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1.
Nat Rev Neurosci ; 23(4): 191-203, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35228740

RESUMO

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials. Although much is known about presynaptic receptors and their mechanisms of action, less is known about when and where these receptor actions alter release, especially in vivo. This Review focuses on emerging evidence for important local presynaptic receptor actions and ideas for future studies in this area.


Assuntos
Comunicação Celular , Receptores Pré-Sinápticos , Potenciais de Ação , Humanos , Neurônios , Transmissão Sináptica
2.
J Neurosci ; 39(8): 1457-1470, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30559150

RESUMO

Dynamic regulation of synaptic transmission at cortical inputs to the dorsal striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αß (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the dorsolateral striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Together, these findings reveal a selective role for presynaptic RIM1 in neurotransmitter release at prominent basal ganglia synapses, and provide evidence that RIM1-dependent processes help to promote the refinement of skilled actions, constrain goal-directed behaviors, and support the learning and use of habits.SIGNIFICANCE STATEMENT Our daily functioning hinges on the ability to flexibly and efficiently learn and control our actions. How the brain encodes these capacities is unclear. Here we identified a selective role for presynaptic proteins RIM1αß in controlling glutamate release from cortical inputs to the dorsolateral striatum, a brain structure critical for action learning and control. Behavioral analysis of mice with restricted genetic deletion of RIM1αß further revealed roles for RIM1αß-dependent processes in the learning and refinement of motor skills and the balanced expression of goal-directed and habitual actions.


Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Proteínas de Ligação ao GTP/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Gânglios da Base/fisiologia , Condicionamento Operante/fisiologia , Comportamento Exploratório/fisiologia , Feminino , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/genética , Ácido Glutâmico/fisiologia , Hábitos , Aprendizagem/fisiologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Destreza Motora/fisiologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Teste de Desempenho do Rota-Rod , Transmissão Sináptica/fisiologia
3.
J Neurosci ; 34(1): 79-94, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24381270

RESUMO

Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.


Assuntos
Encéfalo/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/química
4.
Br J Pharmacol ; 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37258878

RESUMO

Dopamine transmission in the striatum is a critical mediator of the rewarding and reinforcing effects of commonly misused psychoactive drugs. G protein-coupled receptors (GPCRs) that bind a variety of neuromodulators including dopamine, endocannabinoids, acetylcholine and endogenous opioid peptides regulate dopamine release by acting on several components of dopaminergic circuitry. Striatal dopamine release can be driven by both somatic action potential firing and local mechanisms that depend on acetylcholine released from striatal cholinergic interneurons. GPCRs that primarily regulate somatic firing of dopamine neurons via direct effects or modulation of synaptic inputs are likely to affect distinct aspects of behaviour and psychoactive drug actions compared with those GPCRs that primarily regulate local acetylcholine-dependent dopamine release in striatal regions. This review will highlight mechanisms by which GPCRs modulate dopaminergic transmission and the relevance of these findings to psychoactive drug effects on physiology and behaviour.

5.
Alcohol ; 101: 17-26, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35227826

RESUMO

The prefrontal cortex (PFC) is intimately associated with behavioral characteristics of alcohol use disorders, including high motivation to drink and difficulty with moderation. Thus, continued mechanistic research investigating PFC cells and targets altered by ethanol experiences should inform translational efforts to craft new, efficacious treatments. Inhibitory interneurons expressing parvalbumin (PV-INs) comprise only a minor fraction of cells within the PFC, yet these cells are indispensable for coordinating PFC ensemble function, oscillatory activity, and subcortical output. Based on this, PV-INs represent an exciting target for the rational design of breakthrough treatments for alcohol use disorders. Here, we assessed experience-dependent physiological adaptations via ethanol place conditioning. By manipulating the timing of administration relative to conditioning sessions, equivalent ethanol exposure can form either rewarding or aversive memories in different individuals. Here, we found that female mice and male mice on a C57BL/6J background display conditioned place preference (CPP) or aversion (CPA) to an intoxicating dose of ethanol (2 g/kg, intraperitoneal [i.p.]) without overt differences between sexes. Ethanol reward learning was associated with decreased PV-IN excitability in deep layer prelimbic PFC, whereas PV-INs from CPA mice were not different from controls. Furthermore, PV-INs from mice in the CPP group, but not the CPA group, displayed potentiated excitatory synaptic strength that emerged during 1 week of abstinence. Taken together, these findings illustrate that synaptic and intrinsic adaptations associated with ethanol can depend on an individual's experience. These studies provide further context and support for PFC PV-INs as intriguing targets for modulating alcohol associations.


Assuntos
Alcoolismo , Parvalbuminas , Animais , Etanol/farmacologia , Feminino , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo , Recompensa
6.
Mol Pharmacol ; 77(3): 459-68, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20026717

RESUMO

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323:147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[ 4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Linhagem Celular , Cricetinae , Regulação para Baixo/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
7.
Nat Chem Biol ; 4(1): 42-50, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18059262

RESUMO

Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.


Assuntos
Hipocampo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M4/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Regulação Alostérica , Sítio Alostérico , Animais , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Eletrofisiologia , Hipocampo/metabolismo , Humanos , Ligantes , Camundongos , Camundongos Knockout , Estrutura Molecular , Agonistas Muscarínicos/química , Antagonistas Muscarínicos/química , Ligação Proteica , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ensaio Radioligante , Ratos , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/antagonistas & inibidores , Receptor Muscarínico M4/genética , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
8.
Adv Pharmacol ; 88: 193-232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32416868

RESUMO

Metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic transmission throughout the nervous system. Owing to recent advances in development of subtype-selective allosteric modulators of mGlu receptors, individual members of the mGlu receptor family have been proposed as targets for treating a variety of neurological and psychiatric disorders, including substance use disorders. In this chapter, we highlight preclinical evidence that allosteric modulators of mGlu receptors could be useful for reducing alcohol consumption and preventing relapse in alcohol use disorder (AUD). We begin with an overview of the preclinical models that are used to study mGlu receptor involvement in alcohol-related behaviors. Alcohol exposure causes adaptations in both expression and function of various mGlu receptor subtypes, and pharmacotherapies aimed at reversing these adaptations have the potential to reduce alcohol consumption and seeking. Positive allosteric modulators (PAMs) of mGlu2 and negative allosteric modulators of mGlu5 show particular promise for reducing alcohol intake and/or preventing relapse. Finally, this chapter discusses important considerations for translating preclinical findings toward the development of clinically useful drugs, including the potential for PAMs to avoid tolerance issues that are frequently observed with repeated administration of GPCR agonists.


Assuntos
Alcoolismo/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Modelos Animais de Doenças , Humanos , Terapia de Alvo Molecular , Transmissão Sináptica
9.
Neuropsychopharmacology ; 45(9): 1454-1462, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31995814

RESUMO

Dorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the striatum by the cortex and thalamus is a critical determinant of MSN activity and local regulation of dopamine release. However, the relationship between striatal glutamatergic afferents and behavioral reinforcement is not well understood. We evaluated the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, optical stimulation of the DMS reinforced operant lever-pressing behavior. Mice also acquired operant self-stimulation of thalamostriatal terminals when ChR2 expression was virally targeted to the intralaminar thalamus. Stimulation trains that supported operant responding evoked dopamine release in the DMS and excitatory postsynaptic currents in DMS MSNs. Our previous work demonstrated that the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents. Thus, we examined the regulation of thalamostriatal self-stimulation by mGlu2. Administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduced self-stimulation. Conversely, blockade of these receptors increased thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu2 activation.


Assuntos
Corpo Estriado , Receptores de Glutamato Metabotrópico , Animais , Corpo Estriado/metabolismo , Camundongos , Tálamo/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
10.
Alcohol ; 82: 11-21, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31233806

RESUMO

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/metabolismo , Corpo Estriado/efeitos dos fármacos , Etanol/toxicidade , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Fatores Etários , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/genética , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Animais , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glutamato Metabotrópico/genética , Fatores de Tempo
12.
Mol Pharmacol ; 73(4): 1213-24, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18171729

RESUMO

The group III metabotropic glutamate receptors (mGluRs) represent a family of presynaptically expressed G-protein-coupled receptors (GPCRs) with enormous therapeutic potential; however, robust cellular assays to study their function have been difficult to develop. We present here a new assay, compatible with traditional high-throughput screening platforms, to detect activity of pharmacological ligands interacting with G(i/o)-coupled GPCRs, including the group III mGluRs 4, 7, and 8. The assay takes advantage of the ability of the Gbetagamma subunits of G(i) and G(o) heterotrimers to interact with G-protein regulated inwardly rectifying potassium channels (GIRKs), and we show here that we are able to detect the activity of multiple types of pharmacophores including agonists, antagonists, and allosteric modulators of several distinct GPCRs. Using GIRK-mediated thallium flux, we perform a side-by-side comparison of the activity of a number of commercially available compounds, some of which have not been extensively evaluated because of the previous lack of robust assays at each of the three major group III mGluRs. It is noteworthy that several compounds previously considered to be general group III mGluR antagonists have very weak activity using this assay, suggesting the possibility that these compounds may not effectively inhibit these receptors in native systems. We anticipate that the GIRK-mediated thallium flux strategy will provide a novel tool to advance the study of G(i/o)-coupled GPCR biology and promote ligand discovery and characterization.


Assuntos
Bioensaio/métodos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Agonistas Adrenérgicos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Aminoácidos/farmacologia , Animais , Carbacol/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Ligantes , Agonistas Muscarínicos/farmacologia , Toxina Pertussis/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores Muscarínicos/metabolismo , Reprodutibilidade dos Testes , Tálio/metabolismo , Xantenos/farmacologia
13.
Mol Pharmacol ; 74(5): 1345-58, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18664603

RESUMO

Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a positive allosteric modulator (PAM) of mGluR4 that has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency, and poor solubility. Via high-throughput screening, we discovered more than 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle, and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased haloperidol-induced catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Células CHO , Corpo Estriado/efeitos dos fármacos , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
Neuropharmacology ; 117: 114-123, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28159646

RESUMO

The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals. We used optogenetic techniques and recently-discovered pharmacological tools to dissect the effects of a prominent presynaptic GPCR, metabotropic glutamate receptor 2 (mGlu2), on corticostriatal vs. thalamostriatal transmission. We found that an agonist of mGlu2 and mGlu3 induces long-term depression (LTD) at synapses onto MSNs from both the cortex and the thalamus. Thalamostriatal LTD is selectively blocked by an mGlu2-selective negative allosteric modulator and reversed by application of an antagonist following LTD induction. Activation of mGlu2/3 also induces LTD of thalamostriatal transmission in striatal cholinergic interneurons (CINs), and pharmacological activation of mGlu2/3 or selective activation of mGlu2 inhibits CIN-mediated dopamine release evoked by selective stimulation of thalamostriatal inputs. Thus, mGlu2 activation exerts effects on striatal physiology that extend beyond modulation of corticostriatal synapses, and has the potential to influence cognition and striatum-related disorders via inhibition of thalamus-derived glutamate and dopamine release.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Tálamo/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Interneurônios/fisiologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
15.
Neuron ; 96(2): 476-489.e5, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29024667

RESUMO

Changes in cortical and striatal function underlie the transition from novel actions to refined motor skills. How discrete, anatomically defined corticostriatal projections function in vivo to encode skill learning remains unclear. Using novel fiber photometry approaches to assess real-time activity of associative inputs from medial prefrontal cortex to dorsomedial striatum and sensorimotor inputs from motor cortex to dorsolateral striatum, we show that associative and sensorimotor inputs co-engage early in action learning and disengage in a dissociable manner as actions are refined. Disengagement of associative, but not sensorimotor, inputs predicts individual differences in subsequent skill learning. Divergent somatic and presynaptic engagement in both projections during early action learning suggests potential learning-related in vivo modulation of presynaptic corticostriatal function. These findings reveal parallel processing within associative and sensorimotor circuits that challenges and refines existing views of corticostriatal function and expose neuronal projection- and compartment-specific activity dynamics that encode and predict action learning.


Assuntos
Corpo Estriado/fisiologia , Aprendizagem/fisiologia , Córtex Motor/fisiologia , Rede Nervosa/fisiologia , Animais , Corpo Estriado/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Motor/química , Destreza Motora , Rede Nervosa/química , Fotometria/métodos
16.
Neuron ; 96(5): 1112-1126.e5, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29216450

RESUMO

Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior. Here we report that extracellular DA increases induced by selective optogenetic activation of cholinergic neurons in the nucleus accumbens (NAc) are inhibited by CB1 agonists and eCBs. This modulation requires CB1 receptors on cortical glutamatergic afferents. Dopamine increases driven by optogenetic activation of prefrontal cortex (PFC) terminals in the NAc are similarly modulated by activation of these CB1 receptors. We further demonstrate that this same population of CB1 receptors modulates optical self-stimulation sustained by activation of PFC afferents in the NAc. These results establish local eCB actions on PFC terminals within the NAc that inhibit mesolimbic DA release and constrain reward-driven behavior.


Assuntos
Dopamina/metabolismo , Endocanabinoides/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Glutamatos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/citologia , Córtex Pré-Frontal/citologia , Receptor CB1 de Canabinoide/agonistas , Recompensa , Autoestimulação , Transmissão Sináptica/efeitos dos fármacos
17.
Neuron ; 92(2): 269-272, 2016 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-27764658

RESUMO

In this issue of Neuron, Younts et al. (2016) demonstrate that activation of presynaptic CB1 receptors by retrograde endocannabinoid signaling stimulates protein synthesis in axon terminals to induce long-term depression of hippocampal inhibitory transmission.


Assuntos
Moduladores de Receptores de Canabinoides , Receptor CB1 de Canabinoide , Plasticidade Neuronal , Terminações Pré-Sinápticas , Receptores Pré-Sinápticos
18.
19.
Front Cell Neurosci ; 10: 264, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27891077

RESUMO

Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D1- and D2-like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on development of mGlu2 positive allosteric modulators (PAMs).

20.
Neuron ; 86(4): 1029-1040, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25937172

RESUMO

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.


Assuntos
Antipsicóticos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Regulação Alostérica/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Ácido Glutâmico/metabolismo , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Masculino , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/genética , Transdução de Sinais/efeitos dos fármacos
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