Associations between smoking and pain in early recovery in residential substance use treatment-seekers.

INTRODUCTION: A growing literature indicates bidirectional associations between pain and tobacco use. Cigarette smokers are at increased risk for chronic pain, and observational and experimental studies indicate that pain increases motivation to smoke. Tobacco use disorder frequently co-occurs with other substance use disorders, which are also associated with chronic pain vulnerability. Despite evidence that pain significantly predicts smoking and relapse, associations between smoking history/trajectory and changes in pain over the course of treatment have not been characterized. The objective of the study was to determine the association between in-treatment smoking trajectory, pack-years (i.e., number of cigarette packs smoked per day multiplied by smoking duration), pain-related interference in daily activities, and pain intensity over the course of residential treatment. METHODS: In this study, 280 adult smokers in a residential SUD treatment center in North Central Florida completed questionnaires assessing cigarette use, pain intensity, and pain interference at treatment entry and discharge (Mean = 80.3 days, SD = 25.6). Most participants were diagnosed with alcohol use disorder (66.1 %). Opioid (27.9 %) and cannabis use disorders (29.6 %) were also common. Participants were grouped by whether their smoking increased (n = 36), decreased (n = 46), or stayed the same (n = 133) from entry to discharge. RESULTS: Analyses indicated a positive association between pack-years and pain intensity at both baseline (r = 0.185, p = 0.018) and discharge (r = 0.184, p = 0.019). Smoking trajectory was associated with pack-years, with those decreasing smoking having greater pack-years than those sustaining or increasing use [F(2,136) = 8.62, p < 0.01, η2p = 0.114]. Mixed general linear models indicated pain intensity [F(1,274) = 44.15, p < 0.0001, η2p = 0.138] and interference in day-to-day activities [F(1,276) = 31.79, p < 0.0001, η2p = 0.103] decreased significantly over time. However, there was no main effect of smoking trajectory on pain intensity [F(2,212) = 2.051, p = 0.131, η2p = 0.019] or of smoking trajectory by time interaction [F(2, 212) = 1.228, p = 0.295, η2p = 0.011]. CONCLUSIONS: Overall, findings provide evidence that smoking behavior influences pain within the context of residential substance use treatment. Given that pain is associated with urge to use substances and risk of return to use, more consistent and rigorous assessment of pain and proactive pain management is likely to enhance substance use treatment outcomes among people who smoke.

Chronic cocaine causes age-dependent increases in risky choice in both males and females.

Individuals who use cocaine exhibit maladaptive decision-making, overweighting rewards, and underweighting potential risks. We previously showed that chronic cocaine self-administration in young adult male rats causes long-lasting increases in risk taking. The present study expanded upon these findings to determine whether effects of cocaine on risk taking depend on the route of cocaine administration and extend to females. To address the former question, rats in Experiment 1 were trained on the Risky Decision-making Task (RDT), received passively administered cocaine, and were retested in the RDT. Surprisingly, passive cocaine had no effect on risk taking. Experiment 2 determined whether cocaine self-administration increases risk taking in females in a manner comparable to males. Males and females were trained in the RDT, underwent cocaine self-administration, and were retested in the RDT. Unexpectedly, cocaine self-administration had no effect on risk taking in either sex. Because Experiments 1 and 2 involved cocaine exposure at a considerably older age than in previous work, Experiments 3 and 4 determined if cocaine effects on risk taking depend on the age of exposure. Rats began cocaine self-administration at postnatal (PN) day 77 (Experiment 3) or passive cocaine injections starting on PN day 63 (Experiment 4) and were tested in the RDT 3 weeks after cocaine cessation. In these experiments, cocaine increased risk taking in both sexes. These results reveal a limited time window during young adulthood of vulnerability to the effects of chronic cocaine on risk taking. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Regulation of risky decision making by gonadal hormones in males and females.

Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.

Effects of repeated adolescent exposure to cannabis smoke on cognitive outcomes in adulthood.

BACKGROUND: Cannabis (marijuana) is the most widely used illicit drug in the USA, and consumption among adolescents is rising. Some animal studies show that adolescent exposure to delta 9-tetrahydrocannabinol or synthetic cannabinoid receptor 1 agonists causes alterations in affect and cognition that can persist into adulthood. It is less clear, however, whether similar alterations result from exposure to cannabis via smoke inhalation, which remains the most frequent route of administration in humans. AIMS: To begin to address these questions, a rat model was used to determine how cannabis smoke exposure during adolescence affects behavioral and cognitive outcomes in adulthood. METHODS: Adolescent male Long-Evans rats were assigned to clean air, placebo smoke, or cannabis smoke groups. Clean air or smoke exposure sessions were conducted daily during adolescence (from P29-P49 days of age ) for a total of 21 days, and behavioral testing began on P70. RESULTS: Compared to clean air and placebo smoke conditions, cannabis smoke significantly attenuated the normal developmental increase in body weight, but had no effects on several measures of either affect/motivation (open field activity, elevated plus maze, instrumental responding under a progressive ratio schedule of reinforcement) or cognition (set shifting, reversal learning, intertemporal choice). Surprisingly, however, in comparison to clean air controls rats exposed to either cannabis or placebo smoke in adolescence exhibited enhanced performance on a delayed response working memory task. CONCLUSIONS: These findings are consistent with a growing body of evidence for limited long-term adverse cognitive and affective consequences of adolescent exposure to relatively low levels of cannabinoids.

Using rodent models to understand interactions between gambling and substance use.

Substance use is strongly associated with gambling, but the nature of this association can be difficult to determine. Rodents offer the opportunity to test causal models of these relationships through isolation of individual variables of interest. This review describes recent research in rodents showing: a) predisposing factors for both gambling-like behavior and substance use; b) exposure to drugs of abuse increasing gambling-like behavior; c) experience with gambling-like behavior increasing substance use; and d) links between gambling-like behavior and substance use in models of Parkinson's disease therapies. These findings reveal novel relationships between gambling and substance use, and highlight the utility of rodent models for future work in this area.

Distinct relationships between risky decision making and cocaine self-administration under short- and long-access conditions.

Substance use is strongly associated with impaired decision making, with cocaine use particularly linked to elevated risky and impulsive choice. It is not clear, however, whether such maladaptive decision making is a consequence of cocaine use or instead precedes and predisposes individuals to cocaine use. The current study was designed to specifically address the latter possibility with respect to risky choice in both male and female rats. Rats were first trained in a "Risky Decision-making Task" (RDT), in which they made discrete choices between a small, "safe" food reward and a large, "risky" food reward accompanied by increasing probabilities of mild footshock punishment. After reaching stable performance, rats underwent jugular catheter surgery followed by either short-access cocaine self-administration sessions (2 h, 0.5 mg/kg/infusion) for 5 days or long-access cocaine self-administration sessions (6 h, 0.5 mg/kg/infusion) for 14 days. Under short-access conditions, there was no relationship between risk preference and changes in cocaine intake over time, but greater risk aversion in females predicted greater overall cocaine intake. Under long-access conditions, heightened risk taking predicted greater escalation of cocaine intake over the course of self-administration, supporting the notion that pre-existing risk-taking behavior predicts cocaine intake. Collectively, results from these experiments have implications for understanding and identifying pre-existing vulnerabilities to substance use, which may lead to strategies to prevent development of substance use disorders.

Recent Updates in Modeling Risky Decision Making in Rodents.

Excessive preference for risky over safe options is a hallmark of several psychiatric disorders. Here we describe a behavioral task that models such risky decision making in rats. In this task, rats are given choices between small, safe rewards and large rewards accompanied by risk of footshock punishment. The risk of punishment changes within a test session, allowing quantification of decision making at different levels of risk. Importantly, this task can yield a wide degree of reliable individual variability, allowing the characterization of rats as "risk-taking" or "risk-averse." The task has been demonstrated to be effective for testing the effects of pharmacological agents and neurobiological manipulations, and the individual variability (which mimics the human population) allows assessment of behavioral and neurobiological distinctions among subjects based on their risk-taking profile.

Enhancing effects of acute exposure to cannabis smoke on working memory performance.

Numerous preclinical studies show that acute cannabinoid administration impairs cognitive performance. Almost all of this research has employed cannabinoid injections, however, whereas smoking is the preferred route of cannabis administration in humans. The goal of these experiments was to systematically determine how acute exposure to cannabis smoke affects working memory performance in a rat model. Adult male (n = 15) and female (n = 16) Long-Evans rats were trained in a food-motivated delayed response working memory task. Prior to test sessions, rats were exposed to smoke generated by burning different numbers of cannabis or placebo cigarettes, using a within-subjects design. Exposure to cannabis smoke had no effect on male rats' performance, but surprisingly, enhanced working memory accuracy in females, which tended to perform less accurately than males under baseline conditions. In addition, cannabis smoke enhanced working memory accuracy in a subgroup of male rats that performed comparably to the worst-performing females. Exposure to placebo smoke had no effect on performance, suggesting that the cannabinoid content of cannabis smoke was critical for its effects on working memory. Follow-up experiments showed that acute administration of either Δ9-tetrahydrocannabinol (0.0, 0.3, 1.0, 3.0 mg/kg) or the cannabinoid receptor type 1 antagonist rimonabant (0.0, 0.2, 0.6, 2.0 mg/kg) impaired working memory performance. These results indicate that differences in the route, timing, or dose of cannabinoid administration can yield distinct cognitive outcomes, and highlight the need for further investigation of this topic.

Monoaminergic modulation of decision-making under risk of punishment in a rat model.

The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, 'safe' food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.

SOD1 Lysine 123 Acetylation in the Adult Central Nervous System.

Superoxide dismutase 1 (SOD1) knockout (Sod1-/-) mice exhibit an accelerated aging phenotype. In humans, SOD1 mutations are linked to familial amyotrophic lateral sclerosis (ALS), and post-translational modification (PTM) of wild-type SOD1 has been associated with sporadic ALS. Reversible acetylation regulates many enzymes and proteomic studies have identified SOD1 acetylation at lysine 123 (K123). The function and distribution of K123-acetylated SOD1 (Ac-K123 SOD1) in the nervous system is unknown. Here, we generated polyclonal rabbit antibodies against Ac-K123 SOD1. Sod1 deletion in Sod1-/- mice, K123 mutation or preabsorption with Ac-K123 peptide all abolished antibody binding. Using immunohistochemistry, we assessed Ac-K123 SOD1 distribution in the normal adult mouse nervous system. In the cerebellum, Ac-K123 SOD1 staining was prominent in cell bodies of the granular cell layer (GCL) and Purkinje cell dendrites and interneurons of the molecular cell layer. In the hippocampus, Ac-K123 SOD1 staining was strong in the fimbria, subiculum, pyramidal cells and Schaffer collateral fibers of the cornus ammonis field 1 (CA1) region and granule and neuronal progenitor cells of the dentate gyrus. In addition, labeling was observed in the choroid plexus (CP) and the ependyma of the brain ventricles and central canal of the spinal cord. In the olfactory bulb, Ac-K123 SOD1 staining was prominent in axons of sensory neurons, in cell bodies of interneurons and neurites of the mitral and tufted cells. In the retina, labeling was strong in the retinal ganglion cell layer (RGCL) and axons of retinal ganglion cells (RGCs), the inner nuclear layer (INL) and cone photoreceptors of the outer nuclear layer (ONL). In summary, our findings describe Ac-K123 SOD1 distribution to distinct regions and cell types of the normal nervous system.