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.

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 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.

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.

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.

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.

Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence.

Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hypothesized that the escalation of nicotine intake may only occur when animals are given extended-access (21 h per day) self-administration sessions after repeated periods of abstinence (24-48 h), and after chronic inhibition of monoamine oxidase using phenelzine sulfate. Intermittent access (every 24-48 h) to extended nicotine self-administration produced a robust escalation of nicotine intake, associated with increased responding under fixed- and progressive-ratio schedules of reinforcement, and increased somatic signs of withdrawal. The escalation of nicotine intake was not observed in rats with intermittent access to limited (1 h per day) nicotine self-administration or daily access to extended (21 h per day) nicotine self-administration. Moreover, inhibition of monoamine oxidase with daily administration of phenelzine increased nicotine intake by ≈ 50%. These results demonstrate that the escalation of nicotine intake only occurs in animals given intermittent periods of abstinence with extended access to nicotine, and that inhibition of monoamine oxidase may contribute to the escalation of smoking, thus validating both an animal model of the escalation of smoking behavior and the contribution of monoamine oxidase inhibition to compulsive nicotine-seeking.

Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats.

RATIONALE: Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions. OBJECTIVES: The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats. METHODS: Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement. RESULTS: The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination. CONCLUSIONS: The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.

Anxiolytic effects of nicotine in a rodent test of approach-avoidance conflict.

RATIONALE: Nicotine has been reported to produce both anxiolytic and/or anxiogenic effects in humans and animals. OBJECTIVES: This study examined whether pretreatment with nicotine would alter anxiety in a unique runway model of approach-avoidance conflict. MATERIALS AND METHODS: Food-restricted rats were trained to run a straight alley once a day to obtain food upon goal-box entry. Beginning on trial 11, food reward was followed by a series of five foot shocks (0.3-0.4 mA, 0.5 s) in the goal box. Non-shocked control rats continued to run for food only. The resulting association of the goal box with both a positive (food) and negative (foot shock) stimulus produced an approach-avoidance conflict (subjects exhibited "retreat behaviors" in which they would approach the goal box, stop, and then retreat back towards the start box). Once retreats were established, their sensitivity to nicotine pretreatment (0.0, 0.03, 0.045, 0.06, or 0.075 mg/kg, i.v.) was compared to saline. In subsequent tests, the effects of nicotine (0.06 or 0.03 mg/kg) were examined on spontaneous activity (locomotion) and center-square entries in an open field (anxiety). RESULTS: Doses of 0.06 and 0.075 mg/kg, but not lower doses of nicotine, reduced the number of runway retreats, and 0.06 mg/kg nicotine increased the number of open-field center entries relative to saline. No effects on locomotion were observed. CONCLUSIONS: Nicotine reduced approach-avoidance conflict and increased the rats' willingness to enter the center of an open field, suggesting that the drug can produce anxiolytic properties and that such effects may serve as an important factor in the persistence of smoking behavior.

Motivational effects of nicotine as measured in a runway model of drug self-administration.

Traditional operant self-administration and conditioned place preference methods have yielded inconsistent results in studies of nicotine reinforcement thereby hindering efforts to identify the neurobiological systems underlying the drug's motivation and reinforcement. This study was designed to assess the motivation of subjects to seek nicotine using a runway self-administration procedure. Male Sprague-Dawley rats (N=67) were trained to run a straight alley for a single daily intravenous injection of nicotine (0.01-0.09 mg/kg/injection) on each of 21 consecutive trials. Run Speed (1/Run Time) served as the dependent measure for the animals' motivation to traverse the alley and enter a goal-box associated with intravenous nicotine administration. Nicotine induced an inverted U-shaped dose-response curve with the 0.03 mg/kg dose producing optimal runway performance over trials. Subjects running for doses larger or smaller than the optimal dose exhibited slower running and took longer to enter the goal-box. Thus, the runway procedure proved to be an effective methodology for reliably assessing the motivation of trained but nondrugged animals to seek intravenous nicotine.