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1.
Eur J Neurosci ; 45(2): 217-231, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27469080

RESUMO

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.


Assuntos
Benzilaminas/farmacologia , Inibidores da Colinesterase/farmacologia , Indanos/farmacologia , Indóis/farmacologia , Doença de Parkinson/tratamento farmacológico , Piperidinas/farmacologia , Receptores de Serotonina/metabolismo , Animais , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Donepezila , Dopamina/metabolismo , Feminino , Marcha/efeitos dos fármacos , Masculino , Equilíbrio Postural/efeitos dos fármacos , Ratos Sprague-Dawley
2.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 2): 451-60, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24531479

RESUMO

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 Šresolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/química , Cumarínicos/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequenas/química , Proteínas Adaptadoras de Transporte Vesicular/genética , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Células HEK293 , Humanos , Leucina/química , Ligantes , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 24(1): 177-80, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24355129

RESUMO

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Piridinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade
4.
Transl Psychiatry ; 11(1): 74, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495438

RESUMO

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2-/- mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2-/- mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2-/- mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Dopamina , Camundongos , Proteínas do Tecido Nervoso , Receptores de Superfície Celular , Receptores Dopaminérgicos , Recompensa , Área Tegmentar Ventral
5.
Psychopharmacology (Berl) ; 237(1): 289, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650233

RESUMO

After publication of this paper, the authors determined that the "Acknowledgments" section was omitted. Below is the "Acknowledgments" statement.

6.
Psychopharmacology (Berl) ; 236(6): 1701-1715, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30607479

RESUMO

RATIONALE: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT6 receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods. OBJECTIVES: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine. RESULTS: As before, vehicle-treated DL rats fell more frequently, committed more slips, and exhibited more movement stoppages than intact control rats. Repeated intermittent administration of rivastigmine and idalopirdine significantly improved the performance of DL rats. Rivastigmine alone also produced strong trends for reducing falls and slips. The combination treatment was more effective than rivastigmine alone in reducing stoppages and stoppage-associated falls. As before, idalopirdine treatment alone was ineffective. CONCLUSIONS: These results extend the prediction that the combined treatment with idalopirdine and an AChEI improves complex movement control and reduces the propensity for falls in patients with movement disorders. Because of the importance of finding better treatments for gait and balance deficits in PD, the present results may further motivate a clinical exploration of the usefulness of this combination treatment.


Assuntos
Acidentes por Quedas/prevenção & controle , Benzilaminas/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Indóis/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Rivastigmina/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Animais , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Masculino , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley
7.
Eur J Pharmacol ; 585(2-3): 473-82, 2008 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-18417120

RESUMO

Hormone pharmacology has been quite interesting in The Netherlands the past century and this contribution is dedicated to the glucocorticoid hormones underlying adaptation to stress. The story starts in 1936 with Tadeus Reichstein and Ernst Laqueur who discovered corticosterone at the time Hans Selye formulated the stress concept. Today highly sophisticated technologies help to unravel the action mechanism of the glucocorticoids from gene to behaviour. In today's concept glucocorticoids coordinate in concert with other stress mediators the initial stress reactions with the management of later adaptations. Glucocorticoids modulate early life programming of stress reactivity and are a significant factor in brain plasticity underlying adaptation, the aging process and vulnerability to disease. Here we focus on the role of glucocorticoids in emotions, cognitive performance and behavioural sensitisation to cocaine.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cognição/fisiologia , Emoções/fisiologia , Glucocorticoides/fisiologia , Corticosteroides/fisiologia , Animais , Comportamento/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cognição/efeitos dos fármacos , Emoções/efeitos dos fármacos , Glucocorticoides/metabolismo , Humanos , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/fisiologia , Estresse Psicológico/metabolismo
8.
Physiol Rep ; 6(23): e13920, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30548427

RESUMO

In tauopathies, such as Alzheimer's disease with or without concomitant amyloid ß plaques, cerebral arteries display pathological remodeling, leading to reduced brain tissue oxygenation and cognitive impairment. The precise mechanisms that underlie this vascular dysfunction remain unclear. Kv7 voltage-dependent K+ channels contribute to the development of myogenic tone in rat cerebral arteries. Thus, we hypothesized that Kv7 channel function would be impaired in the cerebral arteries of a tauopathy mouse model (rTg4510), which might underlie cerebral hypoperfusion associated with the development of neurofibrillary tangles in tauopathies. To test our hypothesis we performed wire myography and quantitative PCR on cerebral arteries, mesenteric arteries and the inferior frontotemporal region of the brain surrounding the middle cerebral artery from tau transgenic mice (rTg4510) and aged-matched controls. We also performed whole-cell patch clamp experiments on HEK293 cells stably expressing Kv7.4. Here, we show that Kv7 channels are functionally impaired in the cerebral arteries of rTg4510 mice, but not in mesenteric arteries from the same mice. The quantitative PCR analysis of the cerebral arteries found no change in the expression of the genes encoding the Kv7 channel α-subunits, however, we found reduced expression of the ancillary subunit, KCNE5 (also termed KCNE1L), in the cerebral arteries of rTg4510 mice. In the brain, rTg4510 mice showed reduced expression of Kv7.3, Kv7.5, and Kv2.1. Co-expression of KCNE5 with Kv7.4 in HEK293 cells produced larger currents at voltages >0 mV and increased the deactivation time for the Kv7.4 channel. Thus, our results demonstrate that Kv7 channel function is attenuated in the cerebral arteries of Tg4510 mice, which may result from decreased KCNE5 expression. Reduced Kv7 channel function might contribute to cerebral hypoperfusion in tauopathies, such as Alzheimer's disease.


Assuntos
Artérias Cerebrais/metabolismo , Canais de Potássio KCNQ/metabolismo , Tauopatias/metabolismo , Potenciais de Ação , Animais , Artérias Cerebrais/fisiopatologia , Células HEK293 , Humanos , Canais de Potássio KCNQ/genética , Masculino , Camundongos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo
9.
Behav Brain Res ; 177(2): 329-39, 2007 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-17150264

RESUMO

The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy ('ADX': surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals. ADX and SHAM operated mice were subjected to repeated injections of cocaine (15.0mg/kg) or saline for nine consecutive days, followed by a 5-day withdrawal interval and a saline challenge on day 14. All animals were challenged with 7.5mg/kg cocaine on day 15. We report that repeated cocaine exposure induced locomotor sensitisation in both strains, while endocrine sensitisation was only observed in the DBA/2 strain. By contrast, cocaine attenuated corticosterone responses in C57BL/6 mice throughout the sensitisation paradigm. We have therefore identified one strain, the DBA/2 strain, that displays parallel sensitisation of cocaine-induced locomotion and -corticosterone secretion. Most interestingly, ADX prevented locomotor sensitisation only in DBA/2 mice, suggesting that behavioural sensitisation depends on the integrity of adrenal function and on secretion of adrenal glucocorticoids in this strain. The present results demonstrate that adrenal stress hormones facilitate behavioural sensitisation to cocaine in a genotype-dependent manner and suggest that glucocorticoids contribute to strain differences in psychostimulant sensitivity.


Assuntos
Adrenalectomia/métodos , Transtornos Relacionados ao Uso de Cocaína/cirurgia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Hormônio Adrenocorticotrópico/sangue , Animais , Comportamento Animal/fisiologia , Peso Corporal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corticosterona/sangue , Relação Dose-Resposta a Droga , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Especificidade da Espécie , Fatores de Tempo
10.
Neuropharmacology ; 125: 50-63, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28711518

RESUMO

Antagonism of the 5-HT6 receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT6 receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT6 receptor antagonist idalopirdine (Lu AE58054). The 5-HT6 receptor is enriched in brain regions that mediate cognition, where expression predominates on glutamatergic and GABAergic neurons and subsets of GABAergic interneurons. It is proposed that 5-HT6 receptor antagonism modulates the balance between neuronal excitation (glutamate) and inhibition (GABA), which may have widespread implications for neurotransmission and neuronal activity. This is supported by preclinical studies showing that 5-HT6 receptor antagonists increase concentrations of multiple neurotransmitters, and strengthened by recent evidence that idalopirdine facilitates neuronal oscillations and contributes to the recruitment of several neuronal networks relevant in cognition. Some of these effects are observed with idalopirdine monotherapy, whereas others require concomitant treatment with an AChEI. Several hypotheses for the mechanism underlying the synergistic actions between 5-HT6 receptor antagonists and AChEIs are discussed. Collectively, the current evidence suggests that 5-HT6 receptor antagonism adds a unique, complementary mechanism of action to that of AChEIs. The facilitation of multiple neurotransmitters and neuronal activity in brain regions that mediate cognition, and the synergy with AChEIs, are proposed to mediate the procognitive effects of 5-HT6 receptor antagonists in AD patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Psicotrópicos/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Humanos
11.
Eur J Pharmacol ; 799: 1-6, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28188762

RESUMO

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6 receptor (Ki 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).


Assuntos
Acetilcolina/metabolismo , Benzilaminas/farmacologia , Monoaminas Biogênicas/metabolismo , Espaço Extracelular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Indóis/farmacologia , Córtex Pré-Frontal/citologia , Receptores de Serotonina/metabolismo , Animais , Espaço Extracelular/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia
12.
Front Pharmacol ; 8: 279, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28659792

RESUMO

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

13.
Neuropharmacology ; 113(Pt A): 45-59, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27647493

RESUMO

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil-treated AD patients.


Assuntos
Benzilaminas/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Lobo Frontal/fisiologia , Ritmo Gama/efeitos dos fármacos , Indanos/administração & dosagem , Indóis/administração & dosagem , Piperidinas/administração & dosagem , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/administração & dosagem , Fases do Sono/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Animais , Tronco Encefálico/fisiologia , Donepezila , Estimulação Elétrica , Eletroencefalografia , Lobo Frontal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Vigília/efeitos dos fármacos
14.
Neuropharmacology ; 51(3): 438-46, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16740279

RESUMO

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 microg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 microg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.


Assuntos
Apomorfina/farmacologia , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Inibição Neural/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Reflexo de Sobressalto/efeitos da radiação
15.
Neuropharmacology ; 107: 351-363, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27039041

RESUMO

The 5-HT6 receptor has emerged as a promising target for cognitive disorders and combining a 5-HT6 receptor antagonist with an acetylcholinesterase inhibitor (AChEI) represents a novel approach for the symptomatic treatment of Alzheimer's disease (AD). A recent phase 2 trial showed that the selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) improved cognition in patients with moderate AD on stable treatment with the AChEI donepezil. Here we investigated the effects of idalopirdine in combination with donepezil on hippocampal function using in vivo electrophysiology and microdialysis. Network oscillations in the hippocampus were recorded during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and hippocampal acetylcholine (ACh) levels were measured in the freely-moving rat. In addition, potential pharmacokinetic interactions between idalopirdine and donepezil were assessed. Idalopirdine alone did not affect hippocampal network oscillations or ACh levels. Donepezil (0.3 and 1.0 mg/kg i.v.) dose-dependently increased hippocampal theta and gamma power during nPO stimulation. Idalopirdine (2 mg/kg i.v.), administered 1 h prior to donepezil, potentiated the theta and gamma response to 0.3 mg/kg donepezil and prolonged the gamma response to 1 mg/kg donepezil. Donepezil (1.3 mg/kg s.c.) increased extracellular ACh levels in the hippocampus and this was further augmented by administration of idalopirdine (10 mg/kg p.o.) 2 h prior to donepezil. These effects could not be attributed to a pharmacokinetic interaction between the compounds. This study demonstrates that idalopirdine potentiates the effects of donepezil on two pharmacodynamic biomarkers associated with cognition, i.e. neuronal oscillations and extracellular ACh levels in the hippocampus. Such potentiation could contribute to the procognitive effects of idalopirdine observed in donepezil-treated AD patients.


Assuntos
Acetilcolina/metabolismo , Benzilaminas/administração & dosagem , Ondas Encefálicas/fisiologia , Inibidores da Colinesterase/administração & dosagem , Hipocampo/metabolismo , Indóis/administração & dosagem , Receptores de Serotonina/metabolismo , Animais , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/fisiologia , Ondas Encefálicas/efeitos dos fármacos , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia
16.
J Alzheimers Dis ; 49(3): 783-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26519432

RESUMO

Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.


Assuntos
Hipercinese/etiologia , Agitação Psicomotora/etiologia , Tauopatias/complicações , Fatores Etários , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Doxiciclina/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Humanos , Hipercinese/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Mutação/genética , Agitação Psicomotora/prevenção & controle , Tauopatias/genética , Tauopatias/patologia , Fatores de Tempo , Proteínas tau/genética
17.
Brain Res Mol Brain Res ; 116(1-2): 17-26, 2003 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-12941457

RESUMO

The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR) mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes. Hence, an increased ratio of GRbeta to GRalpha may induce relative corticosteroid-resistance, as e.g. presumed to occur in major depression. To investigate whether GRbeta is involved in the human hippocampus, we studied GRalpha and GRbeta expression levels in postmortem hippocampal tissue of control subjects by quantitative PCR (Taqman RT-PCR) and immunocytochemistry. Taqman RT-PCR demonstrated a very low relative abundance of GRbeta in the human hippocampus (GRalpha:GRbeta ratio approximately 14,500:1). Immunohistochemical analysis confirmed the occurrence of isolated profiles indeed displaying nuclear staining in the main hippocampal subregions. Subsequent double immunofluorescent analysis revealed that >98% of these GRbeta positive cells were double positive for leucocyte common antigen, that identifies exclusively blood-derived cells of haematopoietic origin, including microglia. We conclude that GRbeta is present in very low amounts in the control human hippocampus, and that of these low numbers of cells, notably, almost all are derived from blood which is inevitably present in postmortem tissue. A functionally relevant role for the GRbeta in control of the human hippocampus is therefore not very likely. Whether this is altered in disease conditions awaits further research.


Assuntos
Hipocampo/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Glucocorticoides/metabolismo , Transcrição Gênica , Idoso , Northern Blotting , Contagem de Células , Núcleo Celular/genética , Núcleo Celular/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica/métodos , Leucócitos/metabolismo , Fígado/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Isoformas de Proteínas/genética , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/biossíntese , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Receptores de Superfície Celular/metabolismo , Receptores de Glucocorticoides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Taq Polimerase
18.
Ann N Y Acad Sci ; 1018: 192-8, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15240368

RESUMO

Glucocorticoid hormones can modulate the propensity of individuals to develop addictive behavior and, by doing so, contribute to the existence of individual differences in vulnerability to drugs. This article summarizes recent findings that increase our knowledge about drug-induced neuronal adaptations in the brain reward system and the role glucocorticoids may play in this process. Evidence exists that drugs and stress can induce similar changes in excitatory synaptic strength within the mesolimbic dopamine system, suggesting a coordinate mechanism for drugs of abuse and glucocorticoids. The glucocorticoid receptor (GR) plays an essential role in the stress-induced synaptic alterations, and studies using transgenic mice suggest that the GR is a key modulator of the motivation to take drugs and of the behavioral effects of repeated drug intake. The current state of research into the interplay between glucocorticoid hormones and addiction has reached a new phase in which detailed cellular and molecular analyses of the actual mechanisms will become possible. An important role is assigned to the GR, although many issues remain to be addressed, such as the actual site of glucocorticoid action in the brain, the molecular mechanisms and targets of GR-mediated glucocorticoid effects, and their interaction with genetic background.


Assuntos
Glucocorticoides/farmacologia , Psicotrópicos/farmacologia , Animais , Camundongos , Camundongos Transgênicos , Receptores de Glucocorticoides/fisiologia
19.
Psychopharmacology (Berl) ; 221(3): 451-68, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22124672

RESUMO

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 laevis
20.
Psychopharmacology (Berl) ; 217(4): 525-38, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21537941

RESUMO

RATIONALE: Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis. OBJECTIVES: The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain. METHODS: We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine. RESULTS: A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors. CONCLUSION: We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis.


Assuntos
Anfetamina/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Psicoses Induzidas por Substâncias/genética , Anfetamina/farmacocinética , Animais , Região CA1 Hipocampal/metabolismo , Interação Gene-Ambiente , Genes Precoces/efeitos dos fármacos , Microdissecção e Captura a Laser , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Psicoses Induzidas por Substâncias/metabolismo , Psicoses Induzidas por Substâncias/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real
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