The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

BACKGROUND: Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABAB heteroreceptor (GABAB R) is determined by its stability, and hence residence time, on the plasma membrane. AIMS: Here, we show that GABAB R in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression. MATERIALS & METHODS: By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) to the control of GABAB R membrane anchoring and cocaine induced-behavioral sensitization. RESULTS: Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABAB1 R and GABAB2 R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABAB R was also decreased in NAc GAD67 + neurons post cocaine (1 µM) treatment after 5 min. Moreover, the majority of internalized GABAB1 Rs exhibited perinuclear localization, a decrease in GABAB1 R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABAB1 R interaction. CONCLUSION: These findings reveal a new mechanism by which pCaMKII-GABAB R signaling can promote psychostimulant-induced behavioral sensitization.

Unravelling biological roles and mechanisms of GABABR on addiction and depression through mood and memory disorders.

The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.

Rotational Thromboelastometry Reduces the Need for Preemptive Transfusion in Cirrhosis: A Randomized Controlled Trial (NCT:05698134).

Backgrounds and aim: Viscoelastic tests (VET) like rotational thromboelastometry (ROTEM) assess global hemostasis in cirrhosis. We aimed to assess whether ROTEM-guided blood product transfusion results in lower blood product requirements in patients with cirrhosis undergoing elective invasive procedures as compared to standard of care (SOC) based on conventional coagulation test (CCT). Methods: In this open label randomized controlled trial, patients with cirrhosis and abnormal CCT who were undergoing an invasive procedure were randomized to receive blood products either by ROTEM-guidance or SOC. The primary outcome was the difference in blood products (fresh frozen plasma (FFP) or platelets) transfused between the groups. The secondary outcome was procedure-related bleeding or complications within 7 days of the procedure. The trial protocol is registered at clinicaltrails.gov; NCT05698134. Results: From August 2021 to January 2023, a total of 40 patients were recruited (ROTEM (n = 20) and SOC (n = 20)). The trial was terminated earlier during interim analyses due to compelling benefit in the ROTEM group after a scheduled interim analysis. The ROTEM group required substantially less blood transfusion than the SOC group (40% [8/20] vs 100% [20/20], P < 0.001). The benefit was consistent across all types of blood product, including fresh frozen plasma (<0.001) and pooled platelets (P = 0.046). No patients experienced clinically significant bleeding events. Transfusion-associated adverse events occurred in one patient (5%) in the SOC group (allergic reaction) and none in the ROTEM group (P = NS). The mortality in both groups at 30 and 90 days was similar. Conclusions: Viscoelastic tests like ROTEM provide global assessment of hemostasis in patients with cirrhosis. Institution of ROTEM based transfusion strategy significantly reduces the need for blood product transfusion in patients with cirrhosis undergoing elective procedure without any increased risk of bleeding events. Clinical trial number: NCT05698134.