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1.
PLoS One ; 15(2): e0229671, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101569

RESUMO

As in vertebrates, dopaminergic neural systems are key regulators of motor programs in insects, including the fly Drosophila melanogaster. Dopaminergic systems innervate the Mushroom Bodies (MB), an important association area in the insect brain primarily associated to olfactory learning and memory, but that has been also implicated with the execution of motor programs. The main objectives of this work is to assess the idea that dopaminergic systems contribute to the execution of motor programs in Drosophila larvae, and then, to evaluate the contribution of specific dopaminergic receptors expressed in MB to these programs. Our results show that animals bearing a mutation in the dopamine transporter show reduced locomotion, while mutants for the dopaminergic biosynthetic enzymes or the dopamine receptor Dop1R1 exhibit increased locomotion. Pan-neuronal expression of an RNAi for the Dop1R1 confirmed these results. Further studies show that animals expressing the RNAi for Dop1R1 in the entire MB neuronal population or only in the MB γ-lobe forming neurons, exhibit an increased motor output, as well. Interestingly, our results also suggest that other dopaminergic receptors do not contribute to larval motor behavior. Thus, our data support the proposition that CNS dopamine systems innervating MB neurons modulate larval locomotion and that Dop1R1 mediates this effect.


Assuntos
Proteínas de Drosophila/metabolismo , Corpos Pedunculados/metabolismo , Receptores Dopaminérgicos/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Larva/genética , Larva/metabolismo , Locomoção/fisiologia , Masculino , Memória/fisiologia , Neurônios/metabolismo , Receptores Dopaminérgicos/fisiologia , Olfato/fisiologia
2.
Nat Neurosci ; 22(12): 1986-1999, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719672

RESUMO

The importance of neuronal ensembles, termed engram cells, in storing and retrieving memory is increasingly being appreciated, but less is known about how these engram cells operate within neural circuits. Here we tagged engram cells in the ventral CA1 region of the hippocampus (vCA1) and the core of the nucleus accumbens (AcbC) during cocaine conditioned place preference (CPP) training and show that the vCA1 engram projects preferentially to the AcbC and that the engram circuit from the vCA1 to the AcbC mediates memory recall. Direct activation of the AcbC engram while suppressing the vCA1 engram is sufficient for cocaine CPP. The AcbC engram primarily consists of D1 medium spiny neurons, but not D2 medium spiny neurons. The preferential synaptic strengthening of the vCA1→AcbC engram circuit evoked by cocaine conditioning mediates the retrieval of cocaine CPP memory. Our data suggest that the vCA1 engram stores specific contextual information, while the AcbC D1 engram and its downstream network store both cocaine reward and associated contextual information, providing a potential mechanism by which cocaine CPP memory is stored.


Assuntos
Região CA1 Hipocampal/fisiologia , Cocaína/farmacologia , Condicionamento Psicológico/fisiologia , Rememoração Mental/fisiologia , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Transgênicos , Vias Neurais/fisiologia , Optogenética , Receptores Dopaminérgicos/fisiologia
3.
J Pharmacol Sci ; 140(1): 86-93, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31109761

RESUMO

Neuromodulators such as dopamine, enable context-dependent plasticity of neural circuit function throughout the central nervous system. For example, in the retina, dopamine tunes visual processing for daylight and nightlight conditions. Specifically, high levels of dopamine release in the retina tune vision for daylight (photopic) conditions, while low levels tune it for nightlight (scotopic) conditions. This review covers the cellular and circuit-level mechanisms within the retina that are altered by dopamine. These mechanisms include changes in gap junction coupling and ionic conductances, both of which are altered by the activation of diverse types of dopamine receptors across diverse types of retinal neurons. We contextualize the modulatory actions of dopamine in terms of alterations and optimizations to visual processing under photopic and scotopic conditions, with particular attention to how they differentially impact distinct cell types. Finally, we discuss how transgenic mice and disease models have shaped our understanding of dopaminergic signaling and its role in visual processing. Cumulatively, this review illustrates some of the diverse and potent mechanisms through which neuromodulation can shape brain function.


Assuntos
Adaptação Ocular/fisiologia , Dopamina/fisiologia , Neurotransmissores/fisiologia , Retina/fisiologia , Luz Solar , Visão Ocular/fisiologia , Animais , Adaptação à Escuridão/fisiologia , Junções Comunicantes/fisiologia , Humanos , Camundongos Transgênicos , Receptores Dopaminérgicos/metabolismo , Receptores Dopaminérgicos/fisiologia , Transdução de Sinais/fisiologia
4.
Bull Exp Biol Med ; 166(6): 709-713, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020579

RESUMO

An original concept of a two-stage mechanism of positive reinforcement is proposed. The first stage, "virtual" reinforcement, is formed in parallel with the action result acceptor when the result is still not achieved. At this stage, the importance of the planned result and the probability of its achievement are assessed. The greater are these indices, the stronger is "virtual" reinforcement. Hypothetically, the "virtual" reinforcement is mediated by dopamine release from nerve terminals in the mesencephalon. The "real" reinforcement (the second stage) occurs after achievement of the result. Probably, an important role in the mechanisms of the "real" reinforcement is given to endogenous opioids, cannabinoids, and GABA. Based on the advanced hypothesis on interaction between the central and peripheral subdivisions of the corresponding neurochemical systems, the review focuses on possibility of pharmacological intervention into the mechanisms of positive reinforcement by modifying activity of the peripheral opioid and dopamine receptors with the ligands that cannot cross blood-brain barrier.


Assuntos
Retroalimentação Fisiológica/fisiologia , Mesencéfalo/fisiologia , Receptores Dopaminérgicos/fisiologia , Receptores Opioides/fisiologia , Reforço Psicológico , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Canabinoides/metabolismo , Canabinoides/farmacologia , Humanos , Mesencéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Satisfação Pessoal , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
5.
Inflammopharmacology ; 27(6): 1155-1167, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30850920

RESUMO

Previous reports suggest flavonoids as potent analgesic compounds. Based on these observations, the present study investigated the antinociceptive action of flavonol, 3', 4'-dimethoxy flavonol, 6, 3'-dimethoxy flavonol, 7, 2'-dimethoxy flavonol, and 7, 3'-dimethoxy flavonol and the possible mechanisms involved in these effects. The antinociceptive effect of the investigated compounds in doses of 25, 50, 100, and 200 mg/kg was evaluated in male Swiss albino mice using the acetic acid test, formalin-induced nociception, and hot water tail immersion test. The role of opioid, tryptaminergic, adrenergic, dopaminergic, GABAergic, and K+ATP channels in producing the antinociceptive effect was also studied using appropriate interacting agents. Treatment with flavonol and dimethoxy flavonols resulted in a significant reduction in the number of abdominal constrictions in the acetic acid test, a significant inhibition of the paw-licking/biting response time in both the phases of formalin nociception and also a significant increase in mean reaction time in the hot water tail immersion test. These observations revealed the antinociceptive effect of dimethoxy flavonols. The role of opioid, serotonergic (5HT3), and dopaminergic system was identified in the antinociceptive effect of flavonol and all dimethoxy derivatives investigated. In addition, the role of GABAergic, K+ATP channel, and α-2 adrenergic mechanisms were also observed in the antinociceptive action of some of the investigated compounds. The present study identified the antinociceptive effect of flavonol and dimethoxy flavonols in mice acting through different neuronal pathways.


Assuntos
Flavonóis/farmacologia , Analgésicos/farmacologia , Animais , Bicuculina/farmacologia , Formaldeído/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Canais de Potássio/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Dopaminérgicos/fisiologia , Receptores 5-HT3 de Serotonina/fisiologia , Ioimbina/farmacologia
6.
Neuron ; 100(6): 1414-1428.e10, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30392795

RESUMO

Finding food and remaining at a food source are crucial survival strategies. We show how neural circuits and signaling molecules regulate these food-related behaviors in Caenorhabditis elegans. In the absence of food, AVK interneurons release FLP-1 neuropeptides that inhibit motorneurons to regulate body posture and velocity, thereby promoting dispersal. Conversely, AVK photoinhibition promoted dwelling behavior. We identified FLP-1 receptors required for these effects in distinct motoneurons. The DVA interneuron antagonizes signaling from AVK by releasing cholecystokinin-like neuropeptides that potentiate cholinergic neurons, in response to dopaminergic neurons that sense food. Dopamine also acts directly on AVK via an inhibitory dopamine receptor. Both AVK and DVA couple to head motoneurons by electrical and chemical synapses to orchestrate either dispersal or dwelling behavior, thus integrating environmental and proprioceptive signals. Dopaminergic regulation of food-related behavior, via similar neuropeptides, may be conserved in mammals.


Assuntos
Dopamina/farmacologia , Alimentos , Locomoção/efeitos dos fármacos , Vias Neurais/fisiologia , Neuropeptídeos/farmacologia , Sensação/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cálcio/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Dopamina/metabolismo , Vias Neurais/efeitos dos fármacos , Neuropeptídeos/metabolismo , Optogenética , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/fisiologia , Células Receptoras Sensoriais/fisiologia
7.
Neuroscience ; 394: 267-285, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30394321

RESUMO

Deficits in dopaminergic function are thought to underlie attention-deficit/hyperactivity disorder (ADHD). Dopaminergic neurons are the main source of dopamine (DA), a neurotransmitter that acts as a neuromodulator of cognitive function in the prefrontal cortex, including the anterior cingulate cortex (ACC), which receives dopaminergic inputs from the ventral tegmental area. The spontaneously hypertensive rat (SHR) has been widely studied as an animal model of ADHD. The aim of the current study was to investigate the pathophysiological mechanisms of ADHD by examining DA modulation of γ-aminobutyric acid neural (GABAergic) transmission recorded from layer V pyramidal cells of the ACC in SHR compared to control Wistar-Kyoto rats (WKY). Our results showed that DA activity increased the frequency of both miniature and spontaneous inhibitory postsynaptic currents (IPSCs) in control WKY, but not in SHRs. Furthermore, DA activity enhanced the amplitude of evoked and unitary IPSCs from fast-spiking interneurons; the amplitude was also larger in control WKY than in SHRs. Notably, the amplitude of evoked IPSCs was enhanced by the activation of D1-like receptor-mediated pathways. These results suggest that hypofunction of D1-like receptor-mediated regulation of GABAergic inhibitory synaptic transmission onto layer V pyramidal cells of the ACC may contribute to the pathophysiology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Dopamina/fisiologia , Neurônios GABAérgicos/fisiologia , Giro do Cíngulo/fisiologia , Receptores Dopaminérgicos/fisiologia , Potenciais de Ação , Animais , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Regulação para Baixo , Potenciais Pós-Sinápticos Inibidores , Interneurônios/fisiologia , Masculino , Células Piramidais/citologia , Células Piramidais/fisiologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia
8.
Biol Psychiatry ; 84(5): 332-344, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29656800

RESUMO

Tourette syndrome (TS) is thought to involve dopaminergic disturbances, but the nature of those disturbances remains controversial. Existing hypotheses suggest that TS involves 1) supersensitive dopamine receptors, 2) overactive dopamine transporters that cause low tonic but high phasic dopamine, 3) presynaptic dysfunction in dopamine neurons, or 4) dopaminergic hyperinnervation. We review evidence that contradicts the first two hypotheses; we also note that the last two hypotheses have traditionally been considered too narrowly, explaining only small subsets of findings. We review all studies that have used positron emission tomography and single-photon emission computerized tomography to investigate the dopaminergic system in TS. The seemingly diverse findings from those studies have typically been interpreted as pointing to distinct mechanisms, as evidenced by the various hypotheses concerning the nature of dopaminergic disturbances in TS. We show, however, that the hyperinnervation hypothesis provides a simple, parsimonious explanation for all such seemingly diverse findings. Dopaminergic hyperinnervation likely causes increased tonic and phasic dopamine. We have previously shown, using a computational model of the role of dopamine in basal ganglia, that increased tonic dopamine and increased phasic dopamine likely increase the propensities to express and learn tics, respectively. There is therefore a plausible mechanistic link between dopaminergic hyperinnervation and TS via increased tonic and phasic dopamine. To further bolster this argument, we review evidence showing that all medications that are effective for TS reduce signaling by tonic dopamine, phasic dopamine, or both.


Assuntos
Encéfalo/fisiopatologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Síndrome de Tourette/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons , Receptores Dopaminérgicos/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/etiologia
9.
Neuromolecular Med ; 20(1): 1-17, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305687

RESUMO

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.


Assuntos
Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Testes Farmacogenômicos , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Biotransformação/genética , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/fisiologia , Dopamina/metabolismo , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/fisiologia , Humanos , Inibidores da Monoaminoxidase/efeitos adversos , Inibidores da Monoaminoxidase/farmacocinética , Inibidores da Monoaminoxidase/uso terapêutico , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/fisiologia , Resultado do Tratamento
10.
Behav Pharmacol ; 29(2 and 3-Spec Issue): 211-224, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29194070

RESUMO

Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined whether changes in gut microbiota play a role in these behavioral phenomena, by monitoring the development of compulsive checking and locomotor sensitization at the same time as measuring the response of gut microbiota to chronic quinpirole injections. Two groups of rats received nine injections of saline (n=16) or quinpirole (n=15; 0.25 mg/kg), at weekly intervals for the first 5 weeks and then two injections per week until the end of treatment. After each injection, rats were placed on a large open field for 55 min, and their behavior was video recorded for subsequent analysis. Fecal matter was collected after each trial and frozen for bacterial community profiling of the 16S rRNA gene, using paired-end reads of the V3 region. The results indicated that the induction of locomotor sensitization and compulsive checking was accompanied by changes in several communities of bacteria belonging to the order Clostridiales (class Clostridia, phylum Firmicutes), and predominantly in Lachnospiraceae and Ruminococcaceae families of bacteria. It is suggested that changes in these microbes may serve to support the energy use requirements of compulsive checking and obsessive-compulsive disorder.


Assuntos
Comportamento Compulsivo/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Locomoção/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Compulsivo/induzido quimicamente , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Microbioma Gastrointestinal/genética , Locomoção/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Quimpirol/farmacologia , RNA Ribossômico 16S , Ratos , Ratos Long-Evans , Receptores Dopaminérgicos/fisiologia , Comportamento Estereotipado/efeitos dos fármacos
11.
J Neurosci ; 37(46): 11166-11180, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29030431

RESUMO

Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivoSIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is also minimal in the shell in part due to elevated acetylcholinesterase activity. This distinctive modulation of DA transmission in the shell may have functional implications in the acquisition of reward-motivated behaviors and reward seeking.


Assuntos
Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Receptores Dopaminérgicos/fisiologia , Receptores Nicotínicos/fisiologia , Animais , Antagonistas Colinérgicos/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Núcleo Accumbens/efeitos dos fármacos , Técnicas de Cultura de Órgãos
12.
Acta Biomed ; 88(2): 190-195, 2017 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-28845835

RESUMO

Patients with Parkinson's disease (PD) receiving long-term L-Dopa therapy eventually develop motor complications with unpredictable "on-off" response fluctuations and involuntary movements, leading to progressive disability. Hence, the search for alternative therapeutic choices based on continuous dopaminergic stimulation (CDS) becomes crucial for the treatment of advanced PD. Here, we describe the case of a 70-year-old man with a 9-year history of PD, treated with daytime levodopa-carbidopa intestinal gel (LCIG) and overnight Rotigotine transdermal patch. LCIG monotherapy significantly reduced motor fluctuations and prevented the appearance of unpredictable off periods; concurrently, overnight Rotigotine improved his sleep quality and morning akinesia. Both LCIG and Rotigotine induce CDS, which conceptually mimics physiologic striatal dopamine receptor function. Hence, they both represent a good therapeutic option for the treatment of advanced PD.


Assuntos
Carbidopa/administração & dosagem , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Idoso , Combinação de Medicamentos , Géis , Humanos , Masculino , Doença de Parkinson/fisiopatologia , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/fisiologia , Adesivo Transdérmico
13.
Br J Pharmacol ; 174(19): 3173-3190, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28667666

RESUMO

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the National Institute of Mental Health Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia and Research Domain Criteria initiatives) are an important step towards standardization of outcome measures that can be used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Animais , Antipsicóticos/uso terapêutico , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Predisposição Genética para Doença , Humanos , Receptores Dopaminérgicos/fisiologia , Receptores de Glutamato/fisiologia , Receptores Muscarínicos/fisiologia , Esquizofrenia/fisiopatologia
14.
Eur J Neurosci ; 46(4): 2015-2025, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28677227

RESUMO

Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959 has been shown to increase brain-derived neurotrophic factor signalling and suppress activity of glycogen synthase kinase-3 in PFC, two processes important to learning and memory. The purpose of this study was to therefore evaluate the impact of SKF 83959 on oscillatory deficits in methylazoxymethanol acetate (MAM) rat model of schizophrenia. To achieve this, local field potentials were recorded simultaneously from the hippocampus and prefrontal cortex of anesthetized rats at 15 and 90 min following both acute and repeated administration of SKF 83959 (0.4 mg/kg). In MAM rats, but not controls, repeated SKF 83959 treatment increased signal amplitude in hippocampus and enhanced the spectral power of low frequency delta and theta oscillations in this region. In PFC, SKF 83959 increased delta, theta and gamma spectral power. Increased HIP-PFC theta coherence was also evident following acute and repeated SKF 83959. In apparent contradiction to these oscillatory effects, in MAM rats, SKF 83959 inhibited spatial learning and induced a significant increase in thigmotactic behaviour. These findings have uncovered a previously unknown role for SKF 83959 in the positive regulation of hippocampal-prefrontal cortical oscillatory network activity. As SKF 83959 is known to have affinity for a number of receptors, delineating the receptor mechanisms that mediate the positive drug effects on neuronal oscillations could have significant future implications in disorders associated with cognitive dysfunction.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/uso terapêutico , Animais , Disfunção Cognitiva/fisiopatologia , Agonistas de Dopamina/uso terapêutico , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/fisiologia
15.
Psychopharmacology (Berl) ; 234(15): 2325-2336, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28669034

RESUMO

RATIONALE: The ventral tegmental area (VTA) and its projections to the basolateral amygdala (BLA) and nucleus accumbens (NAc) are critical for cannabinoid-related motivational effects. Cannabinoid CB1 receptor (CB1R) transmission modulates VTA dopamine (DA) neuron activity and previous reports demonstrate anatomically segregated effects of CB1R transmission in the VTA. However, the underlying pharmacological and anatomical regions responsible for these effects are currently unknown. OBJECTIVES: The objective of the study is to characterize the motivational effects of localized anterior vs. posterior intra-VTA activation vs. blockade of CB1R transmission and the potential role of intra-BLA and intra-NAc DA transmission in these phenomena. METHODS: Using a conditioned place preference (CPP) procedure, we administered a CB1 agonist (WIN-55,212-2) or antagonist (AM 251) into the posterior VTA (pVTA) or anterior VTA (aVTA) of rats, combined with intra-BLA or intra-NAc DA receptor blockade and intra-VTA co-administration of selective mu vs. kappa opiate-receptor antagonists. RESULTS: Intra-pVTA CB1R activation produced robust rewarding effects through a mu-opiate receptor mechanism whereas CB1R blockade produced conditioned place aversions (CPA) through a kappa-opiate receptor substrate. In contrast, modulation of aVTA CB1R transmission produced no observable effects. Intra-BLA DA receptor blockade prevented the rewarding effects of pVTA CB1R activation, but had no effects on CB1R blockade-induced aversions. In contrast, intra-NAc DA receptor blockade selectively blocked the aversive effects of pVTA CB1R antagonism. CONCLUSIONS: Activation vs. blockade of CB1R transmission in the posterior VTA produces bivalent rewarding or aversive effects through separate mu vs. kappa-opiate receptor substrates. These dissociable effects depend on separate DA receptor transmission substrates in the BLA or NAc, respectively.


Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Canabinoides/farmacologia , Núcleo Accumbens/fisiologia , Receptores Dopaminérgicos/fisiologia , Receptores Opioides/fisiologia , Área Tegmentar Ventral/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/fisiologia , Recompensa , Área Tegmentar Ventral/efeitos dos fármacos
16.
Prog Retin Eye Res ; 61: 60-71, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28602573

RESUMO

In the face of an "epidemic" increase in myopia over the last decades and myopia prevalence predicted to reach 2.5 billion people by the end of this decade, there is an urgent need to develop effective and safe therapeutic interventions to slow down this "myopia booming" and prevent myopia-related complications and vision loss. Dopamine (DA) is an important neurotransmitter in the retina and mediates diverse functions including retina development, visual signaling, and refractive development. Inspired by the convergence of epidemiological and animal studies in support of the inverse relationship between outdoor activity and risk of developing myopia and by the close biological relationship between light exposure and dopamine release/signaling, we felt it is timely and important to critically review the role of DA in myopia development. This review will revisit several key points of evidence for and against DA mediating light control of myopia: 1) the causal role of extracellular retinal DA levels, 2) the mechanism and action of dopamine D1 and D2 receptors and 3) the roles of cellular/circuit retinal pathways. We examine the experiments that show causation by altering DA, DA receptors and visual pathways using pharmacological, transgenic, or visual environment approaches. Furthermore, we critically evaluate the safety issues of a DA-based treatment strategy and some approaches to address these issues. The review identifies the key questions and challenges in translating basic knowledge on DA signaling and myopia from animal studies into effective pharmacological treatments for myopia in children.


Assuntos
Dopamina/fisiologia , Miopia/fisiopatologia , Transdução de Sinais/fisiologia , Agonistas de Dopamina/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Olho/crescimento & desenvolvimento , Humanos , Miopia/tratamento farmacológico , Miopia/etiologia , Receptores Dopaminérgicos/fisiologia , Retina/fisiopatologia
17.
Behav Brain Res ; 326: 303-306, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28341611

RESUMO

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5µg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1µg/side) or MPH+SCH23390 (1.5µg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both ß-adrenergic and D1/D5 dopaminergic receptors.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores Adrenérgicos beta/fisiologia , Receptores Dopaminérgicos/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/administração & dosagem , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores , Timolol/administração & dosagem , Timolol/farmacologia
18.
Eur J Pain ; 21(7): 1285-1294, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28340290

RESUMO

BACKGROUND: Lateral hypothalamus (LH) involves in modulation of tonic pain. Regarding the direct and indirect neural connections between the LH and nucleus accumbens (NAc), we aimed to examine the pain modulatory role of NAc dopamine receptors in modulation of LH-induced analgesia in the formalin test. METHODS: Vehicle-control groups received saline or DMSO into the NAc and saline into the LH. Carbachol-control groups received carbachol (250 nmol/L) into the LH, 5 min after saline or DMSO injection into the NAc. In treatment groups, intra-NAc administration of SCH-23390 or sulpiride (D1-and D2-like dopamine receptor antagonists, respectively) was performed 5 min before carbachol injection. Formalin test was done in all rats 5 min after the second injection. RESULTS: The blockade of NAc dopamine receptors reduced carbachol-induced antinociception during both phases of formalin test and reduction in LH-induced analgesia during the late phase was more than that during the early phase. Furthermore, contribution of D2-like dopamine receptors to mediation of anti-hyperalgesic effect of carbachol was greater than that of D1-like dopamine receptors during the late phase. CONCLUSIONS: The findings suggest that LH-VTA-NAc circuit is contributed to the modulation of formalin-induced pain. These findings demonstrate that transmission at D1- and D2-like dopamine receptors mediates the LH-induced analgesia. SIGNIFICANCE: Blockade of accumbal dopamine receptors attenuated analgesia induced by carbachol injection into the lateral hypothalamus during both phases of formalin test. Effect of blockade of D1- and D2-like dopamine receptors on reduction in antinociception was more during the late phase. Contribution of D2-like dopamine receptors to mediation of antinociception during the late phase was greater than the early phase.


Assuntos
Benzazepinas/farmacologia , Carbacol/farmacologia , Hipotálamo/fisiologia , Núcleo Accumbens/química , Medição da Dor/efeitos dos fármacos , Dor/prevenção & controle , Receptores Dopaminérgicos/química , Sulpirida/farmacologia , Analgesia , Animais , Benzazepinas/química , Masculino , Núcleo Accumbens/fisiologia , Ratos , Ratos Wistar , Receptores Dopaminérgicos/fisiologia
19.
Horm Behav ; 89: 193-200, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28185881

RESUMO

The capacity to flexibly adapt responding to unexpected changes in the environment is crucial for survival. Several neurotransmitters have been implicated in stimulus-outcome reversal learning. Yet, it remains an open question whether inter-individual differences in the neuroactive hormone testosterone may also be related to this type of behavioral flexibility. In this study we assessed the association between endogenous testosterone level and reversal learning in young healthy men. We used an observer reversal learning task, in which subjects viewed computer-based decisions between two stimuli, of which one was currently rewarded while the other one was punished. Contingencies reversed unpredictably every 5-9 trials. Subjects had to indicate the current outcome association before the actual outcome was revealed. In the trial following an unexpected reversal either the same stimulus from the reversal (experienced reversal), or its alternative, for which the reversal had not yet been shown (inferred reversal), could be chosen by the computer, and subjects had to adapt responding accordingly. We found that testosterone predicted better post-reversal performance. This correlation was strongest in the more difficult inferred reversal condition, particularly in impulsive individuals. Collectively, these data support the view that endogenous testosterone may enhance behavioral flexibility in men, particularly when working memory demand is high and subjects have to update several stimulus-outcome contingencies at the same time. It remains to be further elucidated whether this testosterone effect was achieved through an interaction with dopaminergic transmission or through direct interplay with androgen receptors in the brain regions implicated in reversal learning.


Assuntos
Atenção/fisiologia , Reversão de Aprendizagem/fisiologia , Enquadramento Psicológico , Testosterona/sangue , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico , Tomada de Decisões/fisiologia , Humanos , Comportamento Impulsivo/fisiologia , Individualidade , Masculino , Memória de Curto Prazo/fisiologia , Receptores Androgênicos/fisiologia , Receptores Dopaminérgicos/fisiologia , Recompensa , Adulto Jovem
20.
Biol Psychiatry ; 81(1): 67-77, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26946382

RESUMO

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1 receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.


Assuntos
Agonistas de Dopamina/uso terapêutico , Dopamina/fisiologia , Receptores Dopaminérgicos/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Animais , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/uso terapêutico , Humanos , Fenantridinas/administração & dosagem , Fenantridinas/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiologia
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