title: Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: involvement of nitric oxide.
abstract: Activation of purinergic receptors by ATP (P2R) modulates glutamate release and the activation of post-synaptic P2R is speculated to induce nitric oxide (NO) synthesis. Increased glutamatergic and nitrergic signaling have been involved in the neurobiology of stress-related psychiatric disorders such as anxiety and depression. Therefore, the aim of this study was to test the effects of two P2R antagonists (PPADS and iso-PPADS) in animals submitted to models predictive of antidepressant-, anxiolytic- and anticompulsive-like effects. Swiss mice receiving PPADS at 12.5mg/kg showed reduced immobility time in the forced swimming test (FST) similarly to the prototype antidepressant imipramine (30mg/kg). This dose was also able to decrease the number of buried marbles in the marble-burying test (MBT), an anticompulsive-like effect. However, no effect was observed in animals submitted to the elevated plus maze (EPM) and to the open field test. The systemic administration of iso-PPADS, a preferential P2XR antagonist, also reduced the immobility time in FST, which was associated to a decrease in NOx levels in the prefrontal cortex. In addition, P2X7 receptor was found co-immunoprecipitated with neuronal nitric oxide synthase (NOS1) in the prefrontal cortex. These results suggest that P2X7, possibly coupled to NOS1, could modulate behavioral responses associated to stress-related disorders and it could be a new target for the development of more effective treatments for affective disorders.
authors: Department of Pharmacology, School of Medicine, Campus USP, Ribeirão Preto, SP 14049-900, Brazil.
authors: Vitor S
authors: VS
authors: Pereira
authors: Plinio C
authors: PC
authors: Casarotto
authors: Vinícius A
authors: VA
authors: Hiroaki-Sato
authors: Ariandra G
authors: AG
authors: Sartim
authors: Francisco S
authors: FS
authors: Guimarães
authors: Sâmia R L
authors: SR
authors: Joca
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003192:Compulsive Behavior / Q000188:drug therapy*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D058914:Purinergic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D009569:Nitric Oxide; D017374:Paroxetine; D011732:Pyridoxal Phosphate; D052247:Nitric Oxide Synthase Type II
keywords: Forced swimming test; Marble burying; P2 receptor; PPADS; Purinergic system