Role Of Substance Use Disorders Research Articles

Endogenous and Exogenous Opioids: Role in Substance Use Disorders.

Opioid use disorders have become an epidemic in recent years with rates nearly quadrupling since 1999 according to the US Centers for Disease Control and Prevention (Centers for Disease Control, Wide-ranging online data for epidemiologic research (WONDER). CDC, National Center for Health Statistics, Atlanta. Retrieved December 19, 2017, from http://wonder.cdc.gov, 2016). To understand substance use disorder (SUD) as a disease, many aspects must be studied including the circuitry in the brain, adaptations to neuronal circuitry and neurotransmitters, genetic variations increasing the risk for SUD, and treatments available for SUD. The mechanism in which an exogenous opioid may cause SUD is nearly identical to the mechanism of an endogenous opioid. This chapter reviews the clinical and epidemiological aspects of opioid use disorder, as well as the interactions between endogenous and exogenous opioids. Additionally, this chapter discusses current scientific data regarding genetic variations and mechanisms within brain circuitry and the role of endogenous opioids in substance use disorders generally (and opioid use disorder specifically). Future applications of these data to treatment of substance use disorders are also discussed.

Abnormal frontostriatal connectivity and serotonin function in gambling disorder: Apreliminary exploratory study.

The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities. Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (18F-FDOPA), opioid (11C-carfentanil) and serotonin (11C-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches. Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (PFWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC 11C-MADAM binding (p = 0.03) but not in 18F-FDOPA uptake or 11C-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex 11C-MADAM binding (PFWE <0.05). Right NAcc 11C-MADAM binding potential correlated with attentional impulsivity in individuals with gambling disorder (r = -0.73, p = 0.005). Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify potential treatment targets for gambling disorder.

Estradiol receptors inhibit long-term potentiation in the dorsomedial striatum.

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation in ex vivo brain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrus stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus did not exhibit LTP. Furthermore, antagonists of ERα or GPER rescued LTP in estrus females and agonists of ERα or GPER reduced LTP in diestrus females. In males, activating ERα but not GPER reduced LTP. These results uncover an inhibitory action of estradiol receptors on cellular learning in the DMS and suggest a cellular mechanism underlying the impairment in certain types of DMS-based learning observed in the presence of high estradiol. Due to the dorsal striatum's role in drug addiction, these findings may provide a mechanism underlying an estradiol-mediated progression from goal-directed to habitual drug use.Significance StatementThis study examined the role of the female reproductive cycle and female sex hormones in synaptic plasticity, a cellular process that underlies learning behavior, in a brain region involved in goal-directed learning. Synaptic plasticity was similar between male mice and female mice in the low estradiol phase of the cycle. In contrast, female mice in a high estradiol phase of the cycle did not exhibit synaptic plasticity. The effect of estradiol was mediated by two of the three estradiol receptors found in the brain. The results have implications for the role of the female reproductive cycle in the development of drug addiction, which involves a progression from goal-directed learning to habit-based learning as drug use switches from recreational to compulsive.

Ketamine Treatment for Alcohol Use Disorder: A Systematic Review.

Alcohol use disorder (AUD) is a chronic, recurrent condition that demonstrates significant heterogeneity in treatment response to first-line agents. Ketamine may have a therapeutic role in substance use disorders; however, research on this topic is limited. The objective of this systematic review is to qualitatively synthesize the current evidence of ketamine treatment for alcohol use disorder and evaluate its efficacy. A systematic review of Medline, PsycINFO, CINAHL, the Cochrane Library, and Google Scholar was performed to identify completed human studies in English or Spanish (from inception to July 2022) that assess the effectiveness of ketamine therapy for alcohol use disorder. This review was registered on the Open Science Framework. Data were descriptively summarized and presented in tables and tested via narrative synthesis methodology. The risk of bias was measured with Cochrane Collaboration tools and a case series quality assessment tool. A total of 11 studies with 854 adult patients in three different countries (the USA, the UK, and Russia) were analyzed. Sample sizes ranged from 5 to 211 people. Seven studies included patients with alcohol use disorder, one study focused on heavy drinkers, and three studies elaborated extensively on alcohol withdrawal. The overall proportion of patients achieving abstinence and reduced consumption was most favorable in people receiving combination ketamine and psychotherapy treatment. The results were mixed with respect to relapse, craving, and withdrawal. Ketamine may be an effective therapeutic modality for people with alcohol use disorders who fail to respond to FDA-approved first-line agents. More robust clinical trials are necessary to provide a more accurate assessment of efficacy, safety profile, and dosing strategies for ketamine utilization in alcohol use disorder.

An anxiety management intervention for people with substance use disorders (ITASUD): An intervention mapping approach based on Peplau's theory.

The comorbidity of anxiety and drug use disorders complicates treatment prognosis, and one of the greatest challenges is to address the environmental and behavioral factors involved. The aim of this study was to describe the uses of intervention mapping in the design of a theory and evidence-based complex intervention to develop skills around the management of anxiety for cocaine users in outpatient addiction treatment. The six steps of the intervention mapping approach, which are needs assessment, creation of matrices of performance objectives, selection of methods and practical strategies, program development, adoption and implementation, and evaluation were applied to develop the Interpersonal Theory of nursing to Anxiety management in people with Substance Use Disorders (ITASUD) intervention. The theory used for the conceptual model was interpersonal relations theory. All theory-based methods and practical applications were developed at the individual level, acting in behavioral, interpersonal, organizational and community environments. The intervention mapping provided a broad overview of the problem and outcome expectations. The ITASUD intervention consists of five consecutive sessions of 110-min targeting individual determinants of anxiety (knowledge, triggers, relief behaviors, self-efficacy and relations), delivered by a trained nurse using Peplau's concepts of interpersonal relations. Intervention Mapping is a multi-step process that incorporates theory, evidence, and stakeholder perspectives to ensure that implementation strategies effectively address key determinants of change. The intervention mapping approach increases the effectiveness of the intervention since the matrices provide a broad view of all factors that affect the problem and facilitate replication through transparency of the determinants, methods, and applications used. ITASUD addresses all factors that play an important role in substance use disorders based on a theoretical basis, which provides the translation of evidence from research into effective practice, policy, and public health improvements.

The Role of Substance Use Disorders on Suicidal Ideation, Planning, and Attempts: A Nationally Representative Study of Adolescents and Adults in the United States, 2020.

Few nationally representative studies examine suicidality and substance use during 2020; as such, we explored the role of substance use disorders (SUDs) on suicidality among adults and adolescents in 2020. Data were derived from N = 26,084 adult participants, representing 240 million U.S. adults weighted, and N = 5,723 adolescent participants, representing 25 million U.S. adolescents (12-17 years.). Separate logistic regressions for adults and adolescents were used to assess the association of DSM-5 SUDs, related factors, and suicidal thoughts and behaviors (ideation, planning, and attempts). In 2020, adults with SUDs were nearly 4 times more likely to seriously consider suicide (aOR = 3.94, 95% CI: 3.19, 4.86), 3 times more likely to make a suicide plan (aOR = 3.09, 95% CI: 2.25, 4.25), and nearly 4 times more likely to attempt suicide (aOR = 3.77, 95% CI: 2.29, 6.19) than adults without SUDs. Adolescents with SUDs were 4 times more likely to consider suicide (aOR = 3.69, 95% CI: 2.47, 5.51), 5 times as likely to make a suicide plan (aOR = 5.14, 95% CI: 3.25, 8.13) and to attempt suicide (aOR = 5.27, 95% CI: 2.91, 9.53) than adolescents without SUDs. Adult females and individuals experiencing poverty were twice as likely to attempt suicide than adult males and individuals not living in poverty. Adolescent females were 3-5 times more likely to seriously consider, plan, and attempt suicide than adolescent males. Interventions to curb suicidality among individuals with SUDs are crucial.

The role of substance use disorders in the transition from suicide attempt to suicide death: a record linkage study of a Swedish cohort.

Suicidal behavior and substance use disorders (SUDs) are important public health concerns. Prior suicide attempts and SUDs are two of the most consistent predictors of suicide death, and clarifying the role of SUDs in the transition from suicide attempt to suicide death could inform prevention efforts. We used national Swedish registry data to identify individuals born 1960-1985, with an index suicide attempt in 1997-2017 (N = 74 873; 46.7% female). We assessed risk of suicide death as a function of registration for a range of individual SUDs. We further examined whether the impact of SUDs varied as a function of (i) aggregate genetic liability to suicidal behavior, or (ii) age at index suicide attempt. In univariate models, risk of suicide death was higher among individuals with any SUD registration [hazard ratios (HRs) = 2.68-3.86]. In multivariate models, effects of specific SUDs were attenuated, but remained elevated for AUD (HR = 1.86 95% confidence intervals 1.68-2.05), opiates [HR = 1.58 (1.37-1.82)], sedatives [HR = 1.93 (1.70-2.18)], and multiple substances [HR = 2.09 (1.86-2.35)]. In secondary analyses, the effects of most, but not all, SUD were exacerbated by higher levels of genetic liability to suicide death, and among individuals who were younger at their index suicide attempt. In the presence of a strong predictor of suicide death - a prior attempt - substantial predictive power is still attributable to SUDs. Individuals with SUDs may warrant additional suicide screening and prevention efforts, particularly in the context of a family history of suicidal behavior or early onset of suicide attempt.

GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders.

Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

Ginsenoside Rg1 mitigates morphine dependence via regulation of gut microbiota, tryptophan metabolism, and serotonergic system function.

Morphine dependence, a devastating neuropsychiatric condition, may be closely associated with gut microbiota dysbiosis. Ginsenoside Rg1 (Rg1), an active ingredient extracted from the roots of Panax ginseng C.A. Meyer, has potential health-promoting effects on the nervous system. However, its role in substance use disorders remains unclear. Here, we explored the potential modulatory roles of Rg1 in protection against morphine dependence. Conditioned place preference (CPP) was used for establishing a murine model of morphine dependence. 16S rRNA gene sequencing and metabolomics were performed for microbial and metabolite analysis. Molecular analysis was tested for evaluating the host serum and brain responses. Rg1 prevented morphine-induced CPP in mice. The 16S rRNA gene-based microbiota analysis demonstrated that Rg1 ameliorated morphine-induced gut microbiota dysbiosis, specifically for Bacteroidetes. Moreover, Rg1 also inhibited gut microbiota-derived tryptophan metabolism and reduced the serotonin, 5-hydroxytryptamine receptor 1B (5-HTR1B), and 5-hydroxytryptamine receptor 2A (5-HTR2A) levels. However, the Rg1-induced amelioration of CPP was not observed in mice when their gut microbiome was depleted by non-absorbable antibiotics. Subsequently, gavage with Bacteroides vulgatus increased the abundance of Bacteroidetes. B. vulgatus supplementation synergistically enhanced Rg1-alleviated morphine-induced CPP in mice with microbiome knockdown. Co-treatment with B. vulgatus and Rg1 produced suppressive effects against morphine dependency by inhibiting tryptophan metabolism and reducing the serotonin and 5-HTR1B/5-HTR2A levels. The gut microbiota-tryptophan metabolism-serotonin plays an important role in gut-brain signaling in morphine disorders, which may represent a novel approach for drug dependence treatment via manipulation of the gut microbial composition and tryptophan metabolite.

The Role of Dopamine D3 Receptors in Tobacco Use Disorder: A Synthesis of the Preclinical and Clinical Literature.

Tobacco smoking is a significant cause of preventable morbidity and mortality globally. Current pharmacological approaches to treat tobacco use disorder (TUD) are only partly effective and novel approaches are needed. Dopamine has a well-established role in substance use disorders, including TUD, and there has been a long-standing interest in developing agents that target the dopaminergic system to treat substance use disorders. Dopamine has 5 receptor subtypes (DRD1 to DRD5). Given the localization and safety profile of the dopamine receptor D3 (DRD3), it is of therapeutic potential for TUD. In this chapter, the preclinical and clinical literature investigating the role of DRD3 in processes relevant to TUD will be reviewed, including in nicotine reinforcement, drug reinstatement, conditioned stimuli and cue-reactivity, executive function, and withdrawal. Similarities and differences in findings from the animal and human work will be synthesized and findings will be discussed in relation to the therapeutic potential of targeting DRD3 in TUD.

Complex Interactions Between Sex and Stress on Heroin Seeking.

Rationale: Stress plays a dual role in substance use disorders as a precursor to drug intake and a relapse precipitant. With heroin use at epidemic proportions in the United States, understanding interactions between stress disorders and opioid use disorder is vital and will aid in treatment of these frequently comorbid conditions.Objectives: Here, we combine assays of stress and contingent heroin self-administration (SA) to study behavioral adaptations in response to stress and heroin associated cues in male and female rats.Methods: Rats underwent acute restraint stress paired with an odor stimulus and heroin SA for subsequent analysis of stress and heroin cue reactivity. Lofexidine was administered during heroin SA and reinstatement testing to evaluate its therapeutic potential. Rats also underwent tests on the elevated plus maze, locomotor activity in a novel environment, and object recognition memory following stress and/or heroin.Results: A history of stress and heroin resulted in disrupted behavior on multiple levels. Stress rats avoided the stress conditioned stimulus and reinstated heroin seeking in response to it, with males reinstating to a greater extent than females. Lofexidine decreased heroin intake, reinstatement, and motor activity. Previous heroin exposure increased time spent in the closed arms of an elevated plus maze, activity in a round novel field, and resulted in object recognition memory deficits.Discussion: These studies report that a history of stress and heroin results in maladaptive coping strategies and suggests a need for future studies seeking to understand circuits recruited in this pathology and eventually help develop therapeutic approaches.

307Association between patterns of comorbid mental disorders and mortality-related estimates. A Danish register-based cohort study

Abstract Background Comorbidity within mental disorders is common, and people with two or more types of mental disorders have shorter life expectancy compared to those with exactly one type. The aims of this study were to: (a) describe the prevalence of combinations of mental disorders; and (b) estimate the excess mortality for each of these combinations. Methods We conducted a population-based cohort study including all 7,505,576 persons living in Denmark in 1995-2016. Using national registers, we described the most common combinations of mental disorders and investigated excess mortality by means of mortality rate ratios (MRRs) and differences in life expectancy. Results At the end of the 22-year observation, 6.2% individuals were diagnosed with exactly one disorder, and 5.3% with two or more types. People with any combination of disorders had higher mortality rates than those without any diagnosis (MRRs ranging from 1.10 [95% CI 0.67 – 1.84] to 5.97 [95% CI 5.52 – 6.45]) and shorter life expectancies compared to the general population (estimates ranging from 5.06 years [95% CI 5.01 – 5.11] to 17.46 years [95% CI 16.86 – 18.03]). Conclusions Mood disorders and neurotic disorders commonly co-occur, and contribute to many different sets of comorbid mental disorders. The association between mental disorders comorbidity and mortality revealed the prominent role of substance use disorders. Key messages Our study provides prevalence estimates of the most common sets of mental disorders. In light of the substantial contribution of substance use disorders to premature mortality, efforts related to the ‘primary prevention of secondary comorbidity’ warrant added scrutiny.

Somatostatin neurons control an alcohol binge drinking prelimbic microcircuit in mice

Somatostatin (SST) neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance use disorders, including alcohol use disorder (AUD), is not fully characterized. Here, we found that repeated cycles of alcohol binge drinking via the Drinking-in-the-Dark (DID) model led to hypoactivity of SST neurons in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. Alcohol binge drinking disinhibited pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations and reducing spontaneous inhibitory transmission onto pyramidal neurons. Pyramidal neurons additionally displayed increased intrinsic excitability. Direct inhibition of PL pyramidal neurons via hM4Di was sufficient to reduce alcohol binge drinking. Together these data revealed an SST-mediated microcircuit in the PL that modulates the inhibitory dynamics of pyramidal neurons, a major source of output to subcortical targets to drive reward-seeking behaviors and emotional response.

O7.1. ASSOCIATION BETWEEN PATTERNS OF COMORBID MENTAL DISORDERS AND MORTALITY-RELATED ESTIMATES. A NATIONWIDE, REGISTER-BASED COHORT STUDY BASED ON 7.5 MILLION INDIVIDUALS LIVING IN DENMARK

BackgroundComorbidity within mental disorders is common – individuals with one type of mental disorder are at increased risk of subsequently developing other types of disorders. Previous studies are usually restricted to temporally-ordered pairs of disorders. While more complex patterns of comorbidity have been described (e.g. internalizing and externalizing disorders), there is a lack of detailed information on the nature of the different sets of comorbid mental disorders. Additionally, mental disorders are associated with premature mortality, and people with two or more types of mental disorders have a shorter life expectancy compared to those with exactly one type of mental disorder. The aims of this study were to: (a) describe the prevalence and demographic correlates of combinations of mental disorders; and (b) estimate the excess mortality for each of these combinations.MethodsWe conducted a population-based cohort study including all 7,505,576 persons living in Denmark in 1995–2016. Information on mental disorders and mortality was obtained from national registers. First, we described the most common combinations of mental disorders defined by the ICD-10 F-subchapters (substance use disorders, schizophrenia spectrum disorder, mood disorders, neurotic disorders, etc.). Then, we investigated excess mortality using mortality rate ratios (MRRs) and differences in life expectancy after disease diagnosis compared to the general population of same sex and age.ResultsAt the end of the 22-year observation, 6.2% individuals were diagnosed with exactly one type of disorder, 2.7% with exactly two, 1.1% with exactly three, and 0.5% with four or more types. The most prevalent mental disorders were neurotic disorders (4.6%) and mood disorders (3.8%), even when looking particularly at persons with a specific number of disorders (exactly one type, exactly two types, etc.). We observed 616 out of 1,024 possible sets of disorders, but the 52 most common sets (with at least 1,000 individuals each) represented 92.8% of all persons with diagnosed mental disorders. Mood and/or neurotic disorders, alone or in combination with other disorders, were present in 64.8% of individuals diagnosed with mental disorders. People with all combinations of mental disorders had higher mortality rates than those without any mental disorder diagnosis, with MRRs ranging from 1.10 (95% CI 0.67 – 1.84) for the two-disorder set of developmental-behavioral disorders to 5.97 (95% CI 5.52 – 6.45) for the three-disorder set of schizophrenia-neurotic-substance use disorders. Additionally, any combination of mental disorders was associated with shorter life expectancies compared to the general population, with estimates ranging from 5.06 years [95% CI 5.01 – 5.11] for the one-disorder set of organic disorders to 17.46 years [95% CI 16.86 – 18.03] for the three-disorder set of schizophrenia-personality-substance use disorders.DiscussionWithin those with mental disorders, approximately 2 out of 5 had two more types of mental disorders. Our study provides prevalence estimates of the most common sets of mental disorders – mood disorders (e.g. depression) and neurotic disorders (e.g. anxiety) commonly co-occur, and contribute to many different sets of comorbid mental disorders. The association between mental disorders comorbidity and mortality-related estimates revealed the prominent role of substance use disorders with respect to both elevated mortality rates and reduced life expectancies. Substance use disorders are relatively common, and these disorders often feature in sets of mental disorders. In light of the substantial contribution to premature mortality, efforts related to the ‘primary prevention of secondary comorbidity’ warrant added scrutiny.

The role of substance use disorders in experiencing a repeat opioid overdose, and substance use treatment patterns among patients with a non-fatal opioid overdose

BackgroundA non-fatal opioid overdose (NFOO) increases the risk of another overdose and identifies high-risk patients. We estimated the risk of repeat opioid overdose for patients with and without substance use disorder (SUD) diagnoses and the change in substance use treatment utilization rates associated with the first NFOO. MethodsWe selected patients (>18 years of age) from Kaiser Permanente Northern California with a NFOO between 2009-2016 (n = 3,992). Cox proportional hazards models estimated the 1-year risk of opioid overdose associated with SUD diagnoses (opioid, alcohol, cannabis, amphetamine, sedative, and cocaine), controlling for patient characteristics. Among patients with an index NFOO, we calculated monthly utilization rates for outpatient substance use services and buprenorphine before and after the index overdose. Interrupted time series models estimated the change in level and trend in utilization rates associated with the index overdose. ResultsApproximately 7.2 % of patients had a repeat opioid overdose during the year after the index NFOO. The only SUD diagnosis significantly associated with greater risk of repeat overdose was opioid use disorder (OUD) (aHR: 1.51; 95 % CI: 1.13–2.01).Before the index overdose, 4.16 % of patients received outpatient substance use services and 1.32 % received buprenorphine. The index overdose was associated with a 5.94 % (standard error: 0.77 %) absolute increase in outpatient substance use services and a 1.29 % (standard error: 0.15 %) increase in buprenorphine. ConclusionPatients with a NFOO and OUD are vulnerable to another overdose. Low initiation rates for substance use treatment after a NFOO indicate a need to address patient, provider, and system barriers.

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders. In this review, we provide an updated summary of parallel preclinical and human studies that support this hypothesis. Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behavior and amplify responding elicited by discrete, drug-predictive cues. Akin to drug-associated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders. Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies. This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions. We conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches: pharmacology, brain stimulation, mindfulness-based relapse prevention, and cognitive behavioral group therapy. Throughout, we focus on alcohol- and tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

Association of Substance Use Disorders With Conversion From Schizotypal Disorder to Schizophrenia

Understanding the role of substance use disorders in conversion from schizotypal disorder to schizophrenia may provide physicians and psychiatrists with important tools for prevention or early detection of schizophrenia. To investigate whether substance use disorders, in particular cannabis use disorder, are associated with conversion to schizophrenia in individuals with schizotypal disorder. This prospective cohort study included a population-based sample of all individuals born in Denmark from January 1, 1981, through August 10, 2014, with an incident diagnosis of schizotypal disorder and without a previous diagnosis of schizophrenia. Follow-up was completed on August 10, 2014, and data were analyzed from March 10, 2017, through February 15, 2018. Information on substance use disorders combined from 5 different registers. Cox proportional hazards regression using time-varying information on substance use disorders and receipt of antipsychotics and adjusted for parental history of mental disorders, sex, birth year, and calendar year were used to estimate hazard ratios (HRs) and 95% CIs for conversion to schizophrenia. A total of 2539 participants with incident schizotypal disorder were identified (1448 men [57.0%] and 1091 women [43.0%]; mean [SD] age, 20.9 [4.4] years). After 2 years, 16.3% (95% CI, 14.8%-17.8%) experienced conversion to schizophrenia. After 20 years, the conversion rate was 33.1% (95% CI, 29.3%-37.3%) overall and 58.2% (95% CI, 44.8%-72.2%) among those with cannabis use disorders. In fully adjusted models, any substance use disorder was associated with conversion to schizophrenia (HR, 1.34; 95% CI, 1.11-1.63). When data were stratified by substance, cannabis use disorders (HR, 1.30; 95% CI, 1.01-1.68), amphetamine use disorders (HR, 1.90; 95% CI, 1.14-3.17), and opioid use disorders (HR, 2.74; 95% CI, 1.38-5.45) were associated with conversion to schizophrenia. These associations were not explained by concurrent use of antipsychotics, functional level before incident schizotypal disorder, or parental history of mental disorders. Substance use disorders, in particular cannabis, amphetamines, and opioids, may be associated with conversion from schizotypal disorder to schizophrenia. However, conversion rates are high even in those without substance use disorders, indicating a need for universal and substance-targeted prevention in individuals with schizotypal disorder.

The Role of Pleasure Neurobiology and Dopamine in Mental Health Disorders.

Recent evidence and research has demonstrated that the pleasure response and associated neurotransmitters and brain circuits play a significant role in substance use disorders (SUDs). It was thought that negative behaviors associated with SUDs resulted from negative choices, but it is now known that chemical changes in the brain drive those behaviors. Several mental health disorders (e.g., eating disorders, non-suicidal self-injury, compulsive sex behaviors, internet gaming, gambling) are also thought to involve those same pleasure responses, neurotransmitters, and brain regions. Studies have shown that the use of naltrexone, a dopamine antagonist, can reduce symptoms of these disorders. It is important for nurses to understand the underlying physiology of mental health disorders that are thought to have an addictive or craving component. This understanding can help reduce stigma. Educating patients about likely neurobiological causes for their disorders can also help reduce guilt and shame. Nurses should educate patients about these disorders and evidence-based treatments, including off-label use of naltrexone. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 17-21.].

Effects of propofol on conditioned place preference in male rats: Involvement of nitrergic system

ABSTRACTBackground: Drug-induced conditioned place preference (CPP) is linked to the addictive properties of the drug used. The number of studies that have investigated the effects of propofol on CPP is limited. Research findings suggest that nitric oxide (NO) might play an important role in substance use disorders. Objectives: The present study sought to investigate the role of the nitrergic system on the rewarding effects of propofol by using the CPP protocol in rats. Methods: The experiment followed habituation, pre-conditioning, conditioning, and post conditioning sessions. Male Wistar albino rats weighing 240–290 g were divided into eight groups: control (saline), propofol (10, 20, and 40 mg/kg), the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) alone (30 and 60 mg/kg), and in combination with propofol (30 and 60 mg/kg L-NAME plus 40 mg/kg propofol) (n = 8 for each group). The CPP effects of propofol, L-NAME, saline, and their combinations were evaluated. All the drug and saline administrations were performed by intraperitoneal (ip) injections. Results: Propofol (10–40 mg/kg) produced CPP that was statistically significant relative to saline. Propofol-induced CPP was significantly reversed by pretreatment with L-NAME. When administered alone, L-NAME did not produce CPP and also did not produce any significant change on locomotor activity of naïve rats. Conclusion: Our results suggest that propofol produces CPP effects in rats and that NO-related mechanisms may be responsible for propofol-induced CPP. Thus, propofol might have the potential to be addictive, and this possibility should be considered during clinical applications of this drug.

Association of Traffic Injuries, Substance Use Disorders, and ED Visit Outcomes among Individuals Aged 50+ Years

Objectives: Motor vehicle traffic (MVT) injury is the second most frequent type of injury among older emergency department (ED) patients. We examined the role of substance use disorders (SUD) in ED visit outcomes among older MVT injury patients either as drivers, passengers, or pedestrians. Methods: Using the 2012 U.S. National Emergency Department Sample, we employed multinomial logistic regression to analyze the association of SUD with ED visit outcomes among 171,145 ED events by MVT injury patients aged 50+. We estimated marginal probabilities of ED outcomes in three age groups (50–64, 65–74, and 75+) by SUD status. Results: MVT injuries were 2.31%, 1.46%, and 0.73% of ED visits in the 50–64, 65–74, and 75+ age groups, and SUDs were found in 4.08%, 1.92%, and 0.94% of the MVT-injury visits in these age groups. SUD had small to medium effects on the risk of hospital admission (RRR = 3.39, 95% CI = 3.14–3.66), transfer to a facility or discharge with initiation of home health care (RRR = 3.18, 95% CI = 2.28–4.44), relative to treat-and-release. Conclusions: A larger proportion of those with SUD than those without SUD had multiple and more severe injuries that required hospitalization and institutional care. It is important to include MVT injury prevention in the treatment of older substance misusers.