Differential sensitivity of alcohol drinking and partner preference to a CRFR1 antagonist in prairie voles and mice.

Available pharmacotherapies to treat alcohol use disorder (AUD) show limited efficacy. Preclinical studies in mice and rats suggested that antagonists of the corticotropin releasing factor receptor 1 (CRFR1) could be more efficacious for such treatment. However, clinical trials with CRFR1 antagonists were not successful. While a number of potential explanations for this translational failure have been suggested, we hypothesized that the lack of success in clinical trials could be in part due to different neuroanatomical organization of the CRFR1 system in mice and rats versus humans. The CRF system in prairie voles (Microtus ochrogaster), a socially monogamous rodent species, also shows differences in organization from mice and rats. To test our hypothesis, we compared the efficacy of a potent CRFR1 antagonist, CP-376,395, to modulate alcohol drinking in male and female prairie voles versus male and female C57BL/6J mice using an almost identical 2-bottle choice drinking procedure. CP-376,375 (10 and 20 mg/kg, i.p.) significantly decreased alcohol intake (but not alcohol preference) in mice, but not prairie voles. Furthermore, administration of this antagonist (20 mg/kg, i.p.) prior to the partner preference test (PPT) decreased partner preference (PP) in male prairie voles. These findings support our hypothesis that the greater efficacy of CRFR1 antagonists to suppress alcohol consumption in mice and rats versus other mammalian species could be due to the differences in organization of the CRFR1 system between species. They further indicate that activity of the CRFR1 system is necessary for the formation of pair-bonds, but not consumption of high doses of alcohol. Overall, we suggest that testing potential pharmacotherapies should not rely only on studies in mice and rats.

Effects of Pharmacologically Targeting Neuroimmune Pathways on Alcohol Drinking in Mice Selectively Bred to Drink to Intoxication.

BACKGROUND: Rodent models of high alcohol drinking offer opportunities to better understand factors for alcohol use disorders (AUD) and test potential treatments. Selective breeding was carried out to create 2 unique High Drinking in the Dark (HDID-1, HDID-2) mouse lines that represent models of genetic risk for binge-like drinking. A number of studies have indicated that neuroimmune genes are important for regulation of alcohol drinking. We tested whether compounds shown to reduce drinking in other models also reduce alcohol intake in these unique genetic lines. METHODS: We report tests of gabapentin, tesaglitazar, fenofibrate, caffeic acid phenethyl ester (CAPE), ibrutinib, and rolipram. Although these compounds have different mechanisms of action, they have all been shown to reduce inflammatory responses. We evaluated effects of these compounds on alcohol intake. In order to facilitate comparison with previously published findings for some compounds, we employed similar schedules that were previously used for that compound. RESULTS: Gabapentin increased ethanol (EtOH) binge-like alcohol drinking in female HDID-1 and HS/NPT mice. Tesaglitazar and fenofibrate did not alter 2-bottle choice (2BC) drinking in male HDID-1 or HS/NPT mice. However, tesaglitazar had no effect on DID EtOH intake but reduced blood alcohol levels (BAL), and fenofibrate increased DID intake with no effects on BAL. CAPE had no effect on EtOH intake. Ibrutinib reduced intake in female HDID-1 in initial testing, but did not reduce intake in a second week of testing. Rolipram reduced DID intake and BALs in male and female HDID-1, HDID-2, and HS/NPT mice. CONCLUSIONS: A number of compounds shown to reduce EtOH drinking in other models, and genotypes are not effective in HDID mice or their genetically heterogeneous founders, HS/NPT. The most promising compound was the PDE4 inhibitor, rolipram. These results highlight the importance of assessing generalizability when rigorously testing compounds for therapeutic development.

Male-selective effects of oxytocin agonism on alcohol intake: behavioral assessment in socially housed prairie voles and involvement of RAGE.

Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.

Circulating ghrelin changes as a biomarker of the stress response and craving in abstinent smokers.

RATIONALE: There has been growing interest in the role of ghrelin in stress and addiction. Ghrelin regulates central reward mechanisms by mediating the mesolimbic dopaminergic system. Stress also induces neurophysiological activations related to drug reward. However, the extent to which psychosocial stress is associated with changes in ghrelin levels has not been tested in individuals with nicotine dependency undergoing withdrawal, a condition known to induce stress-like symptoms. OBJECTIVES: We investigated the association of stress-induced ghrelin, craving, and smoking lapse. METHODS: Thirty-six smokers attended a laboratory session that included acute stress tasks during the initial phase of quitting. Self-report measures and biochemical samples were collected for the assessment of smoking status. Blood samples for the measurement of ghrelin and self-report measures of craving were collected multiple times throughout the session RESULTS: Multivariate analysis of variance controlling for gender found a significant main effect of sampling time and lapse group (p < 0.05). Ghrelin levels significantly increased over the pre-stress and post-stress periods (ps < 0.001), suggesting a delayed stress response. Those who lapsed during the study had higher ghrelin levels than those who were able to successfully abstain. A ghrelin stress response was calculated and a significant association was found between this response and craving, which changed across time points (ps < 0.008). CONCLUSIONS: The results of this study demonstrate that ghrelin is sensitive to acute manipulation of stress and that there is potential usefulness for ghrelin as a marker of stress, craving, and smoking lapse.

The Prairie Vole Model of Pair-Bonding and Its Sensitivity to Addictive Substances.

The prairie vole (Microtus ochrogaster) is an extensively studied model for understanding the neural mechanisms underlying social affiliations and pair bonds. With clearly observed face and construct validity, this species offers translational insights into mechanisms involved in intimate relationships in humans. Moreover, the prairie vole model promises to advance our understanding - as well as allow for predictions - of the effects of extraneous factors (not normally encountered in nature) on such relationships. This mini review describes some of the neurobiological mechanisms regulating social affiliation in prairie voles, followed by an overview of the effects of alcohol and other drugs of abuse on formation and maintenance of pair-bonds. Based on available literature, we demonstrate that the effects of such extraneous factors on formation and maintenance of pair-bonds are sex-dependent, as well as dependent on the specific nature of the addictive drug. In turn, the lack of similarities in effects of different addictive substances on pair-bond formation suggests that these substances engage different neurocircuits that may or may not overlap with neurocircuits involved in various social behaviors. This lack of consistency of effects across studied drugs of abuse indicates the need to further examine the effects of individual drugs on affiliative behaviors. We highlight the deficiencies in this field of research, particularly the sparsity of studies on effects of drugs of abuse on the maintenance of established bonds. Future investigations in this field could help design strategies to help afflicted individuals.

Implementation and fidelity assessment of the NAVIGATE treatment program for first episode psychosis in a multi-site study.

The NAVIGATE program was developed for the Recovery After Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP) study, which compared NAVIGATE to usual Community Care in a cluster randomized design involving 34 sites and 404 patients. This article describes the approach to training and implementing the NAVIGATE program at the 17 sites (including 134 practitioners) randomized to provide it, and to evaluating the fidelity of service delivery to the NAVIGATE model. Fidelity was evaluated to five different components of the program, all of which were standardized in manuals in advance of implementation. The components included four interventions (Individualized Resiliency Training, Family Education Program, Supported Employment and Education, Personalized Medication Management) and the overall organization (staffing and structure) of the NAVIGATE team. Most of the sites demonstrated acceptable or higher levels of fidelity in their implementation of the four interventions and the organization of the program, with all 17 sites demonstrating at least acceptable overall fidelity to the NAVIGATE program. The results indicate that the NAVIGATE program can be implemented with good fidelity to the treatment model in a diverse array of community mental health care settings serving persons with a first episode psychosis.

Changes in circulating leptin levels during acute stress and associations with craving in abstinent smokers: a preliminary investigation.

Recent research suggests a role for the appetite hormone leptin in cigarette smoking. This study examined patterns of change in leptin in response to stress and associations with craving during the initial phase of a quit attempt. Thirty-six smokers (average age±SEM, 33.4±2.4) interested in smoking cessation set a quit day and were required to be abstinent for 24h. After, they completed a laboratory session including public speaking and cognitive challenges, and attended 4 weekly post-cessation assessments. Blood samples and self-report measures were collected throughout the laboratory session. The results indicated that leptin levels significantly increased following exposure to acute stress. We also found positive correlations between leptin and craving for cigarettes. No differences were observed in leptin levels between smokers who maintained abstinence for 4 weeks and those who relapsed during this period. These findings suggest that leptin levels may change in response to stress and that leptin could be a useful marker of craving for smoking.