Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments

Has Behavioral Science Tumbled Through the Biological Looking Glass? Will Brief, Evidence-Based Training Return It From the Rabbit Hole?

Time constraints and professional demands leave practicing professionals unlikely to enroll in extended training such as a semester-long graduate course. Thus, the three-hour continuing education format has become a standard for those in practice. One may ask what sorts of training strategies optimize that format. To explore that, a three hour training program for seventy-six practicing mental health professionals, most of whom self-identified as psychologists, was devised. It made use of primarily antecedent techniques that have been shown to bring about changed perceptions on a number of topics. Content focused on two areas of importance to behavior analysts, the culture’s increasing acceptance of the biological causation model of disorders such as attentiondeficit hyperactivity disorder (ADHD), unipolar depression, anxiety disorders, and schizophrenia, and the field’s increasing reliance on medications, often to the exclusion of behavioral methods. Pre-post assessment showed that participants had changed their thinking regarding the two content areas. The authors caution that participants’ changed opinions may serve as setting events to changes in practice, but those changes are verbal. One must not assume changes in practice techniques will automatically occur

Physical comorbidities in men with mood and anxiety disorders: a population-based study

Background : The mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden. Methods : This study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations. Results : After adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders. Conclusions : Our study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care

Cerebrospinal fluid thyrotropin-releasing hormone concentrations in patients with anxiety disorders

In a study of 45 patients with anxiety disorders and 11 control subjects, mean cerebrospinal fluid (CSF) concentrations of thyrotropin-releasing hormone (TRH) were not significantly different between nonpsychiatric control subjects and those with panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder. Male subjects, regardless of diagnosis, had significantly higher mean CSF concentrations of TRH than females

Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects

Cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF) were measured in a group of patients with anxiety disorders and normal comparison subjects (NC) to explore the hypothesis that abnormalities in CRF neuronal regulation occur in patients with anxiety disorders. Analysis of variance (ANOVA) revealed no differences in CSF CRF concentrations between the four diagnostic categories: panic disorder (PD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and NCs. Male OCD patients had higher CSF CRF concentrations than men with PD and GAD and male NCs. CSF CRF concentration was positively correlated with age in women but not in men. These findings suggest that central neuronal CRF regulation may be affected by both age and gender

Double‐blind multicenter comparison of fluvoxamine versus sertraline in the treatment of depressed outpatients

Fluvoxamine and sertraline, both selective serotonin reuptake inhibitors (SSRIs), were compared in a 5‐center, 7‐week double‐blind study in outpatients with major depression diagnosed by DSM‐III‐R criteria. Ninety‐five patients were titrated from 50 to 150 mg/day offluvoxamine (n = 49) or 50 to 200 mg/day of sertraline (n = 46). The mean dose administered in Weeks 3‐1 was 123.8 mg/day for fluvoxamine, and 137.1 mg/day for sertraline. Forty‐seven percent (47%) of fluvoxamine‐treated patients and 30% of sertraline‐treated patients were titrated to the maximum permissible dose. Fluvoxamine and sertraline were similarly effective in ameliorating depression as demonstrated by a mean reduction from baseline in the Hamilton Rating Scale for Depression (HAMD) total score of 10.61 ± 7.53 and 10.98 ± 6.08, respectively. Adverse events, mostly mild to moderate in severity, were reported for 93.5% of sertraline patients and 85.7% offluvoxamine patients. The most common events in the sertraline group were insomnia (34.8%), headache (32.6%), diarrhea (23.9%), and ejaculatory difficulty (22.2% of males), and in the fluvoxamine group, nausea (30.6%), headache (26.5%), insomnia (26.5%), and somnolence (24.5%). Significantly more patients reported sexual dysfunction in the sertraline (28%) than in the fluvoxamine (10%) group. An uncharacteristically low dropout rate due to adverse events was observed in the sertraline group (2.2%) compared with the fluvoxamine group (18.4%). The rate of withdrawal due to adverse events in the fluvoxamine group (0–2 patients/center) was comparable to that in the sertraline group (1 patient) for four of the five centers; the fifth center had 4 withdrawals in the fluvoxamine group. The differences in clinical profile of these two SSRIs provide physicians with meaningful choices in antidepressant therapy attuned to individual patient characteristics. Depression 3:163–169 (1995). © 1995 Wiley‐Liss, Inc