Spontaneous seizures in adult Fmr1 knockout mice: FVB.129P2-Pde6b+Tyrc-chFmr1tm1Cgr/J.

The prevalence of seizures in individuals with fragile X syndrome (FXS) is ~25%; however, there are no reports of spontaneous seizures in the Fmr1 knockout mouse model of FXS. Herein, we report that 48% of adult (median age P96), Fmr1 knockout mice from our colony were found expired in their home cages. We observed and recorded adult Fmr1 knockout mice having spontaneous convulsions in their home cages. In addition, we captured by electroencephalography an adult Fmr1 knockout mouse having a spontaneous seizure-during preictal, ictal, and postictal phases-which confirmed the presence of a generalized seizure. We did not observe this phenotype in control conspecifics or in juvenile (age

Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice.

Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HT2CR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HT2ARs at therapeutic doses, we pretreated one group of mice with the selective 5-HT2AR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HT2ARs to AGSs. We also assessed lorcaserin's in vitro pharmacology at human (h) and mouse (m) 5-HT2CRs and 5-HT2ARs and its in vivo interactions at m5-HT2CRs and m5-HT2ARs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HT2CRs and m5-HT2CRs, and near full efficacy agonist activity at h5-HT2ARs and m5-HT2ARs; selectivity for activation of 5-HT2CRs over 5-HT2ARs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HT2CRs and 5-HT2ARs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HT2AR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HT2CR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HT2CRs as well as 5-HT2ARs in mice at doses as low as 3 mg/kg. The similar activity at m5-HT2CRs and m5-HT2ARs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HT2CRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.

(S)-5-(2'-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder.

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow association and rapid dissociation kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.

Stress and opioid use disorder: A systematic review.

Medication assisted treatment (MAT) is highly effective in reducing illicit opioid use and preventing overdose in individuals with opioid use disorder (OUD); however, treatment retention of patients engaged in MAT is a significant clinical concern. The experience of stress may contribute to a decision to drop out of treatment. The current study is a systematic review conducted across multiple databases of empirical studies on primary appraisal of stress and its relationship to opioid craving, opioid use, and OUD treatment outcomes. Primary appraisal of stress is defined as an explicit inquiry into individual perception of feeling stressed using a self-report measure administered in laboratory, clinical, or naturalistic environment. A total of 21 included studies were organized into three categories: observed stress, experimentally-induced stress, and stress-focused interventions. Appraised stress was generally associated with greater craving, but associations with opioid use and treatment retention were mixed. All but one study included MAT samples and every study sample included some form of drug counseling. These findings suggest that individuals experience considerable stress in spite of receiving standard treatment for OUD. Psychopharmacological interventions targeting stress were promising, but no behavioral interventions specific to stress management were found. The preliminary results with clonidine and lofexidine targeting stress in individuals with OUD warrant further studies. To better understand the impact of stress in OUD, future research should consider using repeated assessment of stress in the context of daily life. Utilization of behavioral treatments specifically targeting stress could have benefits in improving OUD outcomes.

Gender moderates the relationship between stressful life events and psychopathology: Findings from a national study.

BACKGROUND: While data suggest a strong relationship between trauma exposure and psychopathology, less research has investigated relationships between psychopathology and stressful life events more broadly, and how these relationships may differ by gender. AIM: To examine strengths of associations between stressful life events and psychiatric disorders (i.e., past-year Axis I and lifetime Axis II, per DSM-IV) and how they may differ by gender. METHODS: Data from Wave 1 of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC; n = 43,093) were analyzed using chi-square tests and multinomial logistic regression analyses. Participants were categorized according to occurrence of stressful life events (low, moderate, and high). RESULTS: Women as compared to men were more likely to report moderate (p < 0.0001) or high occurrence stressful life events (p < 0.0001). Increasing experiences of stressful life events were associated with increasing odds of most past-year Axis I and lifetime Axis II disorders in both gender groups, with the largest odds typically observed in association with more frequent stressful life events. Associations between stressful life events and multiple psychiatric disorders were stronger in women compared to men. CONCLUSIONS: Stressful life events are associated with multiple Axis I and Axis II psychiatric disorders in both men and women. This relationship is moderated by gender. Screening female patients who endorse significant stressors for mood, anxiety, and substance-use problems might be particularly important. The stronger associations in women between stressful life events and personality disorders in particular warrant further investigation.

Gender differences in sexual assault victimization among college students.

College students are at particular risk for sexual assault victimization, yet research tends to focus on women as victims and men as perpetrators. The purpose of this study was to investigate gender differences in the prevalence, context, and predictors of sexual assault victimization among college students. Results showed that women were significantly more likely to have been sexually assaulted in a 2-month time period, but the context of victimization varied little by gender. Victimization was predicted by sexual orientation, time spent socializing and partying, and severe dating violence victimization for men and by year in school, time spent on the Internet, drinking and using drugs, and being a stalking and dating violence victim for women. Results are discussed in the context of routine activities theory and implications for prevention and future research.