Biology subjects

Joca, S. R. L.

Publications and source records attributed to Joca, S. R. L..

5 recordsLinked to original sources

bioRxiv2018

Elevated P2x7r and P2x4r transcripts levels in the Flinders Sensitive Line Rats, a genetic animal model of depression

P2x7 and P2x4 receptors (P2x7R and P2x4R, respectively) are ligand-gated ion channels activated by adenosine triphosphate (ATP), which have been associated to dysfunctional processes in stress responses linked to depression, such as neurotransmitter release, cognition, sleep, energy, appetite, immune and endocrine dysfunction. Clinical studies indicate that polymorphisms in the P2x7r gene results in increased susceptibility for development of depression. Existing studies have investigated the role of P2x7R and P2x4R in animal models based on stress exposure. Therefore, the present work aimed to investigate the transcript and protein levels of these receptors in a genetic animal model of depression, the Flinders Sensitive Line (FSL) and its control group, the Flinders Resistant Line (FRL) rats. We found that FSL rats have increased transcript levels of P2x7R and P2x4R in frontal cortex (FC), ventral and dorsal hippocampus (vHip and dHip, respectively) compared to FRL rats. There were no alterations in the protein levels in the FC and dHip, but the P2x7R was lower in FSL than in FRL rats in the vHip. The results suggest that increased transcripts levels of P2x7r and P2x4r in the FSL rats may contribute to the stress-susceptibility observed in these animals.

neuroscience↗

bioRxiv2018

Activation of the TRKB receptor mediates the panicolytic-like effect of NOS inhibitor aminoguanidine

Nitric oxide (NO) triggers escape reactions in the dorsal periaqueductal gray matter (dPAG), a core structure mediating panic-associated responses, and decreases the release of BDNF in vitro. BDNF mediates the panicolytic effect induced by antidepressant drugs and produces these effects per se when injected into the dPAG. Based on these findings, we hypothesize that nitric oxide synthase (NOS) inhibitors would have panicolytic properties associated with increased BDNF signaling in the dPAG. We observed that the repeated (7 days), but not acute (1day), systemic administration of the NOS inhibitor aminoguanidine (AMG; 15 mg/kg/day) increased the latency to escape from the open arm of the elevated T-maze (ETM) and inhibited the number of jumps in hypoxia-induced escape reaction in rats, suggesting a panicolytic-like effect. Repeated, but not acute, AMG administration (15mg/kg) also decreased nitrite levels and increased TRKB phosphorylation at residues Y706/7 in the dPAG. Notwithstanding the lack of AMG effect on total BDNF levels in that structure, the microinjection of the TRK antagonist K252a into the dPAG blocked the anti-escape effect of this drug in the ETM. Taken together our data suggest that the inhibition of NO production by AMG increased the levels of pTRKB, which is required for the panicolytic-like effect observed.

neuroscience↗

bioRxiv2017

Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN

Renin-angiotensin system (RAS) is associated to peripheral fluid homeostasis and cardiovascular function, but recent evidence has also drawn its functional role in the brain. RAS has been described to regulate physiological and behavioral parameters related to stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain derived neurotrophic factor (BDNF) and TRKB, which are important to neurobiology of depression and antidepressant action. However, interaction between BDNF/TRKB system and RAS in models predictive of antidepressant effect has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treament. Moreover, infusion of losartan into ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a, a blocker of TRK, infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), infused into PL but not into vHC, also prevented systemic losartan effect. Cultured cortical cells of rat embryos indicate that angiotensin II (ANG2), possibly through AGTR2, increases the surface levels of TRKB, and favors its coupling to FYN, a SRC family kinase. The higher levels of agtr2 in cortical cells were decreased after insult with glutamate, and under this condition an interaction between losartan and ANG2 was achieved. Occurrence of TRKB/AGTR2 heterodimers was also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 binding towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, AGTR1 show therapeutic potential as novel antidepressant therapy.

pharmacology and toxicology↗

bioRxiv2016

Antidepressant-like effects of P2 purinergic antagonist PPADS is dependent on serotonergic and noradrenergic integrity

Depression is a common mental disorder affecting around 350 million of individuals globally. The available antidepressant drug monotherapy is far from ideal since it has an efficiency of approximately 60% and takes around 3-4 week to achieve clinical improvement. Attention has been paid to the purinergic signaling regarding neuropathological mechanisms, since it might be involved in psychiatric disorders, such as depression. In fact, blockade of purinergic P2X receptors induces antidepressant-like effects in preclinical models. However, the mechanisms involved in this effect are not yet completely understood. The present work investigated the interplay between a P2X receptor antagonist (PPADS) and clinically used antidepressant drugs on the forced swimming test, an animal model predictive of antidepressant effect. We observed significant synergistic effect of PPADS combined with sub-effective doses of fluoxetine or reboxetine in the FST. Moreover, depletion of serotonergic or noradrenergic systems, with PCPA and DSP-4 treatment, respectively, blocked the antidepressant-like effect of PPADS. No increase in locomotion, a possible source of confusion on FST data, was detected in any of the treated groups. Our results indicate the antidepressant-like effect of PPADS depends on the integrity of serotonergic and noradrenergic transmission.

pharmacology and toxicology↗

bioRxiv2016

Inducible nitric oxide synthase (NOS2) knockout mice as a model of trichotillomania

Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) has been observed in laboratory animals and proposed as TTM model. The neurobiological basis of TTM is not clear, but it seems to involve striatal hyperactivity parallel to hypoactivation of prefrontal cortex. In this study we observed that knockout mice to the inducible isoform of nitric oxide synthase (NOS2) exhibit exacerbated BB following the 4th week of age, as well as increased repetitive movements compared to wild-type mice (WT). These behaviors are associated to decreased levels of NMDA receptor subunit (NR1) in prefrontal cortex, while an increase was observed in striatum of NOS2KO compared to WT. Striatal neurons from NOS2KO also exhibited increased number of branches compared to WT. The repeated treatment with clomipramine, a clinically approved drug to treat TTM in humans, or memantine, an antagonist of NMDA receptors, as well as partial rescue of NOS2 expression in haploinsufficient animals, attenuated the expression of BB. The silencing of NOS2 expression reduced the MAP2 (microtubule-associated protein 2) levels in activity-induced differentiated PC12 cells. Our data led us to propose that NOS2 regulates the neuronal maturation of the inhibitory afferent pathways to striatum during neurodevelopment, and such inadequate inhibition of striatal motor programs might be associated to the observed phenotype.

animal behavior and cognition↗