Evidence for an alcohol-related "harm paradox" in individuals with internalizing disorders: Test and replication in two independent community samples.

BACKGROUND: Internalizing (anxiety and mood) disorders (INTD) commonly co-occur (are "comorbid") with alcohol use disorder (AUD). The literature suggests that excessive alcohol use aimed at coping with INTD symptoms is, at best, a partial explanation for the high comorbidity rates observed. We hypothesized that individuals with INTD experience greater susceptibility to developing AUD symptoms due to the partially shared neurobiological dysfunctions underlying both conditions. We probe this hypothesis by testing the prediction that, after accounting for the volume of alcohol intake, individuals with INTD experience higher levels of alcohol-related symptoms. METHODS: Data from the National Epidemiological Survey on Alcohol-Related Conditions (NESARC) Wave 3 were used for the primary analyses, and NESARC Wave 1 data were used for independent replication analyses. Individuals who reported any alcohol use in the prior year were categorized as: (1) never having had an INTD diagnosis ("INTD-Never"); (2) having a remitted INTD diagnosis only ("INTD-Remitted"); or (3) having current INTD diagnosis ("INTD-Current"). Between-group contrasts of alcohol-related symptoms controlled for total alcohol intake (past year), drinking pattern (e.g., binging) and variables previously shown to mark exaggerated AUD symptoms relative to drinking amount (e.g., SES, gender, and family history). RESULTS: With all covariates in the model, individuals in the INTD-Current group and the INTD-Remitted group reported significantly greater alcohol-related symptoms than those in the INTD-Never group but did not themselves differ in level of alcohol-related symptoms. These results were replicated in the NESARC 1 dataset. CONCLUSIONS: Individuals with INTD experience more alcohol-related symptoms than those who drink at the same level. While considering other explanations, we argue that this "harm paradox" is best explained by the view that INTD confers a neurobiologically mediated susceptibility to the development of AUD symptoms.

Stressed, Lonely, and Overcommitted: Predictors of Lawyer Suicide Risk.

Suicide is a significant public health concern, and lawyers have been shown to have an elevated risk for contemplating it. In this study, we sought to identify predictors of suicidal ideation in a sample consisting of 1962 randomly selected lawyers. Using logistic regression analysis, we found that high levels of work overcommitment, high levels of perceived stress, loneliness as measured by the UCLA loneliness scale, and being male were all significantly associated with an increased risk of suicidal ideation. These results suggest that interventions aimed at reducing work overcommitment, stress, and loneliness, and addressing gender-specific risk factors, may be effective in reducing the risk of suicidal ideation among lawyers. Further research is needed to expand upon these findings and to develop and test interventions specifically tailored to the needs of this population.

World Health Organization (WHO) risk level reductions in inpatients with alcohol use disorder and comorbid anxiety disorders.

OBJECTIVE: Studies have demonstrated that reduced drinking without total abstinence is associated with improved outcomes in outpatients with alcohol use disorder (AUD). We sought to examine this question in AUD inpatients who have comorbid anxiety disorders, a common presentation in AUD. METHOD: This is a secondary analysis of data from a randomized controlled trial for N = 241 inpatients with AUD and comorbid anxiety disorders. Change from baseline drinking level was measured at 1-, 4-, and 12-months postdischarge, and psychological and functional outcomes were measured at 4- and 12-months postdischarge. Three groups were compared: abstinent, reduced (reduced drinking by 1-3 World Health Organization drinking risk levels without abstinence), or nonreduced (maintained or increased drinking risk level). RESULTS: At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly better alcohol dependence severity and alcohol-related problems than nonreducers. CONCLUSIONS: Though abstinence was associated with the best outcomes in this abstinence-based treatment sample, we conclude that reduced drinking is also associated with significant improvements in alcohol-related outcomes in inpatients with AUD and comorbid anxiety disorders.At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The direct effect of drinking to cope on alcohol problems is not mediated by alcohol consumption: Invariance across gender and countries.

Background: Drinking to cope with negative affect confers a direct risk of alcohol problems independently of greater alcohol consumption (i.e., confers susceptibility to the alcohol harm paradox). However, it remains unclear whether this risk is common across gender and countries. Methods: The current study applied path analysis to two cross-sectional samples of 18-25-year-old undergraduate hazardous drinking students recruited from the UK (Study 1; N = 873) and internationally (Study 2; N = 4064 recruited in Argentina, Canada, South Africa, Spain, Uruguay, USA, and England). The Drinking Motives Questionnaire (DMQ) measured drinking to cope with negative affect and drinking to enhance positive affect (i.e., enhancement motives). The Alcohol Use Disorders Identification Test (AUDIT) measured alcohol consumption and problems. Results: In both studies, drinking to cope with negative affect had a direct effect on alcohol problems (S1: ß = 0.259, SE = 0.031, p <.001; S2: ß = 0.255, SE = 0.017, p <.001), and only a negligible proportion of this effect was mediated by alcohol consumption (S1: 2.58 %, p =.550; S2: 0.79 %, p=.538). By contrast, drinking to enhance positive affect had a smaller direct effect on alcohol problems (S1: ß = 0.000, SE = 0.033, p =.989; S2: ß = 0.044, SE = 0.017, p =.009), and a substantial proportion of this effect was mediated by greater alcohol consumption (S1: 99.76 %, p <.001; S2: 60.36 %, p <.001). Crucially, in both studies, the direct effect of drinking to cope on alcohol problems was invariant across gender and countries. Conclusions: These findings suggest that individuals who endorse drinking to cope with negative affect are uniquely susceptible to the alcohol harm paradox, that is, greater alcohol problems which cannot be explained by greater alcohol consumption, and this susceptibility is common across gender and countries.

People, Professionals, and Profit Centers: The Connection between Lawyer Well-Being and Employer Values.

Concerns about the well-being of lawyers are rising against the backdrop of a transforming legal profession, one which many observe to be operating more like a business in recent decades. However, aspects of this change, such as lawyers perceiving that their employers value financial performance and productivity above all else, could be associated with unhealthy work practices detrimental to lawyer well-being. The objective of the present study was to determine whether the perceived values of employers were differentially associated with lawyer well-being, stress, and work overcommitment. To this end, 1959 participants from a random sample of attorneys completed a survey designed to assess well-being. Participants were separated into one of three groups based on what they perceived their employer to value most about them: (1) Professionalism/Individual (professionalism and skills), (2) Financial Worth/Availability (revenue generation and availability), and (3) No Value/No Feedback (feeling unvalued or lacking feedback) and compared on measures of mental and physical health (SF-12), stress (Perceived Stress Scale), and work over commitment (Effort−Reward Imbalance Questionnaire). MANOVA results indicated that mental health, stress, and work overcommitment significantly differed between groups in the following rank order: Professionalism/Individual > Financial Worth/Availability > No Value/No Feedback. Overall, our findings paint a compelling picture of a health hierarchy within legal work environments, one that appears to be linked to employer values.

Risk Pathways Contributing to the Alcohol Harm Paradox: Socioeconomic Deprivation Confers Susceptibility to Alcohol Dependence via Greater Exposure to Aversive Experience, Internalizing Symptoms and Drinking to Cope.

Socioeconomic deprivation is associated with greater alcohol problems despite lower alcohol consumption, but the mechanisms underpinning this alcohol harm paradox remain obscure. Fragmented published evidence collectively supports a multistage causal risk pathway wherein socioeconomic deprivation increases the probability of exposure to aversive experience, which promotes internalizing symptoms (depression and anxiety), which promotes drinking alcohol to cope with negative affect, which in turn accelerates the transition from alcohol use to dependence. To evaluate this proposed risk pathway, 219 hazardous drinkers from an undergraduate population completed questionnaires assessing these constructs in a single, cross sectional, online survey. Partial correlation coefficients revealed that each variable showed the strongest unique association with the next variable in the proposed multistage model, when adjusting for the other variables. Bootstrapped serial mediation analysis revealed that the indirect pathway linking all the variables in the proposed serial order was significant, while all other permutations were non-significant. Network centrality analysis corroborated the serial order of this indirect path. Finally, risk ratios estimated by categorizing the variables suggested that socioeconomic deprivation increased the risk of aversive experience by 32%, which increased the risk of internalizing symptoms by 180%, which increased the risk of drinking to cope by 64%, which increased susceptibility to alcohol dependence by 59%. These preliminary findings need to be corroborated by future research, nevertheless, they call for prevention strategies founded on social justice and the minimization of aversive experience in socially deprived individuals to mitigate mental health problems, maladaptive coping and addiction.

Tobacco withdrawal increases junk food intake: The role of the endogenous opioid system.

BACKGROUND: The aims of this study were to 1) determine whether acute nicotine withdrawal increases the intake of junk food (high in salt, fat, and sugar) and 2) assess whether the endogenous opioid system is involved in junk food intake during nicotine withdrawal using naltrexone as a pharmacological probe. METHODS: Smokers were randomly assigned to 24-hr withdrawal from tobacco products (n = 42) or smoking ad libitum (n = 34). A non-smoking group (n = 29) was included. Participants completed two laboratory sessions where a placebo or 50 mg of naltrexone was administered. At the end of each session, participants were given a tray of snack items that differed in high to low energy density and dimensions of salty, sweet, and fat. Self-reported mood and withdrawal measures were collected immediately before the snacks were offered. Generalized linear and logistic models were used to assess the effects of acute smoking withdrawal, drug, and sex on the intake of snack items and self-reported measures. RESULTS: Choice and consumption of food items were impacted by smoking condition (withdrawal > ad lib smoking and non-smokers; p < .05), the opioid blockade (naltrexone < placebo; p < .05), and sex (male > female; p < .05). The effects were evidenced in high sweet and high fat foods. No differences were found in low sweet and fat foods. CONCLUSIONS: These findings extend earlier studies indicating impact of tobacco use on appetite, and identify the regulatory influence of the endogenous opioid system on appetite during nicotine withdrawal.

Stress, drink, leave: An examination of gender-specific risk factors for mental health problems and attrition among licensed attorneys.

Rates of mental illness and heavy alcohol use are exceedingly high in the legal profession, while attrition among women has also been a longstanding problem. Work overcommitment, work-family conflict, permissiveness toward alcohol in the workplace, and the likelihood of promotion are all implicated but have yet to be systematically investigated. Data were collected from 2,863 lawyers randomly sampled from the California Lawyers Association and D.C. Bar to address this knowledge gap. Findings indicated that the prevalence and severity of depression, anxiety, stress, and risky/hazardous drinking were significantly higher among women. Further, one-quarter of all women contemplated leaving the profession due to mental health concerns, compared to 17% of men. Logistic models were conducted to identify workplace factors predictive of stress, risky drinking, and contemplating leaving the profession. Overcommitment and permissiveness toward alcohol at work were associated with the highest likelihood of stress and risky drinking (relative to all other predictors) for both men and women. However, women and men differed with respect to predictors of leaving the profession due to stress or mental health. For women, work-family conflict was associated with the highest likelihood of leaving, while overcommitment was the number one predictor of leaving for men. Mental health and gender disparities are significant problems in the legal profession, clearly requiring considerable and sustained attention.

Co-Occurring Alcohol Use Disorder and Anxiety: Bridging Psychiatric, Psychological, and Neurobiological Perspectives.

A substantial number of people who have problems with alcohol also experience strong anxiety and mood problems. This article provides an overview of the evolving perspectives of this association in the context of three related disciplines-psychiatry, psychology, and neuroscience. Psychiatric and epidemiological studies show that having either an anxiety- or alcohol-related diagnosis elevates the prospective risk for developing the other disorder. From the psychological perspective, behavioral research demonstrates that drinking to cope with negative affect is a potent marker for current and future problems with alcohol. Neuroscientific research implicates overlapping neurobiological systems and psychological processes in promoting the rise of negative affect and alcohol misuse. The psychiatric perspective that alcohol misuse and co-occurring anxiety represent neurobiologically distinct diagnostic conditions has dominated the field for many decades. However, recent research provides increasing support for the neuroscientific perspective that these conditions share underlying, mutually exacerbating, neurobiological processes.

Assessing the collective utility of multiple analyses on clinical alcohol use disorder data.

OBJECTIVE: The objective of this study was to assess the potential of combining graph learning methods with latent variable estimation methods for mining clinically useful information from observational clinical data sets. MATERIALS AND METHODS: The data set contained self-reported measures of psychopathology symptoms from a clinical sample receiving treatment for alcohol use disorder. We used the traditional graph learning methods: Graphical Least Absolute Shrinkage and Selection Operator, and Friedman's hill climbing algorithm; traditional latent variable estimation method factor analysis; recently developed graph learning method Greedy Fast Causal Inference; and recently developed latent variable estimation method Find One Factor Clusters. Methods were assessed qualitatively by the content of their findings. RESULTS: Recently developed graphical methods identified potential latent variables (ie, not represented in the model) influencing particular scores. Recently developed latent effect estimation methods identified plausible cross-score loadings that were not found with factor analysis. A graphical analysis of individual items identified a mistake in wording on 1 questionnaire and provided further evidence that certain scores are not reflective of indirectly measured common causes. DISCUSSION AND CONCLUSION: Our findings suggest that a combination of Greedy Fast Causal Inference and Find One Factor Clusters can enhance the evidence-based information yield from psychopathological constructs and questionnaires. Traditional methods provided some of the same information but missed other important findings. These conclusions point the way toward more informative interrogations of existing and future data sets than are commonly employed at present.

Causal Network Modeling of the Determinants of Drinking Behavior in Comorbid Alcohol Use and Anxiety Disorder.

BACKGROUND: Anxiety and depression disorders (internalizing psychopathology) occur in approximately 50% of patients with alcohol use disorder (AUD) and mark a 2-fold increase in the rate of relapse in the months following treatment. In a previous study using network modeling, we found that perceived stress and drinking to cope (DTC) with negative affect were central to maintaining network associations between internalizing psychopathology INTP and drinking in comorbid individuals. Here, we extend this approach to a causal framework. METHODS: Measures of INTP, drinking urges/behavior, abstinence self-efficacy, and DTC were obtained from 362 adult AUD treatment patients who had a co-occurring anxiety disorder. Data were analyzed using a machine-learning algorithm ("Greedy Fast Causal Inference"[ GFCI]) that infers paths of causal influence while identifying potential influences associated with unmeasured ("latent") variables. RESULTS: DTC with negative affect served as a central hub for 2 distinct causal paths leading to drinking behavior, (i) a direct syndromic pathway originating with social anxiety and (ii) an indirect stress pathway originating with perceived stress. CONCLUSIONS: Findings expand the field's knowledge of the paths of influence that lead from internalizing disorder to drinking in AUD as shown by the first application in psychopathology of a powerful network analysis algorithm (GFCI) to model these causal relationships.

Association of Childhood Adversity With Differential Susceptibility of Transdiagnostic Psychopathology to Environmental Stress in Adulthood.

Importance: Multivariable comorbidity research indicates that childhood adversity increases the risk for the development of common mental disorders. This risk is explained by underlying internalizing and externalizing transdiagnostic constructs that are amplified by environmental stressors. The differential susceptibility model suggests that this interaction of risk and environment is bidirectional: at-risk individuals will have worse outcomes in high-stress environments but better outcomes in in low-stress environments. Objective: To test the differential susceptibility model by examining how a history of adverse childhood experiences moderates the association between life stress and transdiagnostic psychopathology. Design, Setting, and Participants: Data came from the US National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a population-based observational longitudinal survey administered to adults (≥18 years of age). Participants completed the survey at wave 1 (from 2001 through 2002) and wave 2 (from 2004 through 2005). Responses from 34 458 participants were used for the analyses from March 3, 2017, through October 8, 2018. Main Outcomes and Measures: Latent variables for internalizing-fear, internalizing-distress, externalizing, and general psychopathology were created to represent continuous levels of psychopathology in each wave. Latent variables were also created to represent continuous levels of life stress at each wave. Level of childhood adversity was characterized based on the number of types of childhood adversity experienced (no [0 types], low [1-2 types], and high [≥3 types] exposure). Analyses examined how the interaction between level of childhood adversity and adult life stress was associated with change in adult transdiagnostic psychopathology factors. Results: Of the 34 458 participants included in the analysis (58.0% women and 42.0% men; mean [SD] age, 46.0 [17.4] years at wave 1 and 49.0 [17.3] years at wave 2), 40.5% had no adverse childhood experiences, 34.6% had 1 to 2, and 24.9% had 3 or more. At wave 1, 61.5% of the sample endorsed at least 1 stressful life event and 27.2% met criteria for at least 1 mental disorder; at wave 2, these figures were 64.7% and 29.7%, respectively. Childhood adversity moderated the association between changes in adult life stress and changes in all transdiagnostic psychopathology factors. Specifically, higher levels of childhood adversity had a stronger association between adult life stress and adult transdiagnostic psychopathology factors. Further, significant differences between childhood adversity groups occurred in the mean scores of all transdiagnostic psychopathology factors for both increases and decreases in life stress, providing preliminary evidence of differential susceptibility. Conclusions and Relevance: Results provide empirical support for childhood adversity as a differential susceptibility factor engendering heightened functional and dysfunctional reactivity to later stress.

Methodological Advances in the Study of Hidden Variables: A Demonstration on Clinical Alcohol Use Disorder Data.

Research in the domain of psychopathology has been hindered by hidden variables-variables that are important to understanding and treating psychopathological illnesses but are unmeasured. Recent methodological advances in machine learning have culminated in the ability to discover and identify the influence of hidden variables that confound the observed relationships among measured variables. We apply a combination of traditional methods and more recent advances to a data set of alcohol use disorder patients with comorbid internalizing disorders, and find that the increasingly advanced methods produce increasingly informative and reliable results. These results include novel findings evaluated positively by our psychopathologists, as well as findings validated with knowledge from existing literature. We also find that advanced graph discovery methods can guide the use of latent variable modeling procedures, which can in turn explain the output of the graph discovery methods, resulting in a synergistic relationship between two seemingly distinct classes of methods.

The cortisol awakening response and anterior cingulate cortex function in maltreated depressed versus non-maltreated depressed youth.

Symptomatology of depression among children who have (vs. have not) experienced maltreatment is greater in severity, more resistant to conventional treatment, and associated with elevated risk for suicide. Recent evidence implicates perturbations in stress regulatory systems and heightened negative self-appraisals as factors that increase the severity of psychopathology experienced by depressed maltreated (vs. non-maltreated) youth. Likely explanatory mechanisms for these differences are disturbances in the function of the hypothalamic-pituitary axis (HPA) and persistent negative self-referential biases supported by prefrontal cortex function including the dorsal anterior cingulate cortex (dACC). The cortisol awakening response (CAR) and dACC activity during a self-appraisal task were assessed in maltreated and non-maltreated depressed youth. Hierarchical linear models were employed to model the CAR. Maltreatment group, dACC activity during positive and negative self-appraisals as well as other key predictors, were included in the models. Post hoc analyses explored explanations for significant differences. Results indicated that maltreated depressed youth exhibited a higher CAR compared to non-maltreated youth. At low levels of dACC activity during processing of negative self-descriptors maltreated and non-maltreated depressed youth's CAR did not differ. However, at elevated levels of dACC activity during processing of negative self-descriptors maltreated depressed youth exhibited significantly higher CAR compared to non-maltreated depressed youth.

A network approach to modeling comorbid internalizing and alcohol use disorders.

Internalizing disorders co-occur with alcohol use disorder (AUD) at a rate that exceeds chance and compromise conventional AUD treatment. The "vicious cycle" model of comorbidity specifies drinking to cope (DTC) as a link between these disorders that, when not directly addressed, undermines the effectiveness of conventional treatments. Interventions based on this model have proven successful but there is no direct evidence for how and to what extent DTC contributes to the maintenance of comorbidity. In the present study, we used network analysis to depict associations between syndrome-specific groupings of internalizing symptoms, alcohol craving, and drinking behavior, as well as DTC and other extradiagnostic variables specified in the vicious cycle model (e.g., perceived stress and coping self-efficacy). Network analyses of 362 individuals with comorbid anxiety and AUD assessed at the beginning of residential AUD treatment indicated that while internalizing conditions and drinking elements had only weak direct associations, they were strongly connected with DTC and perceived stress. Consistent with this, centrality indices showed that DTC ranked as the most central/important element in the network in terms of its "connectedness" to all other network elements. A series of model simulations-in which individual elements were statistically controlled for-demonstrated that DTC accounted for all the relationships between the drinking-related elements and internalizing elements in the network; no other variable had this effect. Taken together, our findings suggest that DTC may serve as a "keystone" process in maintaining comorbidity between internalizing disorders and AUD. (PsycINFO Database Record

Cocaine self-administration punished by i.v. histamine in rat models of high and low drug abuse vulnerability: effects of saccharin preference, impulsivity, and sex.

A key feature of substance use disorders is continued drug consumption despite aversive consequences. This has been modeled in the animal laboratory by pairing drug self-administration with electric shock, thereby punishing drug intake (Deroche-Gamonet et al. 2004). In the present experiments, we examined the effects of punishment on i.v. cocaine self-administration by adding histamine to the cocaine solution with three different animal models of high and low vulnerability to drug abuse: rats selectively bred for high (HiS) and low (LoS) saccharin consumption, rats selected for high (HiI) and low (LoI) impulsivity, and sex differences. Animals were allowed to self-administer cocaine (0.4 mg/kg/infusion) to establish a baseline of operant responding. Histamine (4.0mg/kg/infusion) was then added directly into the cocaine solution and its consequent effects on self-administration were compared to baseline. The histamine+cocaine solution was then replaced with a cocaine-only solution, and the rats' operant responding was again compared to baseline. Concurrent histamine exposure was effective in reducing cocaine consumption in all groups of rats; however, LoS and female rats took longer to return to baseline levels of cocaine consumption after histamine was removed compared to HiS and male rats. These data suggest that the reduction of drug self-administration by aversive consequences may differ in groups that vary in drug use vulnerability . Such results may inform pharmacological strategies that enhance the negative aspects of drug consumption.

Attention and recognition memory bias for alcohol-related stimuli among alcohol-dependent patients attending residential treatment.

Though studies have examined attentional bias for alcohol-related information among alcohol-dependent individuals, few have examined memory bias. This study examined attention and recognition memory biases for alcohol-related information among patients recently admitted to residential alcohol treatment (n=100; 40% female). Participants completed a computerized attentional task wherein they classified a centrally-presented digit as odd or even. On some trials, an alcohol word, neutral word, or anagram was presented along with the digit. On these dual trials participants first classified the digit and then classified the other stimulus as a word or nonword. Participants took longer to classify digits that appeared with alcohol words compared to neutral words; suggesting the alcohol words distracted them from processing the digit. In a subsequent recognition memory test, participants showed significantly higher hit rates (i.e., correctly classifying an old item as old) and false alarm rates (i.e., incorrectly classifying a new item as old) to the alcohol words compared to the neutral words, and they also showed a more liberal response bias to alcohol words. The findings suggest that alcohol-dependent individuals exhibit both attention and memory bias for alcohol-related information.

Computer-based recovery support for patients receiving residential treatment for alcohol/drug dependence: relationship between program use and outcomes.

OBJECTIVE: This analysis of administrative data examined whether use of a Web-based recovery support program was related to self-reported post-treatment alcohol use among patients attending residential treatment for a substance use disorder. MATERIALS AND METHODS: The program delivered individually tailored clinical content in a multimedia format over the initial 18 months after discharge from treatment. Post-treatment logins to the program and access of clinical content were measured, as was post-treatment alcohol use. RESULTS: Use of the program was frequent in the first 30 days following treatment but steadily decreased over time. Regression analyses revealed a significant relationship between the number of program logins and self-reported alcohol use in the first 6 months following treatment when controlling for other covariates related to alcohol use. CONCLUSION: These results replicate a previous study of the My Ongoing Recovery Experience (MORE(®)) program (Hazelden, Center City, MN) and suggest that computerized support programs hold therapeutic potential for patients with alcohol/drug dependence.

Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion.

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.