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BACKGROUND: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. AIMS: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. METHODS: We used data from two dose-response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. RESULTS: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. CONCLUSIONS: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal.
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Antipsicóticos , Trastornos Psicóticos , Humanos , Antipsicóticos/efectos adversos , Trastornos Psicóticos/tratamiento farmacológicoRESUMEN
BACKGROUND: Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual's genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual's genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants ('CYP2D6-PGx antipsychotics'). AIMS: This study aims to investigate differences between demographic groups prescribed 'CYP2D6-PGx antipsychotics' and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance. METHODS: A cross-sectional study took place extracting data from 243 patients' medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of 'CYP2D6-PGx antipsychotic' prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of 'CYP2D6-PGx antipsychotic' versus 'non-CYP2D6-PGx antipsychotic'. RESULTS: Two-thirds (164) of patients had been prescribed a 'CYP2D6-PGx antipsychotic' (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a 'CYP2D6-PGx antipsychotic'. CONCLUSIONS: This study demonstrated high rates of prescribing 'CYP2D6-PGx-antipsychotics' in an EIP cohort, providing a rationale for further exploration of how PGx testing can be implemented in EIP services to personalise the prescribing of drugs for psychosis.
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Antipsicóticos , Psicosis Inducidas por Sustancias , Trastornos Psicóticos , Humanos , Antipsicóticos/uso terapéutico , Farmacogenética , Citocromo P-450 CYP2D6/genética , Estudios Transversales , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Psicosis Inducidas por Sustancias/tratamiento farmacológicoRESUMEN
Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.
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In many species, seasonal changes in day length (photoperiod) have profound effects on physiology and behavior. In humans, these include cognitive function and mood. Here we investigated the effect of photoperiod and high fat diets on cognitive deficits, as measured by novel object recognition, in the photoperiod-sensitive F344 rat, which exhibits marked natural changes in growth, body weight and food intake in response to photoperiod. 32 male juvenile F344 rats were housed in either long or short photoperiod and fed either a high fat or nutrient-matched chow diet. Rats were tested in the novel object recognition test before photoperiod and diet intervention and re-tested 28 days after intervention. In both tests during the acquisition trials there was no significant difference in exploration levels of the left and right objects in the groups. Before intervention, all groups showed a significant increase in exploration of the novel object compared to the familiar object. However, following the photoperiod and diet interventions the retention trial revealed that only rats in the long photoperiod-chow group explored the novel object significantly more than the familiar object, whereas all other groups showed no significant preference. These results suggest that changing rats to short photoperiod impairs their memory regardless of diet. The cognitive performance of rats on long photoperiod-chow remained intact, whereas the high fat diet in the long photoperiod group induced a memory impairment. In conclusion, our study suggests that photoperiod and high fat diet have an impact on object recognition in photoperiod-sensitive F344 rats.
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Dieta Alta en Grasa , Fotoperiodo , Animales , Peso Corporal , Cognición , Dieta Alta en Grasa/efectos adversos , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
In psychiatry, the selection of antipsychotics and antidepressants is generally led by a trial-and-error approach. The prescribing of these medications is complicated by sub-optimal efficacy and high rates of adverse drug reactions (ADRs). These both contribute to poor levels of adherence. Pharmacogenetics (PGx) considers how genetic variation can influence an individual's response to a drug. Pharmacogenetic testing is a tool that could aid clinicians when selecting psychotropic medications, as part of a more personalized approach to prescribing. This may improve the use of and adherence to these medications. Yet to date, the implementation of PGx in mental health environments in the United Kingdom has been slow. This review aims to identify the current barriers and enablers to the implementation of PGx in psychiatry and determine how this can be applied to the uptake of PGx by NHS mental health providers. A systematic searching strategy was developed, and searches were carried out on the PsychInfo, EmBase, and PubMed databases, yielding 11 appropriate papers. Common barriers to the implementation of PGx included cost, concerns over incorporation into current workflow and a lack of knowledge about PGx; whilst frequent enablers included optimism that PGx could lead to precision medicine, reduce ADRs and become a more routine part of psychiatric clinical care. The uptake of PGx in psychiatric care settings in the NHS should consider and overcome these barriers, while looking to capitalize on the enablers identified in this review.
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RATIONALE: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. OBJECTIVE: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. METHODS: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. RESULTS: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). CONCLUSIONS: These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.
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Antipsicóticos/farmacología , Atención/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Fenciclidina/administración & dosificación , Disposición en Psicología , Animales , Clozapina/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Habituación Psicofisiológica/efectos de los fármacos , Haloperidol/farmacología , Proyectos Piloto , Ratas , Ratas Endogámicas , Risperidona/farmacología , Factores Sexuales , Estadísticas no ParamétricasRESUMEN
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-ß oligomers (Aßo). These small soluble Aßo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-ß1-42 oligomers (Aßo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aßo1-42 (10µL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1ß, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Aßo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aßo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.
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Péptidos beta-Amiloides/metabolismo , Cognición/fisiología , Inflamación/metabolismo , Trastornos de la Memoria/metabolismo , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Donepezilo/farmacología , Femenino , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Nootrópicos/farmacología , Distribución Aleatoria , Ratas , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Risperidona/farmacología , Rolipram/farmacología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
RATIONALE: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). METHODS: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for 7 days, followed by 7 days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. RESULTS: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial ( p < 0.01). scPCP produced a significant deficit in NOR ( p < 0.05 vs. control) and no PFC dopamine increase was observed. CONCLUSIONS: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.
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Cognición/fisiología , Disfunción Cognitiva/metabolismo , Dopamina/metabolismo , Corteza Prefrontal/metabolismo , Esquizofrenia/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Femenino , Fenciclidina/farmacología , Corteza Prefrontal/fisiopatología , Ratas , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Esquizofrenia/fisiopatologíaRESUMEN
Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4ß2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female Hooded Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.
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Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Recuerdo Mental/efectos de los fármacos , Nicotina/análogos & derivados , Agonistas Nicotínicos/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Inhibidores de la Colinesterasa/farmacología , Donepezilo , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Indanos/farmacología , Locomoción/efectos de los fármacos , Nicotina/farmacología , Piperidinas/farmacología , Ratas , Retención en Psicología/efectos de los fármacos , Risperidona/farmacologíaRESUMEN
Nausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlled trials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity.
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Antieméticos/uso terapéutico , Haloperidol/uso terapéutico , Cuidados Paliativos/métodos , Vómitos/prevención & control , Antineoplásicos/efectos adversos , Humanos , Náusea/etiología , Náusea/prevención & control , Ondansetrón/uso terapéutico , Náusea y Vómito Posoperatorios/tratamiento farmacológico , Resultado del Tratamiento , Vómitos/etiologíaRESUMEN
The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days' washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.
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Trastornos del Conocimiento/tratamiento farmacológico , Isoxazoles/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Agonistas Nicotínicos/uso terapéutico , Fenciclidina/toxicidad , Compuestos de Fenilurea/uso terapéutico , Receptores Nicotínicos/química , Regulación Alostérica , Animales , Atención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/fisiopatología , Aprendizaje Discriminativo/efectos de los fármacos , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Semivida , Alucinógenos/administración & dosificación , Alucinógenos/toxicidad , Isoxazoles/metabolismo , Isoxazoles/farmacocinética , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacocinética , Síndromes de Neurotoxicidad/fisiopatología , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Fenciclidina/administración & dosificación , Compuestos de Fenilurea/metabolismo , Compuestos de Fenilurea/farmacocinética , Ratas , Ratas Endogámicas , Distribución Tisular , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
RATIONALE: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. AIM: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. METHODS: Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mg/kg; s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. RESULTS: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10mg/kg (P<0.01) and 20mg/kg (P<0.001), and in novel object recognition at 10mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). CONCLUSIONS: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.
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Benzamidas/uso terapéutico , Compuestos Bicíclicos con Puentes/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/toxicidad , Agonistas Nicotínicos/uso terapéutico , Fenciclidina/toxicidad , Receptores Nicotínicos/metabolismo , Esquizofrenia/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Benzamidas/administración & dosificación , Benzamidas/sangre , Benzamidas/farmacocinética , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/sangre , Compuestos Bicíclicos con Puentes/farmacocinética , Cognición/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/etiología , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Semivida , Aprendizaje/efectos de los fármacos , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/sangre , Agonistas Nicotínicos/farmacocinética , Distribución Aleatoria , Ratas , Aprendizaje Inverso/efectos de los fármacos , Taquifilaxis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Alucinógenos/farmacología , Fenciclidina/farmacología , Caracteres Sexuales , Animales , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Pruebas Neuropsicológicas , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas EndogámicasRESUMEN
BACKGROUND: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. METHODS: After operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5mg/kg i.p.) or subchronically with PCP (2mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. RESULTS: Deficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments. CONCLUSION: These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.
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Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Alucinógenos/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Aprendizaje Inverso/efectos de los fármacos , Risperidona/farmacología , Animales , Dextroanfetamina/antagonistas & inhibidores , Dextroanfetamina/farmacología , Dibenzocicloheptenos , Esquema de Medicación , Femenino , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Olanzapina , Fenciclidina/administración & dosificación , Fenciclidina/antagonistas & inhibidores , Fenciclidina/farmacología , Ratas , Ratas EndogámicasRESUMEN
Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia.
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Trastornos del Conocimiento , Modelos Animales de Enfermedad , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/farmacología , Atención/efectos de los fármacos , Trastornos del Conocimiento/metabolismo , Femenino , Humanos , Masculino , Ratas , Tiempo de Reacción/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Reconocimiento en Psicología , Aprendizaje Inverso/efectos de los fármacos , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Conducta SocialRESUMEN
Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D(1)-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P<0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D(1)-like receptor antagonist (P<0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P<0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P<0.05). These results suggest a role for D(1)-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.
Asunto(s)
Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Fenciclidina , Receptores de Dopamina D1/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/uso terapéutico , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Pruebas Neuropsicológicas , Receptores de Dopamina D1/agonistasRESUMEN
RATIONALE: 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. AIM: The aim of this study was to investigate the involvement of 5-HT receptor mechanisms in sub-chronic phencyclidine (PCP)-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. METHODS: Adult female hooded Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle intraperitoneally (i.p.) twice daily for 7 days, followed by 7-day washout. Rats then received an acute dose of the 5-HT(7) receptor antagonist SB-269970A (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT(2C) receptor antagonist, SB-243213A acutely (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT(1A) receptor partial agonist, buspirone (0.15625, 0.3125, and 0.625 mg/kg, i.p.) in combination with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.3 and 1.0 mg/kg). RESULTS: In all experiments, sub-chronic PCP significantly impaired reversal phase performance (P < 0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P < 0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P < 0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 and 0.625 mg/kg (P < 0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone's effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. CONCLUSIONS: These studies implicate the role of 5-HT(7), 5-HT(2C), and 5-HT(1A) receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.