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Background: Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), their precursors are the high-affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a crosslike conformation dimer and carry a cholesterol-recognition amino acid consensus in the transmembrane domain. As such qualities were found to be crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR., Methods: Enzyme-linked immunosorbent assay-based binding and nuclear magnetic resonance spectroscopy were performed to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to investigate whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75NTR knockout mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verify how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male wild-type mice and rats., Results: Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes., Conclusions: We hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain's ability for remodeling., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not., Competing Interests: JW, CD, AC, KP, JR, LT, BW No competing interests declared, (© 2023, Wilmot et al.)

Binding events that occur at different times are essential for memory formation. In trace fear conditioning, animals associate a tone and footshock despite no temporal overlap. The hippocampus is thought to mediate this learning by maintaining a memory of the tone until shock occurrence, however, evidence for sustained hippocampal tone representations is lacking. Here, we demonstrate a retrospective role for the hippocampus in trace fear conditioning. Bulk calcium imaging revealed sustained increases in CA1 activity after footshock that were not observed after tone termination. Optogenetic silencing of CA1 immediately after footshock impaired subsequent memory. Additionally, footshock increased the number of sharp-wave ripples compared to baseline during conditioning. Therefore, post-shock hippocampal activity likely supports learning by reactivating and linking latent tone and shock representations. These findings highlight an underappreciated function of post-trial hippocampal activity in enabling retroactive temporal associations during new learning, as opposed to persistent maintenance of stimulus representations., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressant drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Tyr433Phe). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Tyr433Phe mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Tyr433Phe mutant mice (hTRKB.Tyr433Phe) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Tyr433Phe mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task, or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Tyr433Phe mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Tyr433Phe mutants, making them an interesting mouse model for antidepressant research., (© 2023. The Author(s).)

Rats re-exposed to an environment previously associated with the onset of shocks evoke a set of conditioned defensive responses in preparation to an eventual flight or fight reaction. Ventromedial prefrontal cortex (vmPFC) is mutually important for controlling the behavioral/physiological consequences of stress exposure and the one's ability to satisfactorily undergo spatial navigation. While cholinergic, cannabinergic and glutamatergic/nitrergic neurotransmissions within the vmPFC are shown as important for modulating both behavioral and autonomic defensive responses, there is a gap on how these systems would interact to ultimately coordinate such conditioned reactions. Then, males Wistar rats had guide cannulas bilaterally implanted to allow drugs to be administered in vmPFC 10 min before their re-exposure to the conditioning chamber where three shocks were delivered at the intensity of 0.85 mA for 2 s two days ago. A femoral catheter was implanted for cardiovascular recordings the day before fear retrieval test. It was found that the increment of freezing behavior and autonomic responses induced by vmPFC infusion of neostigmine (acetylcholinesterase inhibitor) were prevented by prior infusion of a transient receptor potential vanilloid type 1 (TRPV1) antagonist, N-methyl-d-aspartate receptor antagonist, neuronal nitric oxide synthase inhibitor, nitric oxide scavenger and soluble guanylate cyclase inhibitor. A type 3 muscarinic receptor antagonist was unable to prevent the boosting in conditioned responses triggered by a TRPV1 agonist and a cannabinoid receptors type 1 antagonist. Altogether, our results suggest that expression of contextual conditioned responses involves a complex set of signaling steps comprising different but complementary neurotransmitter pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT 2A ) activation, whereas LSD-induced head twitching is dependent on 5-HT 2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT 2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects., (© 2023. The Author(s).)

Since the brain was found to be somehow flexible, plastic, researchers worldwide have been trying to comprehend its fundamentals to better understand the brain itself, make predictions, disentangle the neurobiology of brain diseases, and finally propose up-to-date treatments. Neuroplasticity is simple as a concept, but extremely complex when it comes to its mechanisms. This review aims to bring to light an aspect about neuroplasticity that is often not given enough attention as it should, the fact that the brain's ability to change would include its ability to disconnect synapses. So, neuronal shrinkage, decrease in spine density or dendritic complexity should be included within the concept of neuroplasticity as part of its mechanisms, not as an impairment of it. To that end, we extensively describe a variety of studies involving topics such as neurodevelopment, aging, stress, memory and homeostatic plasticity to highlight how the weakening and disconnection of synapses organically permeate the brain in so many ways as a good practice of its intrinsic physiology. Therefore, we propose to break down neuroplasticity into two sub-concepts, "upward neuroplasticity" for changes related to synaptic construction and "downward neuroplasticity" for changes related to synaptic deconstruction. With these sub-concepts, neuroplasticity could be better understood from a bigger landscape as a vector in which both directions could be taken for the brain to flexibly adapt to certain demands. Such a paradigm shift would allow a better understanding of the concept of neuroplasticity to avoid any data interpretation bias, once it makes clear that there is no morality with regard to the organic and physiological changes that involve dynamic biological systems as seen in the brain., (© 2022. The Author(s).)

Rationale: Re-exposing an animal to an environment previously paired with an aversive stimulus evokes large alterations in behavioral and cardiovascular parameters. Dorsal hippocampus (dHC) receives important cholinergic inputs from the basal forebrain, and respective acetylcholine (ACh) levels are described to influence defensive behavior. Activation of muscarinic M1 and M3 receptors facilitates autonomic and behavioral responses along threats. Evidence show activation of cholinergic receptors promoting formation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in dHC. Altogether, the action of ACh and NO on conditioned responses appears to converge within dHC., Objectives: As answer about how ACh and NO interact to modulate defensive responses has so far been barely addressed, we aimed to shed additional light on this topic., Methods: Male Wistar rats had guide cannula implanted into the dHC before being submitted to the contextual fear conditioning (3footshocks/085 mA/2 s). A catheter was implanted in the femoral artery the next day for cardiovascular recordings. Drugs were delivered into dHC 10 min before contextual re-exposure, which occurred 48 h after the conditioning procedure., Results: Neostigmine (Neo) amplified the retrieval of conditioned responses. Neo effects (1 nmol) were prevented by the prior infusion of a M1-M3 antagonist (fumarate), a neuronal nitric oxide synthase inhibitor (NPLA), a NO scavenger (cPTIO), a guanylyl cyclase inhibitor (ODQ), and a NMDA antagonist (AP-7). Pretreatment with a selective M1 antagonist (pirenzepine) only prevented the increase in autonomic responses induced by Neo., Conclusion: The results show that modulation in the retrieval of contextual fear responses involves coordination of the dHC M1-M3/NO/cGMP/NMDA pathway., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Re-exposure of rats to a previously fear-conditioned environment arouses great alterations in behavioral and cardiovascular parameters. Pieces of works provide putative evidence for the contribution of the dorsal hippocampus (dHC) to contextual conditioning. dHC gathers massive cholinergic inputs from the basal forebrain, and dHC acetylcholine (ACh) is often described as triggering the retrieval of defensive behavior. ACh acts partially through muscarinic receptors (mAChRs) M1R and M3R subtypes. Hence, activation of mAChRs facilitates autonomic and behavioral responses associated with threats and dangers. Therefore, this study explored the likely involvement of M1R and M3R in rat dHC to establish the behavioral and autonomic changes associated with contextual fear retrieval. Male Wistar rats had stainless steel guide cannula implanted into the dHC before being submitted to contextual fear conditioning (6 footshocks, 1.5 mA, 3 s). A catheter placed within the femoral artery allowed autonomic recordings. A variety of drugs were delivered into the dHC 10 min before contextual re-exposure. The choline reuptake inhibitor hemicholinium induced a decrease of the fear conditioned responses, while did not modify it in non-conditioned animals. The non-selective mAChR antagonist atropine also reduced the fear-conditioned responses, as did the selective M1/M3 mAChRs antagonist fumarate. On the other hand, the M1 selective mAChR antagonist pirenzepine inhibited all the autonomic fear responses without affecting animal freezing. These findings support that cholinergic neurotransmission present in the dHC acts through mAChRs to coordinate the expression of fear evoked by contextual conditioning., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hippocampus can be divided along its longitudinal axis into dorsal and ventral parts, which play different roles in modulating the behavioral responses to stress. However, it is not clear whether the hippocampal subregions could also differently modulate the effect of antidepressant drugs. Since fluoxetine (FLX) effect on extinction of aversive memory is well known to depend on hippocampal BDNF levels, we hypothesized that the hippocampal subregions might play different roles in fluoxetine efficacy in decreasing fear response., Method: Wistar rats were fear-cued conditioned and treated chronically with FLX to subsequently investigate their extinction memory. BDNF levels were assessed separately in the dorsal (dHC) and ventral (vHC) hippocampus in animals chronically treated with FLX. An independent group received K252a (a functional Trk blocker) infusion into the dHC or vHC to assay its interaction with FLX treatment along the fear response. Next, BDNF was directly infused into either the dHC or vHC to the behavior be compared with those induced by chronic FLX treatment. Finally, FLX effect on c-Fos expression was evaluated also considering the dHC and vHC apart, along with subareas of amygdala and medial prefrontal cortex., Results: BDNF levels were increased in the vHC after acute FLX, and in the dHC after chronic FLX treatment. FLX effect on fear response was blocked by K252a administration into either dHC or vHC, after the extinction protocol. BDNF administration into the dHC increased fear response, however its administration into the vHC induced an opposite effect. Besides, a negative correlation between the fear response and c-Fos expression in the dHC CA3/CA1 and vHC CA1/DG was observed after chronic FLX treatment., Conclusion: Both dHC and vHC are essential for the Trk-dependent effect of FLX on extinction memory, although a discrepancy in the fear response was observed with the infusion of BDNF into the dHC or vHC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.

It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery., Competing Interests: Declaration of interests E.C. and M.S. are shareholders of Herantis Pharma PIc that is not related to this study. E.C. has received lecture fees from Janssen-Cilag. Other authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Respiratory compromise in Crotalus durissus terrificus (C.d.t.) snakebite is an important pathological condition. Considering that crotoxin (CTX), a phospholipase A 2 from C.d.t. venom, is the main component of the venom, the present work investigated the toxin effects on respiratory failure. Lung mechanics, morphology and soluble markers were evaluated from Swiss male mice, and mechanism determined using drugs/inhibitors of eicosanoids biosynthesis pathway and autonomic nervous system. Acute respiratory failure was observed, with an early phase (within 2 h) characterized by enhanced presence of eicosanoids, including prostaglandin E2, that accounted for the increased vascular permeability in the lung. The alterations of early phase were inhibited by indomethacin. The late phase (peaked 12 h) was marked by neutrophil infiltration, presence of pro-inflammatory cytokines/chemokines, and morphological alterations characterized by alveolar septal thickening and bronchoconstriction. In addition, lung mechanical function was impaired, with decreased lung compliance and inspiratory capacity. Hexamethonium, a nicotinic acetylcholine receptor antagonist, hampered late phase damages indicating that CTX-induced lung impairment could be associated with cholinergic transmission. The findings reported herein highlight the impact of CTX on respiratory compromise, and introduce the use of nicotinic blockers and prostanoids biosynthesis inhibitors as possible symptomatic therapy to Crotalus durissus terrificus snakebite.

Background: Administration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor TRPV1, usually with opposed consequences on behavior., Methods and Results: Using primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200 nM) induced a significant increase in pTRK levels. Such effect of AEA at 100 nM was blocked by pretreatment with the CB1 antagonist AM251 (200 nM) and, at the higher concentration of 200 nM by the TRPV1 antagonist capsazepine (200 nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200 nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1/TRPV1/TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells., Conclusion: Taken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments., Competing Interests: The authors declare there are no competing interests.

Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.

Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The renin-angiotensin system (RAS) is associated with peripheral fluid homeostasis and cardiovascular function, but recent evidence also suggests a functional role in the brain. RAS regulates physiological and behavioral parameters related to the stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain-derived neurotrophic factor (BDNF) and TRKB, which are important in the neurobiology of depression and antidepressant action. However, the interaction between the BDNF/TRKB system and RAS in depression 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 treatment. Moreover, infusion of losartan into the 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), also prevented the systemic losartan effect when infused into PL but not into vHC. Cultured cortical cells of rat embryos revealed that angiotensin II (ANG2), possibly through AGTR2, increased the surface levels of TRKB and its coupling to FYN, a SRC family kinase. Higher Agtr2 levels in cortical cells were reduced after stimulation with glutamate, and only under this condition an interaction between losartan and ANG2 was achieved. TRKB/AGTR2 heterodimers were also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, the antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, the blockade of AGTR1 has therapeutic potential as a novel antidepressant therapy., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Depression is a common mental disorder that affects millions of individuals worldwide. Available monoaminergic antidepressants are far from ideal since they show delayed onset of action and are ineffective in approximately 40% of patients, thus indicating the need of new and more effective drugs. ATP signaling through P2 receptors seems to play an important role in neuropathological mechanisms involved in depression, since their pharmacological or genetic inactivation induce antidepressant-like effects in the forced swimming test (FST). However, the mechanisms involved in these effects are not completely understood. The present work investigated monoamine involvement in the antidepressant-like effect induced by non-specific P2 receptor antagonist (PPADS) administration. First, the effects of combining sub-effective doses of PPADS with sub-effective doses of fluoxetine (FLX, selective serotonin reuptake inhibitor) or reboxetine (RBX, selective noradrenaline reuptake inhibitor) were investigated in mice submitted to FST. Significant antidepressant-like effect was observed when subeffective doses of PPADS was combined with subeffective doses of either FLX or RBX, with no significant locomotor changes. Next, the effects of depleting serotonin and noradrenaline levels, by means of PCPA (p-Chlorophenylalanine) or DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively, was investigated. Both, PCPA and DSP-4 pretreatment partially attenuated PPADS-induced effects in FST, without inducing relevant locomotor changes. Our results suggest that the antidepressant-like effect of PPADS involves modulation of serotonin and noradrenaline levels in the brain., (Copyright © 2017 Elsevier B.V. All rights reserved.)