Experiment 2b had sucrose delivered on saline sessions and no sucrose on intermixed nicotine sessions followed by MK-801 antagonism tests of the saline CS.MK-801 and phencyclidine dose-dependently attenuated the CR in Experiment 1. Ro-25,6981 enhanced the CR, but did not substitute for nicotine. Other ligands showed inconsistent effects. In Experiment 2a, MK-801 pretreatment reduced goal-tracking when given before nicotine and saline test sessions; mecamylamine pretreatment had no effect. In Experiment 2b, MK-801 dose-dependently attenuated the saline-evoked CR.Combined, the results suggest that MK-801 blocks discriminated goal-tracking by virtue of state-changing properties.

The interoceptive stimulus effects of nicotine acquire control over behavior. This observation, among others, suggests that the stimulus effects of nicotine are important in the development and tenacity of tobacco dependence. Despite this importance, there has been little research examining whether non-reinforced presentations (extinction) of a ligand that share stimulus effects of nicotine will weaken responding controlled by nicotine. Rats were trained to discriminate nicotine (0.4 mg/kg) from saline using a discriminated goal-tracking task in which nicotine signaled intermittent access to sucrose; sucrose was withheld on saline sessions. Experiment 1 examined substitution for nicotine by ABT-418, nornicotine, epibatidine, varenicline, or cytisine in 4-min extinction tests. Experiments 2 to 5 [low dose nicotine (0.05 mg/kg), ABT-418, nornicotine, or varenicline, respectively] examined whether substitution for nicotine would persist if extinction tests were increased to 20 min and repeated daily for 6 days. Finally, generalization of this extinction back to the nicotine training stimulus was assessed. Full substitution in brief 4-min extinction tests was seen for ABT-418, nornicotine, epibatidine, varenicline, and cytisine. Low-dose nicotine, ABT-418, nornicotine, and varenicline, evoked only a partial ‘nicotine-like’ response in the first 20-min extinction test. With repeated extinction, only low-dose nicotine, nornicotine, and varenicline continued to substitute. Extinction with nornicotine and varenicline transferred back to nicotine as indicated by a partial conditioned response to the training stimulus. Interpretations regarding ‘nicotine-like’ effects of a ligand depend on the nature of the test. Understanding the processes mediating transfer of extinction learning with potential pharmacotherapies may reveal new treatment targets.

The cannabinoid CB(1) receptor antagonist/inverse agonist rimonabant (SR 141716) has been shown to block reinforcing and rewarding effects of nicotine. Research has not investigated whether the cannabinoid system is involved in the interoceptive stimulus effects of nicotine functioning as a conditional stimulus (CS).We examined the effects of rimonabant and the CB(1/2) receptor agonist, CP 55,940, on responding evoked by a nicotine CS in rats. Additionally, we determined whether CP 55,940 functioned as a CS or a Pavlovian positive drug featurePavlovian discrimination training involved intermixed nicotine (0.2 mg base/kg) and saline sessions with intermittent access to water only on nicotine. Antagonism tests with rimonabant (0.1-3 mg/kg) and substitution tests with CP 55,940 (0.003-0.1 mg/kg) followed. An effective dose of CP 55,940 was tested against the nicotine generalization curve. A separate group received CS training with CP 55,940 (0.01 mg/kg). Two other groups were trained using CP 55,940 (0.01 or 0.03 mg/kg) as a positive drug feature in which a brief light CS signaled access to water only on CP 55,940 sessions.Rimonabant blocked nicotine-evoked responding. CP 55,940 partially substituted for nicotine and enhanced responding to lower nicotine doses. Overall, CP 55,940 did not acquire control of conditioned responding in either Pavlovian drug discrimination task.The cannabinoid system was involved in the CS effects of nicotine. This finding is counter to the operant drug discrimination research with nicotine as a discriminative stimulus, warranting further research into this possible dissociation.

Vaccines to methamphetamine (meth) were designed by covalently attaching a meth hapten (METH) to peptide constructs that contained a conformationally biased, response-selective molecular adjuvant, YSFKPMPLaR (EP54). Rats immunized with EP54-containing meth vaccines generated serum antibody titers to authentic meth, an immune outcome that altered meth self-administration. Immunization increased meth self-administration suggesting pharmacokinetic antagonism. The ability of immune sera to bind a METH-modified target protein dramatically decreased during and shortly after the meth self-administration assay, suggesting effective sequestration of free meth. However, the binding ability of immune sera to the METH-modified target protein was recovered 34 days after meth-free clearance time.

Bupropion is a promising candidate medication for methamphetamine use disorder. As such, we used a preclinical model of drug-taking to determine the effects of bupropion on the reinforcing effects of methamphetamine (0.025, 0.05 or 0.1 mg/kg/infusion). Specificity was determined by investigating the effects of bupropion on responding maintained by sucrose. In the self-administration study, rats were surgically prepared with indwelling jugular catheters and trained to self-administer methamphetamine under an FR5 schedule. A separate group of rats was trained to press a lever for sucrose. Once responding stabilized, rats were pretreated with bupropion (0, 10, 30 and 60 mg/kg IP) 5 min before chamber placement in a unique testing order. Following acute testing, rats were then repeatedly pretreated with 30 and 60 mg/kg bupropion. Acute treatments of bupropion dose dependently reduced drug intake for 0.025 to 0.1 mg/kg methamphetamine; sucrose deliveries were only reduced with the high bupropion dose. Repeated exposure to 60 mg/kg bupropion before the session resulted in a consistent decrease in methamphetamine intake (0.05 and 0.1 mg/kg) and sucrose deliveries. Considered together, this pattern of findings demonstrates that bupropion decreases responding for methamphetamine, but the effects are only somewhat specific.

Rationale Studies in human and non-human primates demonstrate that social status is an important determinant of cocaine reinforcement. However, it is unclear whether social rank is associated with other traits that also predispose to addiction and whether social status similarly predicts cocaine self-administration in rats. Objectives The objective of this study is to investigate whether social ranking assessed using a resource competition task affects (i) the acquisition, maintenance and reinstatement of cocaine self-administration; (ii) the dopaminergic markers in the striatum; and (iii) the expression of ancillary traits for addiction. Methods Social ranking was determined in group-housed rats based upon drinking times during competition for a highly palatable liquid. Rats were then evaluated for cocaine self-administration and cue-induced drug reinstatement or individual levels of impulsivity, anxiety and novelty-induced locomotor activity. Finally, dopamine content, dopamine transporter (DAT) and dopamine D2/D3 (D2/3) receptor binding were measured postmortem in the dorsal and ventral striatum. Results Rats deemed socially dominant showed enhanced novelty reactivity but were neither more impulsive nor anxious compared with subordinate rats. Dominant rats additionally maintained higher rates of cocaine self-administration but showed no differences in the acquisition, extinction and reinstatement of this behaviour. D2/3 binding was elevated in the nucleus accumbens shell and dorsal striatum of dominant rats when compared to subordinate rats, and was accompanied by elevated DAT and reduced dopamine content in the nucleus accumbens shell. Conclusions These findings show that social hierarchy influences the rate of self-administered cocaine but not anxiety or impulsivity in rats. Similar to non-human primates, these effects may be mediated by striatal dopaminergic systems. Electronic supplementary material The online version of this article (doi:10.1007/s00213-015-4122-8) contains supplementary material, which is available to authorized users.

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 light came to control robust goal tracking (i.e., conditioned responding) only in caffeine sessions. Thus, caffeine disambiguates when the light was paired with sucrose. Decreasing the dose of caffeine decreased the conditioned responding evoked by the light (ED50 = 4.16 mg/kg). Neither nicotine nor amphetamine substituted for the caffeine feature. As a CS, caffeine (10 or 30 mg/kg, Experiments 2a and 2b, respectively) signaled intermittent access to sucrose—no light presentations. No sucrose or lights were presented on intermixed saline sessions. The caffeine CS, regardless of training dose, acquired the ability to evoke only a weak goal-tracking CR. The nature of this dissociation between caffeine as a drug feature and a CS is discussed within the context of past research finding a similar dissociation with amphetamine and chlordiazepoxide, but not with nicotine.

In the development of addiction, drug seeking becomes habitual and controlled by drug-associated cues, and the neural locus of control over behaviour shifts from the ventral to the dorsolateral striatum. The neural mechanisms underlying this functional transition from recreational drug use to drug-seeking habits are unknown. Here we combined functional disconnections and electrophysiological recordings of the amygdalo-striatal networks in rats trained to seek cocaine to demonstrate that functional shifts within the striatum are driven by transitions from the basolateral (BLA) to the central (CeN) amygdala. Thus, while the recruitment of dorsolateral striatum dopamine-dependent control over cocaine seeking is triggered by the BLA, its long-term maintenance depends instead on the CeN. These data demonstrate that limbic cortical areas both tune the function of cognitive territories of the striatum and thereby underpin maladaptive cocaine-seeking habits., Drug seeking behaviour has habitual neural substrates. Here, Murray et al. show that the basolateral amygdala and central nucleus of the amygdala are necessary to recruit and maintain, respectively, the intrastriatal functional transition that underlies cocaine seeking habits.

PURPOSE: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established.METHODS: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians.RESULTS AND CONCLUSION: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med advance online publication 23 July 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.110.

In rats, the pharmacological (interoceptive) effects of nicotine can serve as a signal (conditional stimulus) in a Pavlovian (classical) conditioning task. In this task, nicotine administration (0.4 mg base/kg, subcutaneous) is typically paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Given our limited understanding of the functional relationships controlling conditioned responding to a nicotine conditional stimulus, the present research examined nicotine's sensitivity to several manipulations shown to affect the conditioned responding in more widely studied Pavlovian conditioning tasks that use exteroceptive conditional stimuli: number of nicotine conditional stimulus-sucrose unconditional stimulus pairings per session (0, 3, 9, 18, or 36) and the impact of sucrose deliveries in saline sessions. Differential goal tracking developed in fewer sessions and asymptotic conditioned responding magnitude was greater with more nicotine-sucrose pairings. Further, goal tracking was more resistant to extinction (unconditional stimulus withheld) with more conditional-unconditional stimulus pairings during the acquisition phase. The discrimination was not acquired when sucrose presentations (9 or 18) also occurred during saline sessions. Furthermore, expression of the discrimination was disrupted when sucrose was presented in saline sessions; this disruption resulted from goal tracking in saline sessions. These results are consistent with the notion that nicotine-evoked goal tracking results from interoceptive conditioning processes.

Background The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. Objectives We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine-taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). Methods In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. Results The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive—maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. Conclusion Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer.

The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes.

Nicotine functions as a negative feature in a Pavlovian discriminated goal-tracking task. Whether withholding of responding to the conditional stimulus (CS) reflects nicotine functioning as a conditioned inhibitor is unknown. Accordingly, the present research sought to determine whether nicotine trained as a negative feature passed the retardation-of-acquisition and summation tests, thus characterizing it as a pharmacological (interoceptive) conditioned inhibitor. In the retardation test, rats received either nicotine (0.4 mg/kg) or chlordiazepoxide (5 mg/kg) negative feature training in which the drug state signaled when a 15-sec light CS would not be paired with sucrose; light was paired with sucrose on intermixed saline sessions. Following acquisition of the discrimination, both groups received nicotine CS training in which sucrose was intermittently available on nicotine but not intermixed saline sessions. Acquisition of conditioned responding to the nicotine CS was slower in the nicotine negative feature group than in the chlordiazepoxide negative feature group. In the summation test, rats were assigned to either the nicotine negative feature group or a pseudoconditioning control. In this control, the light CS was paired with sucrose on half the nicotine and half the saline sessions. Both groups also received excitatory training in which a white noise CS was paired with sucrose. The summation test consisted of presenting the white noise in conjunction with nicotine. Conditioned responding evoked by the white noise was decreased in the negative feature but not the pseudoconditioning group. Combined, the results provide the first evidence that an interoceptive stimulus (nicotine) can become a conditioned inhibitor.

N-acetylcysteine (NAC) has been suggested to have therapeutic potential in the treatment of drug addiction through its effects on brain glutamate homeostasis. Here we show that NAC treatment resulted in dose-dependent reductions in cocaine seeking at both early and late stages of acquisition and maintenance of cocaine-seeking behavior, while confirming it had no effect on cocaine reinforcement. The results indicate that NAC is able to significantly diminish the propensity to seek cocaine early and late in the development of addiction and, taken together with previous work, indicates significant potential in relapse prevention.

The discovery that delta-9-tetrahydrocannabinol (Δ(9)-THC) is the primary psychoactive ingredient in marijuana prompted research that helped elucidate the endogenous cannabinoid system of the brain. Δ(9)-THC and other cannabinoid ligands with agonist action (CP 55,940, HU210, and WIN 55,212-2) increase firing of dopamine neurons and increase synaptic dopamine in brain regions associated with reward and drug addiction. Such changes in cellular processes have prompted investigators to examine the conditioned rewarding effects of the cannabinoid ligands using the place conditioning task with rats and mice. As reviewed here, these cannabinoid ligands can condition place preferences (evidence for rewarding effects) and place aversions (evidence for aversive qualities). Notably, the procedural details used in these place conditioning studies have varied across laboratories. Such variation includes differences in apparatus type, existence of procedural biases, dose, number of conditioning trials, injection-to-placement intervals, and pre-training drug exposure. Some differences in outcome across studies can be explained by these procedural variables. For example, low doses of Δ(9)-THC appear to have conditioned rewarding effects, whereas higher doses have aversive effects that either mask these rewarding effects or condition a place aversion. Throughout this review we highlight key areas that need further research.

Although past research has shown that the interoceptive effects of nicotine serve as a conditional stimulus using sucrose as the unconditioned stimulus, very little is known about the importance of dose. Accordingly, rats were assigned to 0.1, 0.2, or 0.4 mg nicotine base/kg as the training dose. Sucrose (4-s access) was delivered 36 times on nicotine sessions; sucrose was withheld on intermixed saline sessions. The discrimination was acquired for all groups, as measured by more photobeam breaks in the dipper receptacle before the first sucrose delivery on nicotine sessions, compared with a similar interval on saline sessions. Thirty nicotine sessions without sucrose deliveries (extinction) decreased conditioned responding with the 0.4 mg/kg dose maintaining higher responding than the lower doses. After reestablishing discrimination performance, rats were tested with their training dose at various injection-to-placement intervals. Conditioned responding diminished with longer intervals; 0.4 mg/kg nicotine-evoked conditioned responding at longer intervals. Subsequent generalization testing with nicotine or saline at the 5-min training interval found that conditioned responding was evoked by lower test doses in the 0.1 mg/kg group than in the other groups. Combined, this research demonstrates that the nicotine conditional stimulus shows some variation with training dose.

Male and female rats were exposed to depleted uranium acetate (DU) in drinking water at doses of 0, 75, or 150 mg/L for either 2 weeks or 6 months. After exposure, the animals were tested for behaviors in the open-field. After testing in the open-field, the brains were examined for levels of lipid oxidation using the thiobarbituric acid (TBA) assay. Behavioral differences (line crossing and rearing) were seen in male rats after 2 weeks exposure to DU in drinking water for the highest dose group. Increased brain lipid oxidation was seen for the highest dose group for both genders. Lipid oxidation levels correlated significantly with line crossing and rearing in the open-field. After 6 months exposure, behavioral differences for male rats in the open-field remained and expanded to include other behaviors (grooming, defecation, and urination). Female rats also demonstrated some behavioral changes after 6 months exposure. Lipid oxidation in the brain continued to be seen; however, these levels no longer correlated with open-field behaviors. These data suggest that DU is a toxin that crosses the blood–brain barrier, producing behavioral changes in male rats and lipid oxidation regardless of gender in as little as 2 weeks in the rat. Longer exposures to DU may produce greater behavioral changes but compensatory mechanisms may reduce the effects of lipid oxidation. Males appear to be more sensitive to the behavioral effects of DU.