Generalization of a positive-feature interoceptive morphine occasion setter across the rat estrous cycle.

INTRODUCTION: Interoceptive stimuli elicited by drug administration acquire conditioned modulatory properties of the induction of conditioned appetitive behaviours by exteroceptive cues. This effect may be modeled using a drug discrimination task in which the drug stimulus is trained as a positive-feature (FP) occasion setter (OS) that disambiguates the relation between an exteroceptive light conditioned stimulus (CS) and a sucrose unconditioned stimulus (US). We previously reported that females are less sensitive to generalization of a FP morphine OS than males, so we investigated the role of endogenous ovarian hormones in this difference. METHODS: Male and female rats received intermixed injections of 3.2 mg/kg morphine or saline before each daily training session. Training consisted of 8 presentations of the CS, each followed by access to sucrose on morphine, but not saline sessions. Following acquisiton, rats were tested for generalization of the morphine stimulus to 0, 1.0, 3.2, and 5.4 mg/kg morphine. Female rats were monitored for estrous cyclicity using vaginal cytology throughout the study. RESULTS: Both sexes acquired stable drug discrimination. A gradient of generalization was measured across morphine doses and this behaviour did not differ by sex, nor did it differ across the estrous cycle in females. CONCLUSIONS: Morphine generalization is independent of fluctuations in levels of sex and endogenous gonadal hormones in females under these experimental conditions.

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

RATIONALE: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. OBJECTIVES: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. METHODS: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. RESULTS: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. CONCLUSIONS: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

Adolescent restraint stress enhances adult nicotine reinforcement in male and female rats.

Adolescent stress is a risk factor for the initiation of nicotine use, but whether adolescent stress can enhance nicotine reinforcement when it is initiated later in adulthood is unknown, and it is unclear whether males and females are equally impacted. Therefore, this study assessed physiological responses (body weight and blood serum corticosterone - CORT) to restraint stress (RS) during adolescence (P28-55) or during adulthood (P70-96) in male and female Sprague-Dawley rats. When all subjects reached adulthood (P69 or 110; 2 weeks after termination of stress exposure), they were tested on sucrose preference and intravenous single-dose nicotine (0.03 mg/kg/infusion) self-administration. It was found that all rats displayed a significant CORT response to RS. Importantly, stress during adolescence, but not during adulthood, enhanced subsequent acquisition of nicotine intake tested in adulthood. Although this effect was observed in both sexes, only males displayed reduced body weight gain and adult sucrose preference. Moreover, regardless of stress exposure, females were more stimulated by nicotine, consumed more nicotine overall, and displayed enhanced nicotine seeking. These results suggest that adolescence is a period of heightened sensitivity to the enhancing effect of repeated stress on the susceptibility to develop nicotine dependence later in life in both sexes.

Sex Differences in the Behavioural Outcomes of Prenatal Nicotine and Tobacco Exposure.

Smoking remains the leading cause of preventable death worldwide. A combination of biological and environmental risk factors make women especially vulnerable to nicotine addiction, making it harder for them to quit smoking. Smoking during pregnancy, therefore, is still a major health concern, with epidemiological data suggesting a role for gestational nicotine exposure in the development of several behavioural disorders. Given there are significant sex-specific behavioural outcomes related to smoking in adolescence and adulthood, it is probable that the behavioural outcomes following gestational nicotine or tobacco exposure are similarly sex-dependent. This is an especially relevant topic as the current landscape of nicotine use shifts toward vaping, a mode of high doses of nicotine delivery that is largely believed to be a safer alternative to cigarettes among the public as well as among pregnant women. Here we review existing clinical and preclinical findings regarding the sex-dependent behavioural outcomes of prenatal nicotine exposure. We also highlight the challenges within this literature, particularly those areas in which further research is necessary to improve consistency within, and between, clinical and preclinical findings.

Regulation of cocaine-related behaviours by estrogen and progesterone.

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.

Addiction-Related Outcomes of Nicotine and Alcohol Co-use: New Insights Following the Rise in Vaping.

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.

Adolescent nicotine and footshock exposure augments adult nicotine self-administration and drug-seeking without affecting baseline anxiety-like behaviour or stress responsivity in male rats.

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: 1 ml/kg, SC, every day), nicotine (NICPRE: 1 mg/kg, SC, alternating daily with saline; 14 total nicotine injections), footshock (SHOCKPRE: 8 of 0.5 s, 0.8 mA 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 (0.03 mg/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.

Sex differences in the discriminative stimulus characteristics of a morphine occasion setter in rats.

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.

The importance of acquisition learning on nicotine and varenicline drug substitution in a drug-discriminated goal-tracking task.

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.

High-dose adolescent nicotine exposure permits spontaneous nicotine self-administration in adult male rats.

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.

Male HIV-1 transgenic rats show reduced cocaine-maintained lever-pressing compared to F344 wildtype rats despite similar baseline locomotion.

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 7 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. Of 8 Tg rats, 5 modestly increased self-administration from sessions 36-50. Of those, only 3 showed a lever discrimination. Of 10 WT rats, 8 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 nonspecific 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.

Cannabinoids, interoception, and anxiety.

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.

Effects of nicotine conditioning history on alcohol and methamphetamine self-administration in rats.

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.

Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine.

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.

Experimental analysis of behavior and tobacco regulatory research on nicotine reduction.

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.

Caring about Power Analyses.

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.

N-acetylcysteine Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake.

BACKGROUND: N-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown. METHODS: We investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks. RESULTS: NAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaine-induced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats. CONCLUSIONS: Our results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum.

Social dominance in rats: effects on cocaine self-administration, novelty reactivity and dopamine receptor binding and content in the striatum.

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.

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care.

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 18 5, 483-493.

Basolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits.

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.