Author: Omoumi, Samira ; Tarahomi, Parnia ; Sedaghat, Katayoun ; Vafaei, Abbas Ali ; Rashidy‐Pour, Ali ; Raise‐Abdullahi, Payman ; Seyedinia, Seyed Ali

AbstractPurposeThe infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) regulates the extinction of conditioned fear memory. Glucocorticoid and gamma‐aminobutyric acid (GABA) receptors are expressed in the mPFC and are also critical in fear extinction. This study investigated the possible interactive effects of the glucocorticoids and GABAergic system in the IL on the regulation of fear extinction.MethodThe rats were trained using an auditory fear conditioning task during which they received three conditioned stimuli (tones, 30 s, 4 kHz, 80 dB), co‐terminated with the three unconditioned stimuli (footshock, 0.8 mA, 1 s). Extinction testing was conducted over 3 days (Ext 1–3). Thirty minutes before the first extinction trial (Ext 1), the rats received bicuculline (BIC, 1 mg/kg/2 mL, intraperitoneal [i.p.]) as a GABAA receptor antagonist or CGP55845 (CGP, 0.1 mg/kg/2 ML, i.p.) as a GABAB receptor antagonist followed by systemic injection of corticosterone (CORT, 3 mg/kg/2 ML, i.p.). Furthermore, separate groups of rats received a bilateral intra‐IL injection of BIC (100 ng/0.3 µL/side) or CGP (10 ng/0.3 µL/side) followed by a systemic injection of CORT (3 mg/kg/2 ML, i.p.) before the first extinction trial (Ext 1). The extracellular signal‐regulated kinase (ERK1) and cAMP response element‐binding (CREB) activity in the IL was examined by Western blot analysis after Ext 1.FindingThe results indicated that systemic CORT injection facilitated fear extinction and increased the expression of ERK1 but not CREB in the IL. Both systemic and intra‐IL co‐injection of BIC or CGP blocked the effects of CORT on fear extinction and ERK1 expression.ConclusionThese findings suggest that glucocorticoids and the GABAergic system may modulate fear extinction through the ERK pathway in the IL.

01 Jul 2021·Brain ResearchQ4 · MEDICINE

Mechanisms of GABA-mediated inhibition of the angiotensin II-induced cytosolic Ca2+ increase in rat subfornical organ neurons

Q4 · MEDICINE

Article

Author: Kokudo, Hina ; Kitamura, Naoki ; Arai, Tazuyo ; Ito, Kenji ; Izumisawa, Yu ; Sugita, Keisuke ; Shibuya, Izumi

Neurons in the subfornical organ (SFO) sense both neurotransmitters and circulating humoral factors such as angiotensin II (AII) and atrial natriuretic peptide (ANP), and regulate multiple physiological functions including drinking behavior. We recently reported that AII at nanomolar concentrations induced a persistent [Ca²⁺]_i increase in acutely dissociated SFO neurons and that this effect of AII was reversibly inhibited by GABA. In the present study, we studied the inhibitory mechanism of GABA using Ca²⁺ imaging and patch-clamp electrophysiology. The AII-induced persistent [Ca²⁺]_i increase was inhibited by GABA in more than 90% of AII-responsive neurons and by other two SFO inhibitory ligands, ANP and galanin, in about 60 and 30% of neurons respectively. The inhibition by GABA was mimicked by the GABA_A and GABA_B receptor agonists muscimol and baclofen. The involvement of both GABA receptor subtypes was confirmed by reversal of the GABA-mediated inhibition only when the GABA_A and GABA_B receptors antagonists bicuculline methiodide and CGP55845 were both present. The GABA_B agonist baclofen rapidly and reversibly inhibited voltage-gated Ca²⁺ channel (VGCC) currents recorded in response to depolarizing pulses in voltage-clamp electrophysiology using Ba²⁺ as a charge carrier (I_Ba). Baclofen inhibition of I_Ba was antagonized by CGP55845, confirming GABA_B receptor involvement; was reduced by N-ethylmaleimide, suggesting downstream Gi-mediated actions; and was partially removed by a large prepulse, indicating voltage-dependency. The magnitude of I_Ba inhibition by baclofen was reduced by the application of selective blockers for N-, P/Q-, and L-type VGCCs (ω-conotoxin GVIA, ω-agatoxin IVA, and nifedipine respectively). Overall, our study indicates that GABA inhibition of the AII-induced [Ca²⁺]_i increase is mediated by both GABA_A and GABA_B receptors, and that GABA_B receptors associated with Gi proteins suppress Ca²⁺ entry through VGCCs in SFO neurons.

01 Jul 2020·NeuroscienceQ3 · MEDICINE

Oligodendrocyte Differentiation and Myelination Is Potentiated via GABAB Receptor Activation

Q3 · MEDICINE

Article

Author: Pérez-Samartín, Alberto ; Luengas-Escuza, Irene ; Ibarra-Aizpurua, Naroa ; Bayón-Cordero, Laura ; Sánchez-Gómez, María Victoria ; Serrano-Regal, Mari Paz ; Matute, Carlos ; Alberdi, Elena

Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the central nervous system (CNS). Several growth factors and neurotransmitters like GABA are postulated as important regulators of that process, and different protein kinases may also participate in OL differentiation and myelination. However, the molecular mechanisms underlying the regulation of myelination by neurotransmitters are only partially known. In the present study, we provide evidence showing that GABA receptors (GABARs) play an important role in OL differentiation. First, we observed that OPCs and OLs synthesize GABA and expressed GABAR and transporters, both in vitro and in vivo and, in contrast to GABA_ARs, the subunits GABA_B1R and GABA_B2R are expressed in OLs over time. Then, we found that exogenous GABA increases the number of myelin segments and MBP expression in DRG-OPC cocultures, indicating that GABA regulates myelination when OLs are in contact with axons. Notably, in purified rat OPC cultures, chronic treatment with GABA and baclofen, specific GABA_BR agonist, accelerates OPC differentiation by enhancing the processes branching and myelin protein expression, effects that are reverted in presence of GABA_BR specific antagonist CGP55845. Exposure of OPCs to baclofen promotes the Src-phosphorylation, and the baclofen-induced maturation is attenuated in presence of the Src-family kinases inhibitor PP2. None of these effects are mediated by the GABA_AR agonist muscimol. Together, these results highlight the relevance of the GABAergic system in OL differentiation, and indicate that this functional role is mediated through GABA_BR involving the participation of Src-family kinases. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

100 Deals associated with CGP-55845

R&D Status

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

CGP-55845

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation