RESUMO
Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.
Assuntos
Neurônios , Reconhecimento Psicológico , Animais , Feminino , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Camundongos , Reconhecimento Psicológico/fisiologia , Histamina/metabolismo , Camundongos Endogâmicos C57BL , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/fisiologia , Rememoração Mental/fisiologiaRESUMO
We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer's disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-ß-peptide (Aß)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1-90.0 nM) and MAO-B (IC50 in the range of 6.7-32.6 nM). Computational studies were conducted to elucidate the structure-activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aß-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.
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Doença de Alzheimer , Anidrases Carbônicas , Doenças Mitocondriais , Neuroblastoma , Humanos , Monoaminoxidase/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Peptídeos beta-Amiloides/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Doença de Alzheimer/tratamento farmacológico , Relação Estrutura-Atividade , Estresse Oxidativo , Encéfalo/metabolismoRESUMO
Purpose: The purpose of this study was to assess the retinal protective activity and ocular hemodynamics after NCX 470 (0.1%) compared to bimatoprost administered as the US Food and Drug Administration (FDA)-approved drug (Lumigan - 0.01% ophthalmic solution, LUM) and at an equimolar dose (0.072%, BIM) to that released by NCX 470. Methods: Endothelin-1 (ET-1) induced ischemia/reperfusion injury model in rabbits was used. ET-1 was injected nearby the optic nerve head (ONH) twice/week for 6 weeks. Starting on week 3, the animals received vehicle (VEH), NCX 470, LUM, or BIM (30 µL/eye, twice daily, 6 days/week) until the end of ET-1 treatment. Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI), and electroretinogram (ERG) data were collected prior to dosing and at different time points postdosing. Reduced glutathione, 8-Hydroxy 2-deoxyguanosine, and Caspase-3 were determined in the retina of treated eyes. DNA fragmentation was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining. Results: ET-1 increased IOP (VEHIOP_Baseline = 20.5 ± 0.8 and VEHIOP_Week6 = 24.8 ± 0.3 mmHg) and OA-RI (VEHOA-RI_Baseline = 0.36 ± 0.02 and VEHOA-RI_Week6 = 0.55 ± 0.01) and reduced rod/cone responses over time. Oxidative stress, inflammation, and apoptotic markers increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6 = 18.1 ± 0.6 mmHg) and OA-RI changes (NCX 470OA-RI_Week6 = 0.33 ± 0.01) and restored ERG amplitude leaving unaltered the respective latency; these effects were only partially demonstrated by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation, and apoptosis in the retinas of treated eyes. BIM and LUM were numerically less effective on these parameters. Conclusions: NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction caused by ischemia/reperfusion via nitric oxide- and bimatoprost-mediated mechanisms. Translational Relevance: If confirmed in clinical setting our data may open new therapeutic opportunities to reduce visual field loss in glaucoma.
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Glaucoma , Disco Óptico , Traumatismo por Reperfusão , Estados Unidos , Animais , Coelhos , Bimatoprost , Citoproteção , Artéria Oftálmica , Hemodinâmica , Retina , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
A vast literature strongly suggests that the endocannabinoid (eCB) system and related bioactive lipids (the paracannabinoid system) contribute to numerous physiological processes and are involved in pathological conditions such as obesity, type 2 diabetes, and intestinal inflammation. The gut paracannabinoid system exerts a prominent role in gut physiology as it affects motility, permeability, and inflammatory responses. Another important player in the regulation of host metabolism is the intestinal microbiota, as microorganisms are indispensable to protect the intestine against exogenous pathogens and potentially harmful resident microorganisms. In turn, the composition of the microbiota is regulated by intestinal immune responses. The intestinal microbial community plays a fundamental role in the development of the innate immune system and is essential in shaping adaptive immunity. The active interplay between microbiota and paracannabinoids is beginning to appear as potent regulatory system of the gastrointestinal homeostasis. In this context, oleoylethanolamide (OEA), a key component of the physiological systems involved in the regulation of dietary fat consumption, energy homeostasis, intestinal motility, and a key factor in modulating eating behavior, is a less studied lipid mediator. In the small intestine namely duodenum and jejunum, levels of OEA change according to the nutrient status as they decrease during food deprivation and increase upon refeeding. Recently, we and others showed that OEA treatment in rodents protects against inflammatory events and changes the intestinal microbiota composition. In this review, we briefly define the role of OEA and of the gut microbiota in intestinal homeostasis and recapitulate recent findings suggesting an interplay between OEA and the intestinal microorganisms.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Endocanabinoides/metabolismo , HomeostaseRESUMO
The nine amino acid neuropeptide oxytocin (OXT, Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2) is one of the most studied hormones of the body [...].
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Aminoácidos , Fragmentos de Peptídeos , Sequência de AminoácidosRESUMO
Cognitive deficits are enduring and disabling symptoms for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. In this study, we reported the synthesis of ß-arylchalcogeno amines bearing sulfurated, selenated, and tellurated moieties (2-4) which are structurally related to amphetamine with good activation properties for Carbonic Anhydrases (CAs) isoforms present in the cortical and hippocampal brain structures (hCA IV and hCA XIV). In addition, these compounds showed selective inhibition against the Monoamine oxidase (MAO) A isoform. In vivo evaluation of two derivatives (2a and 3a) revealed procognitive effects in the object recognition and social discrimination tests. Interestingly, these compounds, despite having a similar structure to amphetamine, did not caused hypophagia or hyperlocomotion, two effects often observed following the administration of amphetamine-like drugs. In this context, ß-arylchalcogeno amines may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases such as attention deficit disorder, Parkinson's disease-related cognitive dysfunction and cognitive disorders associated with depression.
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Anidrases Carbônicas , Humanos , Anidrases Carbônicas/metabolismo , Aminas/farmacologia , Monoaminoxidase , Isoformas de Proteínas , Inibidores da Anidrase Carbônica/química , Relação Estrutura-Atividade , Anidrase Carbônica IX/metabolismoRESUMO
Purpose: Determine whether NCX 470, a nitric oxide (NO)-donating bimatoprost with clinically demonstrated intraocular pressure (IOP)-lowering effects, improves ocular hemodynamics and retinal physiology. Methods: Endothelin-1 (ET-1)-induced ischemia/reperfusion model in New Zealand white rabbits was used. ET-1 was injected next to the optic nerve twice/week (Monday and Thursday) for 6 weeks. Starting on week 3, animals received NCX 470 (0.1% bid, 6 days/week Monday-Saturday) or vehicle until the end of ET-1 treatment. IOP, ophthalmic artery resistive index (OA-RI) and retina physiology (electroretinogram, ERG) were determined before dosing and at different times post-dosing. All measurements were taken on Mondays before the AM daily dosing (36 h treatment-free). Finally, oxidative stress markers were determined in dissected retina and iris/ciliary body of treated eyes. Results: Injection of ET-1 progressively increased IOP (20.7 ± 0.6, 24.9 ± 1.2, and 27.0 ± 0.6 mmHg at baseline, week 2 and 6, respectively) and OA-RI (0.30 ± 0.02, 0.39 ± 0.02, and 0.42 ± 0.03 at baseline, week 2 and 6, respectively) and reduced rods and/or cones response as indicated by changes in ERG amplitudes under different stimulating conditions. NCX 470 re-established baseline IOP (21.8 ± 1.0 mmHg), OA-RI (0.33 ± 0.02), and ERG amplitude by week 6 (mostly rod response, 0.01Dark_AVeh_6week = 32.2 ± 3.0 µV and 0.01Dark_ANCX470_6week 44.3 ± 4.5 µV; mostly cone response, 3.0Dark_AVeh_6week = 87.6 ± 10.1 µV and 3.0Dark_ANCX470_6week = 122.8 ± 11.4 µV; combined rod/cone response, 3.0Light_AVeh_6week = 49.8 ± 6.5 µV and 3.0Light_ANCX470_6week = 64.2 ± 6.8 µV). NCX 470 also reversed ET-1-induced changes in glutathione and manganese superoxide dismutase (oxidative stress markers) in retina and iris/ciliary body. Conclusions: Repeated ocular topical dosing with NCX 470 reverses ET-1-induced changes in IOP, OA-RI, and ERG suggesting improved ocular hemodynamics and retinal physiology likely independently from its demonstrated IOP-lowering effect.
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Hipertensão Ocular , Traumatismo por Reperfusão , Animais , Fenômenos Fisiológicos Celulares , Endotelina-1/farmacologia , Endotelina-1/uso terapêutico , Hemodinâmica , Pressão Intraocular , Hipertensão Ocular/tratamento farmacológico , Nervo Óptico , Coelhos , Traumatismo por Reperfusão/tratamento farmacológico , RetinaRESUMO
Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.
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Anidrases Carbônicas , Hipocampo , Córtex Pré-Frontal , Reconhecimento Psicológico , Animais , Anidrases Carbônicas/fisiologia , Hipocampo/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc-/-) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc-/- and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.
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Dieta , Disbiose , Microbioma Gastrointestinal , Histamina/metabolismo , Comportamento Social , Estresse Psicológico , Animais , Comportamento Animal , Biomarcadores , Peso Corporal , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Locomoção , Masculino , Metagenoma , Metagenômica , Camundongos , Camundongos Knockout , Modelos AnimaisRESUMO
In ballet, a pas de deux (in French it means "step of two") is a duet in which the two dancers perform ballet steps together. The suite of dances shares a common theme of partnership. How could we better describe the fine interplay between oleoylethanolamide (OEA) and histamine, two phylogenetically ancient molecules controlling metabolic, homeostatic and cognitive processes? Contrary to the pas de deux though, the two dancers presumably never embrace each other as a dancing pair but execute their "virtuoso solo" constantly exchanging interoceptive messages presumably via vagal afferents, the blood stream, the neuroenteric system. With one exception, which is in the control of liver ketogenesis, as in hepatocytes, OEA biosynthesis strictly depends on the activation of histaminergic H1 receptors. In this review, we recapitulate our main findings that evidence the interplay of histamine and OEA in the control of food consumption and eating behaviour, in the consolidation of emotional memory and mood, and finally, in the synthesis of ketone bodies. We will also summarise some of the putative underlying mechanisms for each scenario.
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Histamina , Ácidos Oleicos , Cognição , Endocanabinoides , Etanolamina , Histamina/metabolismo , Corpos Cetônicos , Ácidos Oleicos/farmacologiaRESUMO
The histaminergic neuronal system is recently receiving increasing attention, as much has been learned over the past 25 years about histamine role as a neurotransmitter. Indeed, this amine is crucial in maintaining arousal and provides important contributions to regulate circadian rhythms, energy, endocrine homeostasis, motor behavior, and cognition. The extent to which these distinct physiological functions are operated by independent histamine neuronal subpopulation is unclear. In the rat brain histamine neuronal cell bodies are grouped within the tuberomamillary nucleus of the posterior hypothalamus in five clusters, E1-E5, each sending overlapping axons throughout the entire central nervous system with no strict topographical pattern. These features lead to the concept that histamine regulation of a wide range of functions in the central nervous system is achieved by the histaminergic neuronal system as a whole. However, increasing experimental evidence suggesting that the histaminergic system is organized into distinct pathways modulated by selective mechanisms challenges this view. In this review, we summarized experimental evidence supporting the heterogeneity of histamine neurons, and their organization in functionally distinct circuits impinging on separate brain regions and displaying selective control mechanisms. This implies independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections with relevant consequences for the development of specific compounds that affect only subsets of histamine neurons, thus increasing the target specificity.
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Histamina , Neurônios , Animais , Encéfalo/fisiologia , Histamina/metabolismo , Neurônios/metabolismo , Neurotransmissores/metabolismo , RatosRESUMO
Unresolved inflammation represents a central feature of different human pathologies including neuropsychiatric, cardiovascular, and metabolic diseases. The epidemiologic relevance of such disorders justifies the increasing interest in further understanding the mechanisms underpinning the inflammatory process occurring in such chronic diseases to provide potential novel pharmacological approaches. The most common and effective therapies for controlling inflammation are glucocorticoids; however, a variety of other molecules have been demonstrated to have an anti-inflammatory potential, including neuropeptides. In recent years, the oxytocinergic system has seen an explosion of scientific studies, demonstrating its potential to contribute to a variety of physiological processes including inflammation. Therefore, the aim of the present review was to understand the role of oxytocin in the modulation of inflammation occurring in different chronic diseases. The criterion we used to select the diseases was based on the emerging literature showing a putative involvement of the oxytocinergic system in inflammatory processes in a variety of pathologies including neurological, gastrointestinal and cardiovascular disorders, diabetes and obesity. The evidence reviewed here supports a beneficial role of oxytocin in the control of both peripheral and central inflammatory response happening in the aforementioned pathologies. Although future studies are necessary to elucidate the mechanistic details underlying such regulation, this review supports the idea that the modulation of the endogenous oxytocinergic system might represent a new potential pharmacological approach for the treatment of inflammation.
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Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ocitocina/metabolismo , Animais , Doença Crônica , HumanosRESUMO
Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.
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Medo/fisiologia , Ocitocina/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Sítios de Ligação , Extinção Psicológica , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Ratos Wistar , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/fisiologiaRESUMO
It is known that fructose may contribute to myocardial vulnerability to ischemia/reperfusion (I/R) injury. D-tagatose is a fructose isomer with less caloric value and used as low-calorie sweetener. Here we compared the metabolic impact of fructose or D-tagatose enriched diets on potential exacerbation of myocardial I/R injury. Wistar rats were randomizedly allocated in the experimental groups and fed with one of the following diets: control (CTRL), 30% fructose-enriched (FRU 30%) or 30% D-tagatose-enriched (TAG 30%). After 24 weeks of dietary manipulation, rats underwent myocardial injury caused by 30 min ligature of the left anterior descending (LAD) coronary artery followed by 24 h' reperfusion. Fructose consumption resulted in body weight increase (49%) as well as altered glucose, insulin and lipid profiles. These effects were associated with increased I/R-induced myocardial damage, oxidative stress (36.5%) and inflammation marker expression. TAG 30%-fed rats showed lower oxidative stress (21%) and inflammation in comparison with FRU-fed rats. Besides, TAG diet significantly reduced plasmatic inflammatory cytokines and GDF8 expression (50%), while increased myocardial endothelial nitric oxide synthase (eNOS) expression (59%). Overall, we demonstrated that D-tagatose represents an interesting sugar alternative when compared to its isomer fructose with reduced deleterious impact not only on the metabolic profile but also on the related heart susceptibility to I/R injury.
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The physiological mechanisms underlying the complex interplay between life stressors and metabolic factors is receiving growing interest and is being analyzed as one of the many factors contributing to depressive illness. The brain histaminergic system modulates neuronal activity extensively and we demonstrated that its integrity is necessary for peripheral signals such as the bioactive lipid mediator oleoylethanolamide (OEA) to exert its central actions. Here, we investigated the role of brain histamine and its interaction with OEA in response to chronic social defeat stress (CSDS), a preclinical protocol widely used to study physio-pathological mechanisms underlying symptoms observed in depression. Both histidine decarboxylase null (HDC-/-) and HDC+/+ mice were subjected to CSDS for 21 days and treated with either OEA or vehicle daily, starting 10 days after CSDS initiation, until sacrifice. Undisturbed mice served as controls. To test the hypothesis of a histamine-OEA interplay on behavioral responses affected by chronic stress, tests encompassing the social, ethological and memory domains were used. CSDS caused cognitive and social behavior impairments in both genotypes, however, only stressed HDC+/+ mice responded to the beneficial effects of OEA. To detect subtle behavioral features, an advanced multivariate approach known as T-pattern analysis was used. It revealed unexpected differences of the organization of behavioral sequences during mice social interaction between the two genotypes. These data confirm the centrality of the neurotransmitter histamine as a modulator of complex behavioral responses and directly implicate OEA as a protective agent against social stress consequences in a histamine dependent fashion.
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The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory. Impairments of LTM, but not STM, were observed in histamine-deprived animals, either chronically (Hdc-/- mice lacking the histamine-synthesizing enzyme histidine decarboxylase) or acutely (mice treated with the HDC irreversible inhibitor α-fluoromethylhistidine). On the contrary, restriction of histamine release induced by stimulation of the H3R agonist (VUF16839) impaired both STM and LTM. H3R agonism-induced amnesic effect was prevented by pre-treatment with donepezil, an acetylcholinesterase inhibitor. The blockade of the H3R with ciproxifan, which in turn augmented histamine release, resulted in a procognitive effect. In keeping with this hypothesis, the procognitive effect of ciproxifan was absent in both Hdc-/- and αFMH-treated mice. Our results suggest that brain histamine is essential for the consolidation of LTM but not STM in the social recognition test. STM impairments observed after H3R stimulation are probably related to their function as heteroreceptors on cholinergic neurons.