Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABAARs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABAAR-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABAAR-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABAAR antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABAAR-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABAARs. Thus, α6GABAARs are potential therapeutic targets for ET, and α6GABAAR-selective PAMs may be a potential mono- or add-on therapy.

The γ-aminobutyric acid type A receptors (GABAAR) have been reported to contribute to the pathogenesis of epilepsy and the recurrence of chronic seizures. Genetic polymorphisms in GABRA1 and GABRA6 may confer a high risk of epilepsy and multiple drug resistance, but with conflicting results. We aimed to assess the association of GABRA1 rs2279020 and GABRA6 rs3219151 with epilepsy risk using a meta-analysis. The databases of Pubmed, Ovid, Web of Science, and China National Knowledge Infrastructure were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were computed to evaluate the association between the polymorphisms and epilepsy risk using a fixed- or random-effect model. Trial sequential analysis (TSA) was performed to assess the results of the meta-analysis. No significant association between the GABRA1 rs2279020 and GABRA6 rs3219151 and the risk of epilepsy was found in the Asian and Arabic populations. The negative results were also observed when comparing the GABRA1 rs2279020 and GABRA6 rs3219151 polymorphism to antiepileptic drug responsiveness. The trial sequential analysis confirmed the results of the meta-analysis. This meta-analysis suggests that GABRA1 rs2279020 and GABRA6 rs3219151 are not risk factors for the etiology of epilepsy and antiepileptic drug responsiveness in the Asian and Arabic populations.

The GABA receptor is an important epilepsy-associated candidate gene, and has always been a focus in etiology and in the treatment of epilepsy. This study explores the genetic association between GABA receptor gene polymorphisms and epilepsy in a cohort of the Pakistani population. A case-control study was conducted on 150 patients with idiopathic generalized epilepsy (IGE) and 150 controls. Blood samples were collected, and genomic DNA was extracted and amplified using polymerase chain reaction (PCR). The amplified products were subsequently genotyped by Sanger sequencing and the results were analyzed using the chi-square test. Among the five mutational sites observed, two GABRA1 (rs2279020 and novel c.1016_1017insT) and two GABRA6 (rs3219151 and novel c.1344C>G) were found to be significantly associated with IGE. Amino acid alignment showed that a novel insertion mutation, c.1016_1017insT, in GABRA1 disrupted the reading frame and was possibly damaging, whereas c.1344C>G in GABRA6 was responsible for a synonymous mutation. Therefore, both the GABA receptor genes may play critical roles in the development of epilepsy in Pakistani patients.

BACKGROUND: Major depressive disorder (MDD) patients not responding to two or more different antidepressant treatments are currently considered to suffer from treatment resistant depression (TRD). Recently, intranasal esketamine has been approved by both the American Food and Drug Administration and European Medicines Agency for TRD and, more recently, in moderate to severe episode of MDD, as acute short-term treatment for the rapid reduction of depressive symptoms, which, according to clinical judgement, constitute a psychiatric emergency. There is currently no indication for obsessive-compulsive disorder (OCD) although recently published studies have already shown a rapid and significant reduction of OCD-like symptoms following ketamine administration. The etiology of OCD has not yet been fully elucidated but there is a growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical circuitry plays an essential role. This case report exemplifies possible clinical effects of esketamine on both depressive and OCD symptoms.
METHODS: We present the case of a 39-year-old man suffering from TRD. During the first evaluation at our clinic, he also reported the presence of OCD spectrum symptoms, causing him to perform time-consuming mental rituals due to pathological doubts regarding the relationship with his wife as well as intrusive thoughts regarding his mental conditions. He underwent psychometric evaluations, therapeutic drug monitoring analysis, and pharmacogenomic tests. The overall results helped to explain patient\'s treatment-resistance. Moreover, we observed a significant reduction in both depressive and OCD symptoms after administration of esketamine.
CONCLUSIONS: This case underlines the importance of pharmacogenomic tests in profiling TRD patients and confirms the possible use of esketamine in the treatment of comorbid OCD.

Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.