RESUMO
Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain elusive. We recently demonstrated that mice heterozygous for an inactivated allele of the schizophrenia-associated Brd1 gene (Brd1+/- mice) display behaviors reminiscent of schizophrenia, including impaired social cognition and long-term memory. Here, we further characterize performance of these mice by following the preclinical guidelines recommended by the 'Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)' and 'Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS)' initiatives to maximize translational value. Brd1+/- mice exhibit relational encoding deficits, compromised working and long term memory, as well as impaired executive cognitive functioning with cognitive behaviors relying on medial prefrontal cortex being particularly affected. Akin to patients with schizophrenia, the cognitive deficits displayed by Brd1+/- mice are not global, but selective. Our results underline the value of Brd1+/- mice as a promising tool for studying the neurobiology of cognitive deficits in schizophrenia.
Assuntos
Transtornos Cognitivos/genética , Cognição/fisiologia , Função Executiva/fisiologia , Histona Acetiltransferases/genética , Esquizofrenia/genética , Alelos , Animais , Comportamento Animal/fisiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Heterozigoto , Masculino , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Knockout , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologiaRESUMO
In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure-activity relationships for α7 PAM potency, intrinsic hepatic clearance, the structure-property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the α7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).
Assuntos
Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Ciclopropanos/farmacologia , Descoberta de Drogas , Álcool Feniletílico/análogos & derivados , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/induzido quimicamente , Ciclopropanos/administração & dosagem , Ciclopropanos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenciclidina/administração & dosagem , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
Clinical and preclinical evidence suggest a role of nicotinic acetylcholine receptors in major depression. In humans, both nicotine and the nonselective nicotinic acetylcholine receptor antagonist mecamylamine ameliorate depressive symptoms. Similarly, both drugs produce antidepressant-like effects in rodents. In rats, the most consistent finding is antidepressant-like effects of nicotine, but not mecamylamine. Conversely, in mice, several studies show antidepressant-like effects of mecamylamine, whereas nicotine has shown modest or no effects. These contradictory results might be because of genetic differences. Here, we compared the effects of nicotine and mecamylamine in females and males of NMRI, C57BL/6J and BALB/c mice using the mouse forced swim (mFST) and tail suspension tests (mTST). In the mFST, mecamylamine, but not nicotine, increased swim distance in NMRI mice. In contrast, nicotine, but not mecamylamine, increased swim distance in C57BL/6J mice. Both drugs increased swim distance in BALB/c mice. Effects in the mFST were independent of sex. In the mTST, mecamylamine decreased immobility in NMRI mice only, independent of sex. Nicotine was devoid of effects in the mTST, except in female C57BL/6J mice, where it increased immobility. We hypothesize that nicotine and mecamylamine produce antidepressant-like effects through partially different mechanisms.
Assuntos
Antidepressivos/farmacologia , Elevação dos Membros Posteriores , Mecamilamina/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Fatores Sexuais , Especificidade da Espécie , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologiaRESUMO
Neuropeptide Y (NPY) is thought to be implicated in depressive disorders. The mouse forced swim test (FST) is an animal model widely used as a predictor of the efficacy of antidepressant drugs. The present study was undertaken to explore the possible contribution of endogenous serotonin (5-HT) systems in the behavioral effects elicited by NPY in this model. The selective serotonin re-uptake inhibitor (SSRI), fluoxetine, was also tested for comparison. 5-HT was depleted prior to testing by the administration of the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 300 mg/kg, i.p., each day for 3 days; control mice received saline-vehicle over the same period). On the fourth day, mice received NPY (3 nmol, I.C.V.), fluoxetine (16 mg/kg, i.p.) or saline injections before testing in the FST. Both NPY and fluoxetine significantly reduced immobility time in saline-treated control animals. Pre-treatment with PCPA significantly blocked the effects of fluoxetine in the FST, confirming the role of endogenous 5-HT. Similarly, pre-treatment with PCPA also significantly attenuated the anti-immobility effects of NPY, thus suggesting a role for 5-HT in the effects of NPY in the FST. Quantitative receptor autoradiography revealed increases in specific [125I][Leu31, Pro34]PYY sites that were sensitive to BIBP3226 (Y1-like sites) in various brain regions. Specific [125I]GR231118 and [125I]PYY(3-36) binding levels were not changed following PCPA treatment, suggesting that depletion of endogenous 5-HT resulted in an apparent increase in the level of Y1 sites in their high-affinity state. Taken together, these results suggest a role for 5-HT-related systems in the antidepressant-like properties of NPY.
Assuntos
Antidepressivos/administração & dosagem , Modelos Animais de Doenças , Fenclonina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Neuropeptídeo Y/antagonistas & inibidores , Serotonina/fisiologia , Animais , Fluoxetina/administração & dosagem , Fluoxetina/antagonistas & inibidores , Masculino , Camundongos , Atividade Motora/fisiologia , Neuropeptídeo Y/administração & dosagem , Neuropeptídeo Y/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Natação/fisiologiaRESUMO
Here, we present a preliminary pharmacological characterisation of Lu AF33241, a novel, brain penetrant phosphodiesterase inhibitor of (PDE) 2A and 10A tool compound, in in vitro/in vivo assays indicative of PDE2A and/or PDE10A inhibition, and in vivo models/assays relevant to cognitive processing and antipsychotic-like activity. An assay was also included to investigate potential effects on motor activity. The in vitro selectivity of Lu AF33241 was determined against a panel of PDE enzymes. Lu AF33241 potently inhibited both full-length recombinant hPDE2A (Ki=4.2nM) and hPDE10A (Ki=42nM). The compound moderately inhibited both hPDE1C (Ki=1200nM), hPDE7B (Ki=890nM), and hPDE11A (Ki=1800nM). Lu AF33241 displayed a Ki above 5000nM against all other tested members of the PDE family. Albeit within a narrow dose range, Lu AF33241 attenuated sub-chronic phencyclidine-induced deficits in novel object recognition (3 and 10mg/kg), displayed antipsychotic-like activity in the conditioned avoidance response paradigm (10mg/kg), and did not induce catalepsy within a dose-range of 2-6mg/kg. Further catalepsy studies are needed to investigate a predictive safety window. Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool compound that may serve to further the understanding of the roles played by these enzymes in various CNS disorders.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Quinoxalinas/farmacologia , Triazóis/farmacologia , Animais , Antipsicóticos/metabolismo , Antipsicóticos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Permeabilidade Capilar , Catalepsia/induzido quimicamente , Cognição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/toxicidade , Quinoxalinas/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Triazóis/metabolismoRESUMO
This review aims to give a brief overview of NPY receptor distribution and physiology in the brain and summarizes series of studies, test by test and region by region, aimed at identification receptor subtypes and neuronal circuitry mediating anxiolytic-like effects of NPY. We conclude that from four known NPY receptor subtypes in the rat (Y(1), Y(2), Y(4), Y(5)), only the NPY Y(1) receptor can be linked to anxiety-regulation with certainty in the forebrain, and that NPY Y(2) receptor may have a role in the pons. Microinjection studies with NPY and NPY receptor antagonists support the hypothesis that the amygdala, the dorsal periaqueductal gray matter, dorsocaudal lateral septum and locus coeruleus form a neuroanatomical substrate that mediates anxiolytic-like effects of NPY. The release of NPY in these areas is likely phasic, as NPY receptor antagonists are silent on their own. However, constant NPY-ergic tone seems to exist in the dorsal periaqueductal gray, the only brain region where NPY Y(1) receptor antagonists had anxiogenic-like effects. We conclude that endogenous NPY has an important role in reducing anxiety and serves as a physiological stabilizer of neural activity in circuits involved in the regulation of arousal and anxiety.
Assuntos
Ansiolíticos/metabolismo , Química Encefálica , Encéfalo/metabolismo , Neuropeptídeo Y/fisiologia , Receptores de Neuropeptídeo Y/análise , Receptores de Neuropeptídeo Y/fisiologia , Animais , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Comportamento Animal , Humanos , Modelos Animais , Neuropeptídeo Y/administração & dosagem , Neuropeptídeo Y/farmacologiaRESUMO
The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY) in the mouse forced swimming test, an animal model widely used for the screening of potential antidepressant drugs. In addition, experiments were performed, using agonists and selective antagonists, to assess the potential role of NPY Y(1) and Y(2) receptor subtypes in this model. Complementary studies were performed in an open field apparatus to rule out any changes in locomotor activity that might have interfered with the interpretation of data from the mouse forced swimming test. Intracerebroventricular injections (0.03 nmole-3 nmole) of NPY, [Leu(31)Pro(34)]PYY (Y(1) agonist), NPY(13-36) (Y(2) agonist), BIBP3226, BIBO3304 (Y(1) antagonists) and BIIE0246 (Y(2) antagonist) were performed 30 min prior to testing in the mouse forced swimming test and open field. NPY administration significantly reduced immobility time in a dose dependent manner (p <.01 vs. control group), as did [Leu(31)Pro(34)]PYY (p <.01 vs. control group) and BIIE0246 (p <.05 vs. control group). In contrast, BIBO3304, BIBP3226 and NPY(13-36) did not display any activity at the doses tested. However, pretreatment with BIBO3304 or BIBP3226 significantly blocked the anti-immobility effects of NPY. Data from the open field demonstrated that BIIE0246 increased horizontal ambulation at the dose found to be active in the forced swimming test. Taken together, our results demonstrate that NPY displays antidepressant-like activity in the mouse forced swimming test, and suggest that this activity is mediated by the NPY Y(1) receptor subtype.
Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Arginina/análogos & derivados , Atividade Motora/efeitos dos fármacos , Neuropeptídeo Y/fisiologia , Receptores de Neuropeptídeo Y/fisiologia , Natação , Animais , Arginina/farmacologia , Benzazepinas/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Avaliação Pré-Clínica de Medicamentos/métodos , Imobilização/fisiologia , Masculino , Camundongos , Atividade Motora/fisiologia , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Natação/fisiologia , Natação/psicologiaRESUMO
The behavioural phenotype of mice lacking neuropeptide Y (NPY) Y(2)-type receptors was assessed in two well documented animal models of anxiety: namely, the elevated plus maze and the open field. NPY Y(2)-/- mice made more entries into, and spent significantly more time on, the open arms of the elevated plus maze when compared to their wild-type Y(2)+/+ controls (P<0.001). This effect was not due to non-specific changes in locomotor activity as the number of closed arm entries did not differ between groups. In addition, NPY Y(2)-/- mice displayed increased preference for the central area of the open field when compared to Y(2)+/+ animals (P<0.01), whereas total entries did not differ between groups. This study suggests that NPY Y(2) receptors may play an inhibitory role and supports the hypothesis that Y(2) receptors are involved in the regulation of anxiety-like behaviours by NPY.
Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Receptores de Neuropeptídeo Y/fisiologia , Animais , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Atividade Motora/genética , Atividade Motora/fisiologia , Fenótipo , Receptores de Neuropeptídeo Y/genéticaRESUMO
The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs.
Assuntos
Antidepressivos/farmacologia , Benzimidazóis/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos , Naloxona/farmacologia , Receptores Opioides , Natação , Receptor de Nociceptina , NociceptinaRESUMO
Neuropeptide Y (NPY) is widely distributed throughout the central nervous system (CNS) and is one of the most conserved peptides in evolution, suggesting an important role in the regulation of basic physiological functions. In addition, both pre-clinical and clinical evidence have suggested that NPY, together with its receptors, may have a direct implication in several psychiatric disorders, including depression and related illnesses. NPY-like immunoreactivity and NPY receptors are expressed throughout the brain, with varying concentrations being found throughout the limbic system. Such brain structures have been repeatedly implicated in the modulation of emotional processing, as well as in the pathogenesis of depressive disorders. This review will concentrate on the distribution of NPY, its receptors, and the putative role played by this peptide in depressive illness based on both pre-clinical and clinical evidence.
Assuntos
Pesquisa Biomédica , Encéfalo/metabolismo , Depressão/metabolismo , Avaliação Pré-Clínica de Medicamentos , Neuropeptídeo Y/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Receptores de Neuropeptídeo Y/metabolismoRESUMO
Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.
Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Animais , Antipsicóticos/farmacocinética , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Hipocampo/metabolismo , Humanos , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fenciclidina/antagonistas & inibidores , Fenciclidina/farmacologia , Inibidores de Fosfodiesterase/farmacocinética , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Proteínas Recombinantes , Filtro Sensorial/efeitos dos fármacosRESUMO
Autoinduction in drug metabolism is a known phenomenon observed when a drug induces the enzymes responsible for its own metabolism. The potency, rate and extent of autoinduction following a given treatment paradigm may have therapeutic implications in clinic as well as for in vivo pharmacological assessments in animals. RO4938581, an imidazo-triazolo-benzodiazepine, is a novel GABAAα5 negative modulator recently pursued for the treatment of cognitive dysfunctions. As circulating plasma levels of RO4938581 were shown to decrease rapidly after repeated dosing in rats, with CYP1A2 being involved in the metabolism of the compound, we examined the potential role of RO4938581-mediated autoinduction of CYP1A2. Incubation of rat hepatocytes with RO4938581 revealed potent CYP1A2 induction with significant increase in enzymatic activity at concentrations of 0.1nM and RO4938581 was shown to be 700-fold more potent than ß-napththoflavone. Ex vivo studies revealed a 7-fold increase in metabolic CYP1A2 activity in liver microsomes prepared from rats administered with 0.1mg/kg of RO4938581 24h before. This induction profile was reflected in vivo in pharmacokinetic studies in rats where an 8-fold reduction in plasma exposure was observed after a second dose. The reduction in plasma exposures due to CYP1A2 autoinduction were confirmed functionally in contextual fear conditioning paradigm in rats, where a positive pharmacological effect observed after acute drug administration disappeared completely after sub-chronic dosing. Together, these findings suggest that RO4938581 possesses potent CYP1A2 autoinductive properties in rats and may serve as a tool for mechanistic metabolism or drug-drug interaction studies encircling this enzyme in rats.
Assuntos
Benzodiazepinas/farmacologia , Citocromos/biossíntese , Moduladores GABAérgicos/farmacologia , Imidazóis/farmacologia , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinas/farmacocinética , Células Cultivadas , Condicionamento Clássico/efeitos dos fármacos , Citocromo P-450 CYP1A2 , Medo/efeitos dos fármacos , Moduladores GABAérgicos/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacocinética , Masculino , RatosRESUMO
As affective and cognitive disturbances frequently co-occur in psychiatric disorders, research into opportunities to simultaneously target both entities is warranted. These disorders are typically treated with monoamine reuptake inhibitors (MRIs), whereas ongoing research suggests that symptoms also improve by nicotinic acetylcholine receptor (nAChR) activation. Preclinical studies have corroborated this and also demonstrated a synergistic antidepressant-like action when nAChR agonists and MRIs are combined. Here, we present the in vitro and in vivo profile of NS9775, a combined full α7 nAChR agonist and triple MRI. NS9775 potently inhibited [(3)H]α-bungarotoxin binding in vitro (Ki: 1.8 nM), and ex vivo (ED50: 3.6 mg/kg), showing negligible activity at α4ß2-(Ki: 1720 nM) or α1-containing nAChRs (Ki: 12,200 nM). In α7-expressing oocytes, NS9775 displayed an EC50 value of 280 nM, with a maximal response of 77% relative to a saturating acetylcholine concentration. Furthermore, NS9775 inhibited cortical [(3)H]5-HT, [(3)H]NA and [(3)H]DA uptake equipotently (14-43 nM), and inhibited striatal [(3)H]WIN35,428 binding (ED50: 9.1 mg/kg). Behaviourally in mice, NS9775 (0.3-3.0 mg/kg) reversed scopolamine-induced deficits in a modified Y-maze and MK-801-induced learning deficits in 5-trial inhibitory avoidance. Swim distance in the forced swim test was increased by 30 mg/kg NS9775, and 10 and 30 mg/kg NS9775 reduced digging behaviour in the marble burying paradigm and increased the number of punished crossings in the four plate test. This pro-cognitive, antidepressant-like and anxiolytic-like effect of NS9775 suggests that combining α7 nAChR agonism and triple monoamine reuptake inhibition could be a step in the evolution of pharmacological treatments of affective and/or cognitive disturbances.
Assuntos
Sintomas Afetivos/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Naftalenos/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Bungarotoxinas , Transtornos Cognitivos/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Naftalenos/uso terapêutico , Punição , Ensaio Radioligante , Cintilografia , TrítioRESUMO
Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED(50) to displace [³H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [³H]5-HT uptake, SSR180711 inhibited [³H]5-HT uptake with an ED50 of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.
Assuntos
Antidepressivos/uso terapêutico , Benzamidas/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos com Pontes/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/química , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Animais , Antidepressivos/administração & dosagem , Antidepressivos/metabolismo , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Benzamidas/metabolismo , Benzamidas/farmacocinética , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/metabolismo , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Endogâmicos , Terapia de Alvo Molecular , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Receptores Nicotínicos/administração & dosagem , Receptores Nicotínicos/metabolismo , Serotonina/metabolismo , Distribuição Tecidual , Receptor Nicotínico de Acetilcolina alfa7RESUMO
RATIONALE: A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals. OBJECTIVES: The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively. RESULTS: In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABA(A) α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats. CONCLUSIONS: Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.
Assuntos
Benzodiazepinas/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Imidazóis/farmacologia , Fenciclidina/toxicidade , Receptores de GABA-A/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Células CHO , Estimulantes do Sistema Nervoso Central/farmacologia , Transtornos Cognitivos/induzido quimicamente , Cricetinae , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipercinese/induzido quimicamente , Masculino , Oócitos , Parvalbuminas/metabolismo , Fenciclidina/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Xenopus laevisRESUMO
Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson's disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca(2+)-activated K(+) channels (SK channels), in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA signaling and DA-related behaviors. Here we show that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3 > SK2 > > > SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior.
RESUMO
Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Accordingly, nicotine enhances antidepressant-like actions of reuptake inhibitors selective for serotonin or noradrenaline in the mouse forced swim test and the mouse tail suspension test. Both high-affinity α4ß2 and low-affinity α7 nicotinic acetylcholine receptor subtypes are implicated in nicotine-mediated release of serotonin and noradrenaline. The present study therefore investigated whether selective agonism of α4ß2 or α7 nicotinic acetylcholine receptors would affect the mouse forced swim test activity of two antidepressants with distinct mechanisms of action, namely the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine. Subthreshold and threshold doses of citalopram (3 and 10 mg/kg) or reboxetine (10 and 20 mg/kg) were tested alone and in combination with the novel α4ß2-selective partial nicotinic acetylcholine receptor agonist, NS3956 (0.3 and 1.0 mg/kg) or the α7-selective nicotinic acetylcholine receptor agonist, PNU-282987 (10 and 30 mg/kg). Alone, NS3956 and PNU-282987 were devoid of activity in the mouse forced swim test, but both 1.0 mg/kg NS3956 and 30 mg/kg PNU-282987 enhanced the effect of citalopram and also reboxetine. The data suggest that the activity of citalopram and reboxetine in the mouse forced swim test can be enhanced by agonists at either α4ß2 or α7 nicotinic acetylcholine receptors, suggesting that both nicotinic acetylcholine receptor subtypes may be involved in the nicotine-enhanced action of antidepressants.
Assuntos
Antidepressivos/farmacologia , Azepinas/farmacologia , Citalopram/farmacologia , Morfolinas/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/fisiologia , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Feminino , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Reboxetina , Natação , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Phencyclidine (PCP) induces a behavioral syndrome in rodents that bears remarkable similarities to some of the core symptoms observed in schizophrenic patients, among those cognitive deficits. The successful alleviation of cognitive impairments associated with schizophrenia (CIAS) has become a major focus of research efforts as they remain largely untreated. The aim of the present study was to investigate the effects of selected antipsychotic and cognition enhancing drugs, namely haloperidol, risperidone, donepezil, and modafinil in an animal model widely used in preclinical schizophrenia research. To this end, the novel object recognition (NOR) task was applied to rats abstinent following sub-chronic treatment with PCP. Rats were administered either PCP (5 mg/kg, i.p.) or vehicle twice a day for 7 days, followed by a 7-day washout period, before testing in NOR. Upon testing, vehicle-treated rats successfully discriminated between novel and familiar objects, an effect abolished in rats that had previously been exposed to PCP treatment. Acute treatment with modafinil (64 mg/kg, p.o.) ameliorated the PCP-induced deficit in novel object exploration, whereas haloperidol (0.1 mg/kg, s.c.), risperidone (0.2 mg/kg, i.p.), and donepezil (3 mg/kg, p.o.) were without significant effect. Given the negligible efficacy of haloperidol and risperidone, and the contradictory data with donepezil to treat CIAS in the clinic, together with the promising preliminary pro-cognitive effects of modafinil in certain subsets of schizophrenic patients, the sub-chronic PCP-NOR abstinence paradigm may represent an attractive option for the identification of potential novel treatments for CIAS.
RESUMO
In an effort to investigate the potential antimanic-like activity of K(v)7 channel openers, we decided to test: (1) the subtype non-selective K(v)7 opener retigabine, (2) the K(v)7.4-K(v)7.5 (and K(v)7.5/3 heteromers) preferring channel opener BMS-204352 (Maxipost), and (3) the novel K(v)7.2/3 preferring channel opener ICA-27243, in the amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity paradigm in mice, a test often used to assess potential antimanic-like activity of novel compounds. Lithium and lamotrigine were included as positive controls. Pretreatment with lithium attenuated AMPH/CDP-induced hyperactivity, without affecting the activity of AMPH- or CDP-alone, and thus confirmed some predictive validity for the test paradigm. Pretreatment with lamotrigine significantly attenuated AMPH/CDP-induced effects, but also reduced motility when tested in the presence of CDP-alone. Pretreatment with retigabine or ICA-27243 attenuated AMPH/CDP-induced hyperactivity without affecting basal locomotor activity. In contrast, pretreatment with BMS-204352 failed to decrease AMPH/CDP-induced hyperactivity at lower doses (3 and 10 mg/kg). At higher doses BMS-204352 attenuated hyperactivity induced by the AMPH/CDP mix, but only at doses decreasing basal locomotor activity (30 and 60 mg/kg). None of the K(v)7 openers tested significantly affected AMPH-induced hyperactivity. In contrast, retigabine and ICA-27243 were shown to induce significant reductions in motility when administered in combination with CDP-alone. In conclusion, the results with lithium confirm some predictive validity for the test paradigm. However, our data highlight an important confounder for interpreting a role for K(v)7 channels in the alleviation of manic-like symptoms when employing the AMPH/CDP hyperactivity model in mice. It is imperative that relevant control studies (AMPH- and CDP-alone) be incorporated and reported routinely to enable thorough interpretation of data generated by means of this behavioural test.
Assuntos
Anticonvulsivantes/uso terapêutico , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/toxicidade , Hipercinese/tratamento farmacológico , Canais de Potássio KCNQ/agonistas , Anfetamina/toxicidade , Animais , Anticonvulsivantes/administração & dosagem , Antimaníacos/administração & dosagem , Benzamidas/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Carbamatos/uso terapêutico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Clordiazepóxido/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipercinese/psicologia , Indóis/uso terapêutico , Injeções Intraperitoneais , Canais de Potássio KCNQ/classificação , Lamotrigina , Compostos de Lítio/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fenilenodiaminas/uso terapêutico , Piridinas/uso terapêutico , Triazinas/uso terapêuticoRESUMO
Current literature suggests that nicotinic acetylcholine receptors (nAChRs) are involved in major depression. In rodents, antidepressant-like effects of both nicotine and the non-selective nAChR antagonist mecamylamine have been reported. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Thus, we hypothesise that nicotine may enhance the behavioural effects of serotonin (e.g., citalopram) and/or noradrenaline (e.g., reboxetine) reuptake inhibitors. Here, we tested if nicotine enhanced the activity of citalopram or reboxetine in the mouse forced swim test (mFST) and the mouse tail suspension test (mTST). The potential for mecamylamine to augment antidepressant drug action was also investigated. Sub-threshold and threshold doses of citalopram (3 and 10mg/kg) or reboxetine (3, 10 and 20mg/kg) were tested alone and in combination with nicotine (0.3 and 1.0mg/kg) and mecamylamine (1 and 3mg/kg). Locomotor activity experiments were performed to rule out non-specific stimulant effects. Nicotine (1.0mg/kg) enhanced the effect of 10mg/kg citalopram and 20mg/kg reboxetine in the mFST. Similarly, nicotine (1.0mg/kg) enhanced the effect of 3 and 10mg/kg citalopram and 3 and 10mg/kg reboxetine in the mTST. No concomitant locomotor stimulation was observed at the tested dose combinations. Mecamylamine was effective on its own in some tests, but did not augment the effects of citalopram or reboxetine at the doses tested. The data show that nicotine enhances the effects of both serotonin and noradrenaline reuptake inhibitors, possibly reflecting nicotine's facilitating effects on the release of these two neurotransmitters, and indicating that nicotine may enhance antidepressant action.