Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.

Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.

Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission.

Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the Gria1-/- animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the Gria1-/- mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of Gria1-/- mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the Gria1-/- mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers.

Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice.

Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1-/- mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1-/- mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1-/- mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1-/- mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1-/- mice to the level shown by the wild-type Gria1+/+ mice. Gria1-/- mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1-/- mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1-/- mouse line can be utilized in screening for new therapeutics.

Surgical treatment of ovarian cancer and early detection of venous thromboembolism.

INTRODUCTION: Deep vein thrombosis (DVT) is present in 10.6% patients after operative treatment for ovarian malignancy. We undertook the present study to find the risk factors for venous thromboembolism (VTE) after surgical treatment for ovarian cancer and to clarify the prognostic value of D-dimer and a positive PTP test (Wells score) in these patients. MATERIAL AND METHODS: A total of 31 consecutive patients with histologically confirmed ovarian cancer after surgery, clinically suspicious for DVT were followed from January 2006 to December 2008. All patients were operatively treated at the Clinical Center of Serbia. Study variables included age, cardiovascular disease, FIGO stage, histology, BMI, presence of massive ascites and tumor size, D-dimer level and Wells score. All patients were postoperatively administered anticoagulant therapy. RESULTS: DVT was found in nine of 31 patients (29.0%). High BMI and presence of massive ascites were significantly associated with DVT. D-dimer (DD) levels were high in 27 of out 31 patients (87.1%). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 100, 18.2, 33.3 and 100%. Results of the PTP test (according to Wells score) was positive in 20 out of 31 patients (64.5%). PTP score was not significantly different in patients with or without VTE (p = 0.606). Sensitivity, specificity, PPV and NPV were 66.7, 36.4, 30.0 and 72.7%, respectively. CONCLUSION: Incidence of VTE after gynecological operations for ovarian cancer in our study was similar to other investigators. Obesity and the massive ascites are statistically significant risk factors. Measurement of DD level and ultrasonography could become the standard in predicting VTE in ovarian cancer surgery. The use of Wells score is not satisfying in these patients. Prediction of VTE after gynecological surgery needs further confirmation in randomized controlled trials.

Preoperative preparation of pregnant women.

All the elective surgeries are to be avoided during pregnancy and pregnant women should undergo only emergency surgical interventions. Pregnancy is associated with different physiological changes in the organism, which should be taken into account in preparative preparation of the pregnant women. Expanded body fluid volume leads to dilutional anemia, however other hematological disorders may be present as well. Extreme obesity is a frequent comorbidity, while hypertension is associated with the highest risks since it may lead to a life-threatening complication--eclampsia. As for other coexisting diseases, urinary tract infections and gestational diabetes are the most common as well as hyperthyroidism and other diseases that may also develop. The type and severity of the acute surgical disease, extensiveness of the planned surgery as well as the type of planned anesthesia to be applied, occasionally necessitate, depending on the gestational age, termination of pregnancy to be considered. Gynecological-obstetric consultations are mandatory in all surgical interventions planned in pregnant women.