Insomnia Severity Mediates the Association between COVID-19 Related Anxiety and Increase in Tobacco Smoking During the COVID-19 Pandemic among Adults.

OBJECTIVES: Examining the associations of COVID-19 related anxiety and insomnia with increased smoking following the outbreak of the COVID-19 pandemic, and investigating whether increased insomnia severity mediates the association between COVID-19 related anxiety and increased smoking. METHODS: 598 participants, aged 18-40, out of whom 140 self-identified as smokers, completed online questionnaires during the third wave of the COVID-19 pandemic. Measures included two items assessing COVID-19 related anxiety, the Pittsburgh Sleep Quality Index, and the Insomnia Severity Index, which included a pre-pandemic retrospective report. RESULTS: Compared with nonsmokers, smokers reported lower sleep quality and more severe symptoms of insomnia. Among smokers, more severe symptoms of insomnia were associated with greater odds of increased smoking during the COVID-19 outbreak. COVID-19 related anxiety was indirectly associated with greater odds of increased smoking through greater insomnia severity during the COVID-19 outbreak, after controlling for pre-pandemic levels of insomnia. CONCLUSIONS: Smokers experienced more sleep difficulties during the COVID-19 pandemic than nonsmokers. The results also lend support to the suggestion that anxiety, such that was experienced during the COVID-19 pandemic, may lead to further exacerbation of sleep difficulties, leading in turn to increase in smoking. These findings have important clinical implications that may be particularly relevant to attempts to minimize smoking during stressful circumstances.

Associations Between Childhood Stressors, COVID-19-Related Anxiety, and Sleep Quality of Adults During the Third Wave of the COVID-19 Pandemic in Israel.

Purpose: Studies point to a persistent effect of the COVID-19 pandemic on sleep quality and mental health, including anxiety. Exposure to stressors during childhood increases the susceptibility to anxiety in later life. Given the negative effects of anxiety on sleep quality, the present study aimed to examine the associations between various childhood stressors and poor sleep quality of adults during the COVID-19 pandemic, and whether these associations are mediated by COVID-19-related anxiety. Participants and Methods: A total of 586 participants aged 18-40 (mean age 27.53± 6.48 years, 301 females) were recruited to take part in an online survey conducted in Israel between February 7 and 15, 2021, during the third wave of the COVID-19 pandemic. Participants completed questionnaires assessing retrospectively adverse childhood experiences (ACEs), childhood harshness (indexed separately by exposure to morbidity and mortality and low socioeconomic status, SES), and childhood unpredictability. COVID-19-related anxiety was assessed using two items. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and insomnia symptoms with the Insomnia Severity Index (ISI). Participants were asked to complete the ISI concerning two time points: (a) retrospectively, before the COVID-19 outbreak, and (b) currently, during the pandemic. Results: Path analysis indicated that poor sleep quality (PSQI) was directly and indirectly (through COVID-19-related anxiety) predicted by the number of ACEs and childhood morbidity-mortality exposure, directly predicted by childhood low SES, and indirectly predicted by childhood unpredictability. Insomnia symptoms increase (ISI) was indirectly predicted by the number of ACEs, childhood morbidity-mortality exposure, and childhood unpredictability. Conclusion: ACEs as well as harsh and unpredictable childhood environments are predictive of poorer sleep during the COVID-19 pandemic. COVID-19-related anxiety mediates the effects of childhood stressors (other than low SES) on sleep. These findings may have clinical implications relevant to stressful periods in general.

The effects of sleep deprivation on the processing of emotional facial expressions in young adults with and without ADHD.

The ability to recognize emotions from facial expressions is essential to the development of complex social cognition behaviors, and impairments in this ability are associated with poor social competence. This study aimed to examine the effects of sleep deprivation on the processing of emotional facial expressions and nonfacial stimuli in young adults with and without attention-deficit/hyperactivity disorder (ADHD). Thirty-five men (mean age 25.4) with (n = 19) and without (n = 16) ADHD participated in the study. During the five days preceding the experimental session, the participants were required to sleep at least seven hours per night (23:00/24:00-7:00/9:00) and their sleep was monitored via actigraphy. On the morning of the experimental session, the participants completed a 4-stimulus visual oddball task combining facial and nonfacial stimuli, and repeated it after 25 h of sustained wakefulness. At baseline, both study groups had poorer performance in response to facial rather than non-facial target stimuli on all indices of the oddball task, with no differences between the groups. Following sleep deprivation, rates of omission errors, commission errors and reaction time variability increased significantly in the ADHD group but not in the control group. Time and target type (face/non-face) did not have an interactive effect on any indices of the oddball task. Young adults with ADHD are more sensitive to the negative effects of sleep deprivation on attentional processes, including those related to the processing of emotional facial expressions. As poor sleep and excessive daytime sleepiness are common in individuals with ADHD, it is feasible that poor sleep quality and quantity play an important role in cognitive functioning deficits, including the processing of emotional facial expressions that are associated with ADHD.

The Impact of Sleep Deprivation on Continuous Performance Task Among Young Men With ADHD.

Objective: To identify the impact of sleep deprivation on functioning of young adults with or without ADHD on a continuous performance attention task. Method: Thirty-four men (M age = 25.38) with (n = 16) or without (n = 18) ADHD completed a continuous performance task before and after 25 hr of sustained wakefulness in a controlled environment. Results: In both groups, sleep deprivation caused a decline in performance on all variables: omission errors, commission errors, reaction time, and reaction time variability. In addition, the ADHD group made more omission and commission errors, and had greater reaction time variability. Conclusion: Sleep deprivation has a detrimental effect on attention functioning among young adults. In addition, although young adults with ADHD generally perform worse on continuous performance tasks than young adults without ADHD, the groups are similarly affected by sleep deprivation.

The Role of Endocrine Stress Systems and Sex Hormones in the Enhancing Effects of Stress on Mental Rotation Capabilities.

The possible effects of stress and neurobiological stress mechanisms on visuospatial abilities remain largely unknown. In the current study, we examined the combined effect of sex hormones and both the hypothalamic-pituitary-adrenal axis (HPA-A) and the sympathetic nervous system (SNS) on stress-induced changes in visuospatial performance. A total of 107 participants completed a mental rotation task and were subsequently exposed to either to the Trier social stress test (TSST) or to a control condition before completing the mental rotation task again. HPA-A and SNS reactivity of the participants were evaluated by measuring salivary alpha amylase (sAA; an SNS activation marker) and cortisol in four saliva samples. Pre-stress levels of sex hormones (progesterone, estradiol, and testosterone) were also measured. The TSST enhanced mental rotation performance, and this enhancement was negatively correlated with baseline estradiol levels and positively correlated with the level of cortisol reactivity among men. In addition, controlling for baseline levels of testosterone, estradiol, and progesterone diminished this effect of stress. These results imply that the stress-induced facilitation of mental rotation performance is modulated by baseline sex hormones and provide preliminary support to the notion that a complex interaction between sex hormones and neuroendocrine stress mechanisms mediates the influence of stress on visuospatial performance.

Interactive role of endocrine stress systems and reproductive hormones in the effects of stress on declarative memory.

The effects of stress on memory performance, and the neuroendocrine mechanisms mediating such effects, are not well understood. Given the interrelationship between reproductive hormones and both the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal axis (HPA-A), we examined their combined effect on stress-induced modulation of declarative memory. Before and after exposure either to the Trier Social Stress Test (TSST) procedure or to a non-stress condition, 112 participants completed the Rey Auditory Verbal Learning Test. We analyzed participants' HPA-A and SNS reactivity by measuring cortisol and salivary alpha-amylase (sAA, an SNS activation marker) in four saliva samples. In addition, testosterone, estradiol, and progesterone were sampled prior to the stress exposure. Exposure to the TSST attenuated memory recall after an introduction of an interference list during the declarative memory task. Importantly, controlling for testosterone, estradiol, and progesterone diminished this effect of stress, suggesting the importance of baseline reproductive hormones in stress-induced modulation of memory functions. Furthermore, a multiple regression model revealed that stress-induced declines in memory performance were negatively associated with participants' stress-induced cortisol reactivity, but only among individuals with high testosterone levels. In addition, stress-induced declines in memory performance were negatively associated with participants' stress-induced increases in sAA, but only in individuals with low progesterone levels. These findings suggest that the effects of stress on memory performance may be modulated by baseline reproductive hormones and provide a preliminary indication for specific modulatory interrelationships between reproductive hormones and neuroendocrine stress mechanisms in mediating the effects of stress on memory.

The Effect of Sleep Deprivation on Recognition of Ambiguous Emotional Facial Expressions in Individuals With ADHD.

Objective: The present study sought to investigate whether young adults with ADHD have more difficulty recognizing emotional facial expressions compared with young adults without ADHD, and whether such a difference worsens following sleep deprivation. Method: Thirty-one young men (M = 25.6) with (n = 15) or without (n = 16) a diagnosis of ADHD were included in this study. The participants were instructed to sleep 7 hr or more each night for one week, and their sleep quality was monitored via actigraph. Subsequently, the participants were kept awake in a controlled environment for 30 hr. The participants completed a visual emotional morph task twice-at the beginning and at the end of this period. The task included presentation of interpolated face stimuli ranging from neutral facial expressions to fully emotional facial expressions of anger, sadness, or happiness, allowing for assessment of the intensity threshold for recognizing these facial emotional expressions. Results: Actigraphy data demonstrated that while the nightly sleep duration of the participants with ADHD was similar to that of participants without ADHD, their sleep efficiency was poorer. At the onset of the experiment, there were no differences in recognition thresholds between the participants with ADHD and those without ADHD. Following sleep deprivation, however, the ADHD group required clearer facial expressions to recognize the presence of angry, sad, and, to a lesser extent, happy faces. Conclusion: Among young adults with ADHD, sleep deprivation may hinder the processing of emotional facial stimuli.

The Sleepiness Curve of Young Men With and Without Attention-Deficit Hyperactivity Disorder (ADHD).

Objectives: The present study aimed at comparing the sleepiness curve of young men with attention-deficit hyperactivity disorder (ADHD) to that of young men without ADHD before, during, and after a night of sleep deprivation. Participants: Thirty young men (age 18-30) of whom 14 were diagnosed with ADHD combined type (ADHD-C) and 16 without ADHD. Methods: The participants' sleep was monitored for 5 days via actigraphy. Subsequently, the participants were kept continuously awake in a controlled environment for 25 hr (8:00 a.m.-9:00 a.m.). The sleepiness of the participants was assessed every hour by the Karolinska Sleepiness Scale (KSS) in order to obtain the sleepiness curve of both study groups. Results: Actigraphy data demonstrated that the two groups did not differ in their total sleep time, sleep onset latency, or sleep efficiency during the 5 nights preceding the experimental session. However, during the experimental session, the ADHD group demonstrated higher sleepiness scores, particularly following midnight and on the morning following the night of sleep deprivation. Moreover, on the morning following sleep deprivation the proportion of participants reporting extreme levels of sleepiness (KSS > 7) was significantly higher in the ADHD group than in the control group. Conclusions: Young men with ADHD suffer from sleepiness more than their counterparts from the general population, and are particularly vulnerable to the effects of sleep deprivation on sleepiness. As excessive daytime sleepiness negatively affects cognition and increases the risk for motor vehicle crash and other accidents, these findings may have important clinical implications.

The Interplay Between Tobacco Dependence and Sleep Quality Among Young Adults.

Objective/Background: Sleep disturbances are considered among the negative consequences of smoking. However, the relationship between sleep quality and smoking among young adults, a population in which the prevalence of smoking is highest, has scarcely been examined. The current study aimed at examining differences in sleep indices, assessed by both subjective and objective (actigraphy) measures, between smokers and nonsmokers, and whether such differences are associated with levels of nicotine dependence. Participants: Eighty-six young (19-28 years old) volunteers, of them 46 nonsmokers (69.6% women) and 40 regular smokers (70.0% women) smoking at least 10 cigarettes a day. Methods: The participants completed the State-Trait Anxiety Inventory, Beck Depression Inventory, Brief Questionnaire on Smoking Urges, the Fagerstrom Test for Nicotine Dependence, and the Pittsburgh Sleep Quality Index. Their sleep was monitored objectively for one week using an actigraph. Results: Smokers' self-reported sleep quality was similar to that of nonsmokers. However, actigraphy data pointed to lower sleep continuity in smokers compared to nonsmokers as reflected by increased wake time after sleep onset (Mean ± SD: 18.56 ± 15.29 vs. 11.21 ± 11.19, p < .01) and decreased sleep efficiency (Mean ± SD: 95.63 ± 3.53 vs. 97.23 ± 2.62, p < .012). Total sleep time and sleep onset latency did not differ between the groups. Notably, severity of nicotine dependence was negatively associated with sleep efficiency (ß = -.32; p < .05). Conclusion: Young adult smokers have lower sleep continuity without necessarily subjectively experiencing their sleep as poor. Nevertheless, their lower sleep continuity is related to their level of nicotine dependence.

Individuals With Type 2 Diabetes: An Exploratory Study of Their Experience of Family Relationships and Coping With the Illness.

PURPOSE: The purpose of this qualitative study is to explore familial patterns that may be related to type 2 diabetes (T2DM) and to patients' ways of coping with the illness. METHODS: A purposive sample of 32 Israeli Jewish (n = 12) and Arab (n = 20) individuals with T2DM were recruited from a community population and interviewed about their familial experiences and their illness. Interview data were analyzed using Colaizzi's phenomenological method. RESULTS: Many participants, particularly from the Arab society, reported familial patterns that suggest fused relationships and emotional cutoff. They described highly close and positive family relationships, on one hand, but demonstrated unwillingness to share their difficulties with their family members, on the other hand. Precipitating stressful or traumatic events and day-to-day stress appeared as leading perceived causes of the illness. Maintaining an appropriate lifestyle, stress reduction, and family support were the main coping strategies with the illness. CONCLUSIONS: The findings suggest a possible avenue in which fusion with family members and inability to attenuate emotional distress by sharing difficulties with others may contribute to the development of T2DM. Assessment of such family dynamics and ways of coping with stress could lead to more appropriately nuanced treatment for individuals with T2DM and prediabetes.

Depressive symptoms mediate the relationship between sleep disturbances and type 2 diabetes mellitus.

BACKGROUND: The current study aimed at examining whether individuals diagnosed with type 2 diabetes mellitus (T2DM) have more severe sleep disturbances compared to individuals who are healthy or have prediabetes and whether depressive symptoms mediate the relationship between sleep disturbances and having T2DM. METHODS: T2DM patients (n = 107) were compared to individuals with prediabetes (n = 48) and healthy individuals (n = 154) regarding the severity of depressive symptoms, measured via the Beck Depression Inventory-II (BDI-II), and sleep disturbances, measured via the Mini Sleep Questionnaire (MSQ). Mediation analysis examined whether depressive symptoms mediated the relationship between sleep disturbances and T2DM. RESULTS: Compared to healthy individuals and individuals with prediabetes, T2DM patients had more depressive symptoms and higher levels of insomnia, hypersomnia, and overall more sleep disturbances. The prediabetes group did not differ from the healthy control group on these measures, and these groups were thus combined for further analysis. Sleep disturbances were correlated with severity of depressive symptoms (r =0.43). After controlling for age, gender, and ethnic background, both severity of sleep disturbances (odds ratio [OR]: 1.04; 95% CI: 1.01-1.07, P <.001) and severity of depressive symptoms (OR: 8.54, 95% CI: 3.37-21.69, P <.001) predicted T2DM. Depression symptoms mediated the relationship between sleep disturbances and T2DM, whereas the direct relationship between sleep disturbances and T2DM was nonsignificant. CONCLUSIONS: The findings imply that sleep disturbances may contribute to the development and progression of T2DM by promoting depressive symptoms. Thus, treatments for the emotional distress associated with sleep disturbances may help reduce the risk for T2DM and the progression of the disease.

Depressive Symptoms Mediate the Relationship between Emotional Cutoff and Type 2 Diabetes Mellitus.

BACKGROUND: Differentiation of self is a family systems construct defined as the ability to balance intimacy and autonomy and to separate instinctually driven emotional reactions and thoughtfully considered goal-directed functioning. In theory, low differentiation of self is reflected by four components: a low tendency to take an I-position in relationships (i.e., to own one's thoughts and feelings); emotional cutoff from others; a greater tendency to fuse with others; and a tendency towards emotional reactivity. Low differentiation of self is associated with anxiety and depression, which are risk factors for type 2 diabetes mellitus. The current study examines the relationship between differentiation of self and type 2 diabetes mellitus. METHOD: Individuals with type 2 diabetes mellitus (N = 107) and healthy individuals (N = 145) completed the Differentiation of Self Inventory-Revised (DSI-R), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI-II). RESULTS: Compared with healthy individuals, participants with type 2 diabetes had more severe depressive symptoms, higher levels of emotional cutoff, and a lower tendency to take an I-position, but had similar levels of trait anxiety, emotional reactivity, and fusion with others (factor analysis revealed these factors were not separable in the current sample and thus were merged into a single construct). Importantly, the severity of depressive symptoms mediated the relationship between emotional cutoff and being in the type 2 diabetes study group rather than the healthy group. CONCLUSION: These findings suggest a new perspective on the role of psychological patterns in type 2 diabetes mellitus development and progression.

The Relationship Between Tobacco Smoking, Cortisol Secretion, and Sleep Continuity.

Background: Existing theories hold that chronic tobacco smoking leads to the development of adverse psychological symptoms, thus producing a compulsive urge to smoke in order to alleviate these sensations. Sleep disturbances are often considered among the negative consequences of chronic smoking. Objectives: The current study aimed at examining whether dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis may be involved in this disruption of sleep quality among smokers. Methods: Smokers and non-smokers provided saliva samples following awakening for assessment of cortisol concentrations as a measure of HPA activity. Subsequently the participants completed the State-Trait Anxiety Inventory, Brief Questionnaire on Smoking Urges, the Fagerstrom Test for Nicotine Dependence, and the Pittsburgh Sleep Quality Index. Next, their sleep was monitored objectively for one week using an actigraph. Results: While smokers' self-reported sleep quality was similar to that of non-smokers, their sleep recording data pointed to diminished sleep continuity (increased wake time after sleep onset; WASO), while total sleep time and sleep onset latency were similar to that of non-smokers. Cortisol secretion was higher among smokers. However, among smokers only, cortisol was negatively correlated with WASO, suggesting that the direct enhancing effect of smoking on WASO is somewhat balanced by an indirect process related to higher cortisol levels. Possible interpretations for this inconsistent mediation are discussed. Conclusions/Importance: Smoking is associated with reduced sleep continuity and the relationship between smoking and sleep continuity may involve the HPA axis.

Gonadal hormones modulate the HPA-axis and the SNS in response to psychosocial stress.

Exposure to stress activates both the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). A growing body of research points to the contribution of sex hormones (testosterone, estrogen, and progesterone), the end products of the hypothalamus-pituitary-gonadal (HPG) axis, in modulating stress reactivity. The present study aimed at investigating the potential modulating role of sex hormones on HPA and SNS reactivity to psychosocial stress. The reactivity, induced by the Trier Social Stress Test, was analyzed by measuring the levels of cortisol and alpha-amylase (markers for SNS activity) in four saliva samples each of 21 men and 37 women (17 not using oral contraceptives and in their luteal phase, and 20 women using oral contraceptives). In addition, basal sex hormones were sampled prior to the psychosocial stress exposure. Results revealed that controlling for testosterone, estrogen, and progesterone diminished the impact of stress on cortisol reactivity and on alpha-amylase reactivity. Moreover, controlling for sex hormones also diminished the differential pattern of cortisol reactivity in each experimental group among responders. Furthermore, correlation analyses revealed differences between groups in the association between sex hormones and alpha-amylase. The present findings indicate a modulatory role for sex hormones in HPA and SNS reactivity and emphasize the need for control of sex hormone fluctuations when examining cortisol and alpha-amylase reactivity to stress.

Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus.

RATIONALE: Limited access nicotine self-administration decreases hippocampal neurogenesis, providing a mechanism for the deleterious effects of nicotine on hippocampal neuronal plasticity. However, recent studies have shown that limited access nicotine self-administration does not exhibit key features of nicotine dependence such as motivational withdrawal and increased motivation for nicotine after deprivation. OBJECTIVES: The present study used extended access nicotine self-administration (0.03 mg/kg/infusion, 21 h/day, 4 days) with intermittent periods of deprivation (3 days) for 14 weeks, to test the hypothesis that this model enhances nicotine seeking and produces distinct responses in hippocampal neurogenesis when compared with limited access (1 h/day, 4 days) intake. Animals in the extended access group were either perfused prior to or following their final deprivation period, whereas animals in the limited access group were perfused after their last session. RESULTS: Limited- and extended access nicotine self-administration with periodic deprivation did not affect proliferation and differentiation of oligodendrocyte progenitors in the medial prefrontal cortex (mPFC). Conversely, extended access nicotine self-administration with periodic deprivation enhanced proliferation and differentiation of hippocampal neural progenitors. Furthermore, in the hippocampus, the number of differentiating NeuroD-labeled cells strongly and positively correlated with enhanced nicotine seeking in rats that experienced extended access nicotine self-administration. CONCLUSIONS: These findings demonstrate that extended versus limited access to nicotine self-administration differentially affects the generation of new oligodendroglia and new neurons during adulthood. The increases in the number of differentiating cells in extended access nicotine self-administering rats may consequently contribute to aberrant hippocampal neurogenesis and may contribute to maladaptive addiction-like behaviors dependent on the hippocampus.

Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats.

Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self-administration. Here, we tested the hypothesis that the activation of corticotropin-releasing factor-1 (CRF1 ) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self-administration. ShA and LgA rats were tested for anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5α)pyrimidin-7-amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence-induced increases in anxiety-like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra-CeA MPZP infusion prevented abstinence-induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self-administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended-intermittent access to nicotine self-administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence-induced anxiety-like behavior, hyperalgesia and excessive nicotine intake.

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.

Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal.

Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.

Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

Addiction as a stress surfeit disorder.

Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Animal models of nicotine exposure: relevance to second-hand smoking, electronic cigarette use, and compulsive smoking.

Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine and that a large proportion of smokers eventually become dependent on nicotine. In humans, nicotine acutely produces positive reinforcing effects, including mild euphoria, whereas a nicotine abstinence syndrome with both somatic and affective components is observed after chronic nicotine exposure. Animal models of nicotine self-administration and chronic exposure to nicotine have been critical in unveiling the neurobiological substrates that mediate the acute reinforcing effects of nicotine and emergence of a withdrawal syndrome during abstinence. However, important aspects of the transition from nicotine abuse to nicotine dependence, such as the emergence of increased motivation and compulsive nicotine intake following repeated exposure to the drug, have only recently begun to be modeled in animals. Thus, the neurobiological mechanisms that are involved in these important aspects of nicotine addiction remain largely unknown. In this review, we describe the different animal models available to date and discuss recent advances in animal models of nicotine exposure and nicotine dependence. This review demonstrates that novel animal models of nicotine vapor exposure and escalation of nicotine intake provide a unique opportunity to investigate the neurobiological effects of second-hand nicotine exposure, electronic cigarette use, and the mechanisms that underlie the transition from nicotine use to compulsive nicotine intake.