ABSTRACT
The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.
Subject(s)
Anxiety/metabolism , Anxiety/psychology , Prefrontal Cortex/metabolism , Receptors, Cannabinoid/metabolism , Stress, Psychological/metabolism , Acute Disease , Amides/administration & dosage , Amides/pharmacology , Amides/therapeutic use , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Cannabidiol/analogs & derivatives , Chronic Disease , Cyclohexanes/pharmacology , Cyclohexanes/therapeutic use , Estrenes/pharmacology , Gene Knockdown Techniques , Injections, Intraperitoneal , Male , Mice, Inbred C57BL , Pyridines/administration & dosage , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrrolidinones/pharmacology , Resorcinols/pharmacology , Resorcinols/therapeutic use , Restraint, Physical , Signal Transduction , Stress, Psychological/drug therapy , SwimmingABSTRACT
In addition to debilitating sensory and motor deficits, patients with spinal cord injury (SCI) may experience chronic hyperpathic pain (SCI-pain). Recent studies have revealed that translocator protein (TSPO) is involved in repairing neural cells as well as reducing anxiety and depression. However, the role of TSPO in SCI-pain and pain-induced depression remains unknown. The present study aimed to determine the effects of a new TSPO ligand, ZBD-2, on SCI-pain and consequent pain-induced depressive-like behaviors in mice. Treatment with ZBD-2 at either dose significantly attenuated the symptoms of chronic SCI-pain and pain-induced depressive-like behaviors. ZBD-2 reversed SCI-induced elevation of serum corticosterone levels, an index of hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, administration of ZBD-2 inhibited decreases in the expression of synaptic plasticity-related signaling proteins, including brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding protein (CREB). Moreover, ZBD-2 administration reversed chronic, SCI-induced gliocyte activation at the lesion site. Therefore, ZBD-2 may improve chronic SCI-pain and pain-induced depressive-like behaviors via suppression of gliocyte activation and restoration of the synaptic plasticity-related signaling systems.
Subject(s)
Acetamides/pharmacology , Central Nervous System Agents/pharmacology , Chronic Pain/drug therapy , Depression/drug therapy , Motor Activity/drug effects , Purinones/pharmacology , Spinal Cord Injuries/drug therapy , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Chronic Pain/pathology , Chronic Pain/physiopathology , Chronic Pain/psychology , Depression/pathology , Depression/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Mice, Inbred C57BL , Motor Activity/physiology , Random Allocation , Receptors, GABA/metabolism , Recovery of Function/drug effects , Recovery of Function/physiology , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/physiopathology , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/psychologyABSTRACT
Huntington's disease (HD) is an autosomal dominant inherited disease characterized by movement, psychiatric, and cognitive disorders. Previous research suggests that Praeruptorin C (Pra-C), an effective component in the root of Peucedanum praeruptorum dunn, a traditional Chinese medicine, may function in neuroprotection. The present study was conducted to evaluate the effectiveness of Pra-C in the treatment of HD-like symptoms in a 3-nitropropionic acid (3-NP) mouse model, and to explore the possible mechanism of the drug's activity. We treated 3-NP-injected mice with two different doses of Pra-C (1.5 and 3.0mg/kg) for 3 days. Motor behavior was tested using the open field test (OFT) and rotarod test, while psychiatric symptoms were tested using the forced swimming test (FST) and tail suspension test (TST). We found that Pra-C alleviated the motor deficits and depression-like behavior in the 3-NP-treated mice, and protected neurons from excitotoxicity. Western blot analysis revealed that Pra-C upregulated BDNF, DARPP32, and huntingtin protein in the striatum of 3-NP mice. These results taken together suggest that Pra-C may have therapeutic potential with respect to the movement, psychiatric, and cognitive symptoms of HD.
