RESUMO
A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days' post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal-amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.
Assuntos
Quinolonas , Transtornos de Estresse Pós-Traumáticos , Animais , Modelos Animais de Doenças , Escitalopram , Medo , Camundongos , Quinolonas/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , TiofenosRESUMO
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.
Assuntos
Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dopamina/fisiologia , Serotonina/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Cognição/fisiologia , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Dopamina D2/fisiologia , Resultado do TratamentoRESUMO
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.
Assuntos
Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopamina/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Serotoninérgicos/química , Serotoninérgicos/metabolismo , Serotonina/metabolismo , Tiofenos/química , Tiofenos/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Humanos , Masculino , Ligação Proteica/fisiologia , Quinolonas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Tiofenos/farmacologiaRESUMO
Environmental stimuli repeatedly associated with the self-administered drugs may acquire motivational importance. Because dopamine (DA) D(2) /D(3) partial agonists and D(3) antagonists interfere with the ability of drug-associated cues to induce drug-seeking behaviour, the present study investigated whether bifeprunox, 7-[4-([1,1'biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone mesylate), a high-affinity partial agonist of the D(2) subfamily of DA receptors and of serotonin(1A) receptors, influences reinstatement of drug-associated cue-induced nicotine-seeking behaviour. The study also explored whether bifeprunox reduced motivated behaviour by evaluating its effects on reinstatement induced by stimuli conditioned to sucrose. To verify whether bifeprunox interferes with the primary reinforcing properties of either drug or sucrose, we compared its effects on nicotine self-administration and on sucrose-reinforced behaviour. Different groups of experimentally naïve, food-restricted Wistar rats were trained to associate a discriminative stimulus with response-contingent availability of nicotine or sucrose and tested for reinstatement after extinction of nicotine or sucrose-reinforced behaviour. Bifeprunox (4-16 µg/kg, s.c.) dose-dependently attenuated the response-reinstating effects of nicotine-associated cues. Higher doses (64-250 µg/kg, s.c.) reduced spontaneous locomotor activity and suppressed operant responding induced by sucrose-associated cues and by the primary reinforcing properties of nicotine or sucrose. Provided they can be extrapolated to abstinent human addicts, these results suggest the potential therapeutic use of partial DA D(2) receptor agonist to prevent cue-controlled nicotine-seeking and relapse. The profile of action of high doses of bifeprunox remains to be examined for potential sedation or anhedonia effects.
Assuntos
Benzoxazóis/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Comportamento de Procura de Droga/efeitos dos fármacos , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Tabagismo/tratamento farmacológico , Tabagismo/economia , Análise de Variância , Animais , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Nicotina/administração & dosagem , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Recidiva , Reforço Psicológico , Autoadministração , Sacarose/administração & dosagemRESUMO
BACKGROUND: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS: DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Antagonistas dos Receptores de Dopamina D2/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Mania/tratamento farmacológico , Animais , Antipsicóticos/administração & dosagem , Dibenzocicloeptenos/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Feminino , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Risperidona/farmacologiaRESUMO
The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.
Assuntos
Benzilaminas/química , Benzilaminas/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Indóis/química , Indóis/uso terapêutico , Fenciclidina/toxicidade , Receptores de Serotonina/metabolismo , Reconhecimento Psicológico/fisiologia , Antagonistas da Serotonina/uso terapêutico , Animais , Benzilaminas/metabolismo , Células Cultivadas , Transtornos Cognitivos/induzido quimicamente , Cricetinae , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/metabolismo , Masculino , Fenciclidina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismoRESUMO
The study explored effects of brexpiprazole (partial D2/5-HT1A agonist, 5-HT2A and α1B/2C-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0mg/kg, PO), escitalopram (5.0mg/kg, IP) and their combination were administered twice daily for 14 days, starting 14 days after exposure to PSS or sham-PSS, shortly after a situational stress reminder. One day after last treatment behavioral responsivity was assessed. Brexpiprazole+escitalopram-treated rats spent more time in open arms, entered open arms more often and exhibited a lower anxiety index in the elevated plus maze than vehicle-treated, PSS-exposed rats. Adjunct brexpiprazole+escitalopram treatment reduced startle amplitude, compared with vehicle-treated, PSS-exposed rats. Treatment with either drug alone did not attenuate anxiety-like behaviors following PSS exposure. Use of cut-off behavioral criteria confirmed that adjunct treatment shifted prevalence of PSS-exposed rats from extreme towards minimal behavioral responders. One day following behavioral tests, brains were prepared for immunohistochemical analysis of number of BDNF-positive cells and of NPY-positive cells/fibers. PSS exposure decreased BDNF levels in hippocampus, but this was not affected by drug treatments. PSS exposure decreased number of NPY positive cells/fibers in paraventricular and arcuate nuclei of hypothalamus. Adjunct treatment with brexpiprazole+escitalopram increased NPY in PSS- and sham-exposed rats. Treatment with brexpiprazole alone had no effects, while treatment with escitalopram alone increased NPY in the arcuate nucleus of PSS-exposed rats. In conclusion, treatment with brexpiprazole+escitalopram may be an effective intervention for the attenuation of PTSD-like stress responses, which in part may be mediated by activating NPY function.
Assuntos
Citalopram/farmacologia , Neuropeptídeo Y/metabolismo , Peptídeos Cíclicos/farmacologia , Quinolonas/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Tiofenos/farmacologia , Adrenérgicos/farmacologia , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Odorantes , Comportamento Predatório , Distribuição Aleatória , Ratos Sprague-Dawley , Serotoninérgicos/farmacologia , Transtornos de Estresse Pós-Traumáticos/patologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologiaRESUMO
RATIONALE: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life. OBJECTIVE: In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze. RESULTS: The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved. CONCLUSION: These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.
Assuntos
Antipsicóticos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Clozapina/uso terapêutico , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Haloperidol/uso terapêutico , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Masculino , Fenciclidina , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Risperidona/uso terapêutico , Psicologia do EsquizofrênicoRESUMO
The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.
Assuntos
Di-Hidropiridinas/farmacologia , Indóis/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D4/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1 , Animais , Animais não Endogâmicos , Benzodiazepinas/farmacologia , Cebus , Citalopram/farmacologia , Clozapina/farmacologia , Cognição/efeitos dos fármacos , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Haloperidol/farmacologia , Haplorrinos , Humanos , Indóis/química , Masculino , Camundongos , Estrutura Molecular , Olanzapina , Piperazinas/química , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Risperidona/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Sulfonamidas/farmacologiaRESUMO
Previous studies have shown that partial and full 5-HT1A receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D2 antagonism or partial agonism and 5-HT1A receptor agonism have a low propensity to induce extrapyramidal side effects (EPS), as reflected by low cataleptogenic activity in rodents. In the present experiments, we attempted to explore the importance of pre- and postsynaptic 5-HT1A agonistic properties of brexpiprazole and aripiprazole in the context of neurological side-effect liabilities. Additional measures of prefrontal cortical serotonin (5-HT) and DA levels using microdialysis were used to support that brexpiprazole has a preferential agonist effect on presynaptic 5-HT1A receptors. Brexpiprazole (3.0 and 10mg/kg, p.o.) as well as aripiprazole (8.0 and 30mg/kg, p.o.) failed to induce catalepsy in rats. Brexpiprazole (10mg/kg, p.o.) significantly reduced the cataleptic response induced by haloperidol (0.63mg/kg, s.c.), while aripiprazole (1.0-100mg/kg, p.o.) failed to reverse the effect of haloperidol and only showed a numeric decrease at 10mg/kg, (p.o.). When 5-HT1A receptors were blocked by the selective antagonist, WAY100635 (1.0mg/kg, s.c.), cataleptogenic properties of brexpiprazole (10mg/kg; p.o), but not aripiprazole (8.0 and 30mg/kg, p.o.) were unmasked. The ("biased") 5-HT1A receptor agonists F15599 (postsynaptic preference) and F13714 (presynaptic preference) had differential effects on haloperidol-induced catalepsy: F13714 (0.16mg/kg, s.c.) counteracted catalepsy, whereas F15599 (0.040mg/kg, s.c.) had no significant effect at regionally-selective doses. These data support a role of presynaptic 5-HT1A receptors in the anticataleptic effect of brexpiprazole. The selective 5-HT2A antagonist M100907 (0.10mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT2A receptors in the cataleptogenic profile of brexpiprazole. The findings with brexpiprazole were supported using microdialysis studies: Brexpiprazole (3.0 and 10mg/kg, p.o.) decreased extracellular 5-HT levels in the medial prefrontal cortex (mPFC), while it failed to affect extracellular DA in the same samples, suggesting that the 5-HT1A agonist properties of brexpiprazole may be preferentially presynaptic. In conclusion, these results confirm that brexpiprazole and aripiprazole have low propensities to induce EPS. However, the low EPS risk of brexpiprazole is more likely dependent on its agonist properties on presynaptic 5-HT1A receptors, while that of aripiprazole is less sensitive to 5-HT1A receptor antagonism.
Assuntos
Doenças dos Gânglios da Base/induzido quimicamente , Quinolonas/toxicidade , Receptor 5-HT1A de Serotonina/fisiologia , Tiofenos/toxicidade , Animais , Aripiprazol/toxicidade , Catalepsia/induzido quimicamente , Dopamina/análise , Haloperidol/farmacologia , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/análiseRESUMO
RATIONALE: Bipolar disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient's quality of life, better treatments are needed. OBJECTIVES: Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3 and 5-HT1A receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania. METHODS: The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the behavioral pattern monitor (BPM) and Iowa gambling task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively. RESULTS: DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice. CONCLUSIONS: Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model.
Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/psicologia , Comportamento de Escolha/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Quinolonas/farmacologia , Assunção de Riscos , Serotoninérgicos/farmacologia , Tiofenos/farmacologia , Animais , Transtorno Bipolar/genética , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptor 5-HT1A de SerotoninaRESUMO
Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at α1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.
Assuntos
Antipsicóticos/farmacologia , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Quinolonas/farmacologia , Núcleos Talâmicos/efeitos dos fármacos , Tiofenos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Ondas Encefálicas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Análise de Fourier , Masculino , Vias Neurais/fisiologia , Fenciclidina/farmacologia , Piperazinas/farmacologia , Córtex Pré-Frontal/citologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Núcleos Talâmicos/citologiaRESUMO
AIM: Asenapine is a new atypical antipsychotic prescribed for the treatment of psychosis/bipolar disorders that presents higher affinity for serotonergic than dopaminergic receptors. The objective of this study was to investigate its antidepressant-like and antimanic-like properties on relevant animal models of depression and mania and to assess the acute and chronic effect of Asenapine on dorsal raphe nucleus (DRN) 5-HT cell firing activity. METHODS: We assessed the effects of Asenapine using in vivo electrophysiological and behavioral assays in rats. RESULTS: Behavioral experiments showed that Asenapine had no significant effect on immobility time in the forced swim test (FST) in control rats. In the ACTH-treated rats, a model of antidepressant-resistance, Asenapine failed to alter immobility time in the FST. In contrast in the sleep deprivation (SD) model of mania, acute administration of Asenapine significantly decreased the hyperlocomotion of SD rats. In the DRN, acute administration of Asenapine reduced the suppressant effect of the selective 5-HT7 receptor agonist LP-44 and of the prototypical 5-HT1A receptor agonist 8-OH-DPAT on 5-HT neuronal firing activity. In addition, chronic treatment with Asenapine enhanced DRN 5-HT neuronal firing and this effect was associated with an alteration of the 5-HT7 receptor responsiveness. CONCLUSION: These results confirm that Asenapine displays robust antimanic property and effective in vivo antagonistic activity at 5-HT1A/7 receptors.
Assuntos
Afeto/efeitos dos fármacos , Antipsicóticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Hormônio Adrenocorticotrópico/farmacologia , Afeto/fisiologia , Animais , Dexmedetomidina/farmacologia , Dibenzocicloeptenos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Núcleos Septais/citologia , Serotoninérgicos/farmacologia , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismo , Natação/psicologiaRESUMO
Cognitive deficits in schizophrenia are associated with poor functional outcome, and may be further aggravated by treatment with antipsychotics. In the present study the acute and chronic (3 weeks of treatment) effects of clozapine, olanzapine, and sertindole on performance in the Morris water maze in rats was compared, using pharmacologically and/or clinically relevant dose regimens. An experimental design consisting of three trials/day over 3 days was used. Performance was expressed as the distance and latency to find a submerged platform, as well as the percentage of "non-finders", i.e. percentage of trials where the rat was unable to find the platform within the total trial time of 60 s. Clozapine (40 mg/kg, p.o.) and olanzapine (2.5 mg/kg, s.c.) impaired water maze performance when given acutely. However, tolerance developed to the deficit induced by clozapine, whereas the olanzapine-mediated impairment was enhanced after chronic treatment. Sertindole (2.5 mg/kg, p.o.) had no disruptive effect on performance after either acute or chronic treatment. Exposure measurements confirmed that all three compounds were present in the serum at least at clinically effective concentrations. Thus, the three antipsychotics tested differentially affected rodent cognition, whereby sertindole appeared to have a lower potential than either clozapine or olanzapine to induce cognitive impairment. The hypothesis that the low potency of sertindole in inducing dopamine D2 receptor blockade, combined with lack of antimuscarinic and histamine H1 antagonist activity in vivo is discussed. Clearly further studies are needed to assess the potential cognition-enhancing effects of sertindole vs. other antipsychotics in a relevant animal model of schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Análise de Variância , Animais , Antipsicóticos/sangue , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/sangue , Benzodiazepinas/farmacologia , Clozapina/sangue , Clozapina/farmacologia , Relação Dose-Resposta a Droga , Imidazóis/sangue , Imidazóis/farmacologia , Indóis/sangue , Indóis/farmacologia , Masculino , Olanzapina , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Antipsychotic drugs given acutely increase the threshold for intracranial self-stimulation elicited from the ventral tegmental area. As all the antipsychotic drugs share the dopamine D2-receptor antagonism it is reasonable to believe that this is the cause for suppression of intracranial self-stimulation behaviour. The objective of this investigation was to examine the effect of classical (haloperidol) as well as novel antipsychotic drugs (clozapine, olanzapine and sertindole) on intracranial self-stimulation behaviour. Furthermore, the effects of different specific receptor antagonists on intracranial self-stimulation behaviour were examined. Our results showed that both the classical (haloperidol) and the three novel antipsychotic drugs increase the threshold for intracranial self-stimulation. The results obtained with the receptor specific antagonists showed that dopamine D2, alpha1-adrenoceptor and serotonin 5-HT2A receptor antagonisms inhibit intracranial self-stimulation behaviour and that muscarinic receptor antagonism is without effect. Even though all the tested antipsychotic drugs inhibited intracranial self-stimulation behaviour, there seems to be a difference in their ratio between doses that inhibits intracranial self-stimulation behaviour and those that produce antipsychotic effect in a preclinical model (amphetamine hyperactivity). Sertindole was the only antipsychotic drug able to produce antipsychotic effect without significant inhibition of intracranial self-stimulation behaviour at a narrow dose interval. The remaining antipsychotic drugs all inhibited intracranial self-stimulation behaviour at equal or lower doses than those producing antipsychotic effect.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Motivação , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , AutoestimulaçãoRESUMO
The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.
Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D4/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Animais , Fluorbenzenos/administração & dosagem , Generalização Psicológica/efeitos dos fármacos , Indóis/administração & dosagem , Masculino , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Prazosina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D4/antagonistas & inibidores , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagemRESUMO
The enhancement of central serotonin system function underlies the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs), which have become the most commonly used class of antidepressant agents. However, many individuals experience depressive episodes that are resistant to SSRI treatment. Homeostatic mechanisms that limit the extent to which SSRIs enhance serotonergic neurotransmission have been implicated in this phenomenon. Here, we report a novel strategy for enhancing the efficacy of SSRIs. Using in vivo microdialysis methods in rats, the nonselective 5-HT2 receptor antagonist ketanserin was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular serotonin levels. Similar effects were also observed in cortex. The potentiation of SSRI-induced increases in hippocampal serotonin levels was reproduced by the 5-HT(2C) receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT(2A) receptor-selective antagonist MDL 100 907. Although 5-HT(2C) receptor antagonists augmented the actions of SSRIs, they had no effect on extracellular serotonin levels or tail suspension responses when administered alone. These results were in strong accord with independent findings using a line of 5-HT(2C) receptor-null mutant mice. Although this mutation did not affect baseline extracellular serotonin levels or tail suspension test (TST) behavior, it enhanced fluoxetine effects on serotonin levels and immobility in the TST. These findings reveal an unanticipated pharmacological action of 5-HT(2C) receptors that warrants consideration in the development of novel strategies for the treatment of depression.
Assuntos
Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Elevação dos Membros Posteriores/fisiologia , Ketanserina/farmacologia , Masculino , Microdiálise , Ratos , Ratos Wistar , Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
The synthesis and resolution of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin (6-methoxymianserin, 6) are described. Furthermore, the in vitro and in vivo effects of 6 and its enantiomers are presented. 6 displayed high affinity for the 5-HT2A/2C receptors, only moderate affinity for the adrenoceptors, and no affinity for the NA reuptake site. Surprisingly, 6 also showed moderate to high affinity for the dopamine D2 receptor, an effect that resides in the (R)-(-)-enantiomer.
Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacologia , Mianserina/análogos & derivados , Mianserina/síntese química , Mianserina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Antidepressivos/química , Sítios de Ligação , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Técnicas In Vitro , Masculino , Mianserina/química , Microdiálise , Mirtazapina , Norepinefrina/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Although acute neurotensin receptor stimulation exerts diverse behavioural effects that resemble those seen after administration of antipsychotic drugs, data on effects after repeated exposure to neurotensin receptor agonism is relatively sparse. Here, we demonstrate that repeated administration of the novel neurotensin-(8-13) analogue NT69L [(N-methyl-Arg), Lys, Pro, L-neo-Trp, tert-Leu, Leu] induce tolerance to its suppressant effect on conditioned avoidance behaviour in rats, a predictive assay for antipsychotic activity. In contrast, the inhibitory effect of haloperidol on this behaviour was sustained despite repeated administration of this classical antipsychotic drug. These findings indicate that repeated exposure to neurotensin receptor stimulation induces tolerance to the antipsychotic-like effects of neurotensin receptor agonists.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Tolerância a Medicamentos , Neurotensina/análogos & derivados , Neurotensina/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Antipsicóticos/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The serotonin6 (5-HT(6)) receptor has received attention for its proposed role in cognitive impairments associated with schizophrenia and Alzheimer's disease. This has lead to a search for selective 5-HT(6) receptor ligands useful for in vivo imaging in animals and humans. The novel 5-HT(6) receptor antagonist Lu AE60157 (8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) displays high affinity for the human (h) 5-HT(6) receptor (K(d) 0.2nM), and broad profiling in 60 additional binding and enzyme assays showed that Lu AE60157 displays 16-fold selectivity to the h5-HT(2A) receptor (K(i) 3.2nM) and >100-fold selectivity to all other evaluated targets. Lu AE60157 was labeled with tritium in the N-methyl group and evaluated as a radioligand in vitro as well as in vivo in rats and mice. Autoradiography experiments showed that [(3)H]Lu AE60157 bound preferentially to rat brain regions with expected high 5-HT(6) receptor density. Furthermore, [(3)H]Lu AE60157 showed good brain penetration after systemic administration and high (about 75%) specific in vivo binding to the striatal 5-HT(6) receptor in rats. The striatal binding of [(3)H]Lu AE60157 was fully displaced by selective 5-HT(6) receptor antagonists (SB-742457; Lu AE58054) and antipsychotics known to inhibit the binding of 5-HT(6) receptors in vitro (clozapine; olanzapine; sertindole), but was not displaced by antipsychotics lacking high 5-HT(6) receptor affinities (risperidone; haloperidol; quetiapine). No specific binding to mouse brain tissue in vivo could be obtained. In conclusion, [(3)H]Lu AE60157 is suitable for measuring in vivo occupancies of 5-HT(6) receptor ligands in rat brain regions in which 5-HT(2A) receptors do not interfere.