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1.
Psychopharmacology (Berl) ; 237(6): 1681-1689, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125484

RESUMO

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.


Assuntos
Analgésicos Opioides/administração & dosagem , Compostos Aza/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores da Captação de Dopamina/uso terapêutico , Norepinefrina/antagonistas & inibidores , Remifentanil/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Animais , Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Nicotina/administração & dosagem , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Estereoisomerismo
2.
Science ; 367(6484): 1362-1366, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193325

RESUMO

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.


Assuntos
Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Motivação/efeitos dos fármacos , Sulpirida/farmacologia , Adolescente , Núcleo Caudado/metabolismo , Comportamento de Escolha , Tomada de Decisões , Dopamina/biossíntese , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Feminino , Fixação Ocular , Humanos , Masculino , Memória , Recompensa , Movimentos Sacádicos , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
3.
Psychopharmacology (Berl) ; 237(5): 1533-1543, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32067136

RESUMO

RATIONALE: Low doses of psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine and norepinephrine by inhibiting their reuptake, are the most commonly used treatment for attention deficit hyperactivity disorder (ADHD). Therapeutic doses of these drugs may improve focused attention at the expense of hindering other cognitive functions, including the ability to adapt behavior in response to changing circumstances-cognitive flexibility. Cognitive flexibility is thought to depend on proper operation of the prefrontal cortex (PFC) and is also linked to reward processing, which is dopamine-dependent. Additionally, reward outcome signals have been recorded from the PFC. OBJECTIVES: This study tested the hypothesis that therapeutic doses of MPH impair cognitive flexibility and that this impairment in performance resulted from interference in reward signals within the PFC. METHODS: Four rhesus monkeys were given therapeutically relevant doses of oral MPH (0, 3, and 6 mg/kg) while performing an oculomotor switching task to evaluate its effect on task performance. Single-unit recordings in the PFC of two monkeys were taken before and after MPH administration during task performance. RESULTS: The results show that MPH does hinder switching task performance, an effect that was correlated with a reduction in the amplitude of outcome signals found in the discharges of some neurons in the PFC. CONCLUSIONS: Methylphenidate impaired task-switching performance, which can be used as a measure of cognitive flexibility. This detriment may result from degraded outcome signaling within the PFC. This study has implications for the use of MPH in the treatment of ADHD.


Assuntos
Inibidores da Captação de Dopamina/farmacologia , Metilfenidato/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Cognição/efeitos dos fármacos , Cognição/fisiologia , Inibidores da Captação de Dopamina/toxicidade , Relação Dose-Resposta a Droga , Macaca mulatta , Masculino , Metilfenidato/toxicidade , Córtex Pré-Frontal/fisiologia , Desempenho Psicomotor/fisiologia , Transdução de Sinais/fisiologia
4.
Psychopharmacology (Berl) ; 237(5): 1331-1342, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32034448

RESUMO

RATIONALE: Searches for antidotes to cocaine, and for cognition enhancers potentially applicable to Alzheimer's disease, have revealed a novel regulatory site on nicotinic acetylcholine receptors. In the presence of an agonist, inhibitors binding to this site changed the ion channel equilibrium from the open-channel form towards the closed form. Other, related, molecules could bind to the site without changing the equilibrium. These latter compounds were predicted to displace the inhibitors without affecting receptor function per se. These compounds alleviated the inhibition. One of them is ecgonine methyl ester (EME), which is generally described as inactive, but this work suggested a beneficial effect on cognition. OBJECTIVE: This in vivo study tested for cognitive enhancement by EME in scopolamine-impaired, and aged, rats. METHODS: Memory was the primary endpoint, but thigmotaxis became an important secondary endpoint in the light of observations made during the study. Impaired cognition was pharmacologically induced by scopolamine in young rats, and spontaneously present in aged rats. Learning ability before and after administration of EME was tested in Morris water maze protocols. Concentrations of EME in the brain and plasma were analyzed by gas chromatography-mass spectrometry. RESULTS: A single dose of EME reversed scopolamine impairment, indicating involvement of acetylcholine receptors. Longer-term treatment improved cognition in aged rats, with enhanced rates of learning in the absence of an exogenous cognition-impairing compound. Impairment returned with a new challenge; the improvement could be re-established with continued dosing. EME also reversed thigmotaxis seen in aged rats; thigmotaxis is believed to indicate anxiety. The concentrations of EME in the brain proved adequate drug exposure. CONCLUSIONS: Since other investigators have shown cognition impairment caused by cocaine in aged rats, this work shows that cocaine and EME have opposite effects in Morris water maze models. EME might induce cognitive enhancement and relief of anxiety in cocaine-impaired humans, and in other cognitive disorders.


Assuntos
Envelhecimento/efeitos dos fármacos , Antagonistas Colinérgicos/toxicidade , Cocaína/análogos & derivados , Cognição/efeitos dos fármacos , Entorpecentes/farmacologia , Escopolamina/toxicidade , Envelhecimento/fisiologia , Envelhecimento/psicologia , Animais , Cocaína/farmacologia , Cocaína/uso terapêutico , Cognição/fisiologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Inibidores da Captação de Dopamina/farmacologia , Inibidores da Captação de Dopamina/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Entorpecentes/uso terapêutico , Ratos , Ratos Sprague-Dawley
5.
Psychopharmacology (Berl) ; 237(5): 1317-1330, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31965252

RESUMO

RATIONALE: Methamphetamine (METH) enhances exocytotic dopamine (DA) signals and induces DA transporter (DAT)-mediated efflux in brain striatal regions such as the nucleus accumbens (NAc). Blocking sigma receptors prevents METH-induced DA increases. Sigma receptor activation induces Ca2+ release from intracellular stores, which may be responsible for METH-induced DA increases. OBJECTIVES: The role of intracellular and extracellular Ca2+ in METH-induced DA increases and associated behavior was tested. METHODS: METH-induced Ca2+ release was measured in hNPC-derived DA cells using ratiometric Ca2+ imaging. In mouse brain slices, fast-scan cyclic voltammetry was used to measure METH effects on two measures of dopamine: electrically stimulated and DAT-mediated efflux. Intracellular and extracellular Ca2+ was removed through pharmacological blockade of Ca2+ permeable channels (Cd2+ and IP3 sensitive channels), intracellular Ca2+ chelation (BAPTA-AM), or non-inclusion (zero Ca2+). Lastly, METH effects on dopamine-mediated locomotor behavior were tested in rats. Rats received intra-NAc injections of ACSF or 2-aminoethoxydiphenyl borate (2-APB; IP3 receptor blocker) and intraperitoneal METH (5 mg/kg) to test the role of intracellular Ca2+ release in DA-mediated behaviors. RESULTS: Reducing Ca2+ extracellular levels and Ca2+ release from intracellular stores prevented intracellular Ca2+ release. Intracellular Ca2+ chelation and blocking intracellular Ca2+ release reduced METH effects on voltammetric measures of dopamine. Blocking intracellular Ca2+ release via 2-APB resulted in increased METH-induced circling behavior. CONCLUSIONS: METH induces NAc DA release through intracellular Ca2+ activity. Blocking intracellular Ca2+ release prevents METH effects on DA signals and related behavior.


Assuntos
Cálcio/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
6.
J Med Chem ; 63(1): 391-417, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31841637

RESUMO

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Modafinila/análogos & derivados , Modafinila/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Tiazóis/farmacologia , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacocinética , Células HEK293 , Humanos , Masculino , Modafinila/metabolismo , Modafinila/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Ligação Proteica , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/síntese química , Inibidores da Recaptação de Serotonina e Norepinefrina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismo , Tiazóis/farmacocinética
7.
Psychopharmacology (Berl) ; 237(3): 723-734, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31822924

RESUMO

RATIONALE: The N-phenylpropyl-N'-substituted piperazines SA-4503 (N-phenylpropyl-N'-(3,4-dimethoxyphenethyl)piperazine) and YZ-185 (N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine) bind to sigma (σ) receptors and block the development of cocaine-induced conditioned place preference at concentrations that inhibit cocaine-induced hyperactivity. YZ-067 (N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine) also binds to sigma receptors and attenuates cocaine-induced hyperactivity in mice. OBJECTIVES: The present study determined the effect of YZ-067 on the development and expression of cocaine (66 µmol/kg or 33 µmol/kg) conditioned place preference (CPP) and locomotor sensitization in mice. RESULTS: YZ-067 (10 or 31.6 µmol/kg) did not have intrinsic effects on place preference or place aversion. Interestingly, the 31.6 µmol/kg YZ-067 dose enhanced the development of cocaine place preference, while 10 µmol/kg YZ-067 attenuated the development of cocaine-induced locomotor sensitization. However, YZ-067 did not alter the expression of cocaine place preference nor cocaine-induced locomotor sensitization. In follow-up studies, YZ-067 did not affect performance in the zero maze or rotarod, indicating that sigma receptors probed by this ligand do not regulate anxiety-like or coordinated motor skill behaviors, respectively. CONCLUSION: Overall, these results are consistent with previous studies demonstrating a role for sigma receptors in the behavioral effects of cocaine. However, the present findings also indicate that N-phenylpropyl-N'-substituted piperazines do not strictly block cocaine's behavioral effects and that sigma receptor may differentially mediate cocaine-induced hyperactivity and place conditioning.


Assuntos
Cocaína/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Piperazinas/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Recompensa , Animais , Cocaína/farmacologia , Condicionamento Psicológico/fisiologia , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia
8.
J Neurochem ; 152(3): 284-298, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31520531

RESUMO

We recently demonstrated that a tonic activation of adenosine A2A receptors (A2A Rs) is required for cocaine-induced synaptic depression and increase in the activity of STriatal-Enriched protein tyrosine Phosphatase (STEP). In this study, we elaborated on the relationship between A2A R and STEP using genetic, pharmacological, and cellular tools. We found that the activities of protein tyrosine phosphatases (PTPs), and in particular of STEP, are significantly increased in the striatum and hippocampus of a transgenic rat strain over-expressing the neuronal A2A R (NSEA2A ) with respect to wild-type (WT) rats. Moreover the selective A2A R agonist 4-[2-[[6-Amino-9-(N-ethyl-ß-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride up-regulates PTPs and STEP activities in WT but not in NSEA2A rats, while the selective A2A R antagonist 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol restores the tyrosine phosphatase activities in NSEA2A , having no effects in WT rats. In addition, while cocaine induced the activation of PTP and STEP in WT rats, it failed to increase phosphatase activity in NSEA2A rats. A2A Rs modulate STEP activity also in the SH-SY5Y neuroblastoma cell line, where a calcium-dependent calcineurin/PP1 pathway was found to play a major role. In summary, the present study identified a novel interaction between A2A R and STEP that could have important clinical implications, since STEP has emerged as key regulator of signaling pathways involved in neurodegenerative and neuropsychiatric diseases and A2A Rs are considered a promising target for the development of therapeutic strategies for different diseases of the central nervous system. Read the Editorial Highlight for this article on page 270.


Assuntos
Neurônios/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Receptor A2A de Adenosina/metabolismo , Animais , Linhagem Celular , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Feminino , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
9.
Mol Pharmacol ; 97(3): 171-179, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31871303

RESUMO

Bupropion, a Food and Drug Administration-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and noncompetitively inhibits nicotinic acetylcholine and serotonin (5-HT) type 3A receptors (5-HT3ARs). 5-HT3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system, presynaptically and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on mouse homomeric 5-HT3A and heteromeric 5-HT3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Coapplication of bupropion or hydroxybupropion with 5-HT dose dependently inhibited 5-HT-induced currents in heteromeric 5-HT type 3AB receptors (5-HT3ABRs) (IC50 = 840 and 526 µM, respectively). The corresponding IC50s for bupropion and hydroxybupropion for homomeric 5-HT3ARs were 10- and 5-fold lower, respectively (87 and 113 µM). The inhibition of 5-HT3ARs and 5-HT3ABRs was non-use dependent and voltage independent, suggesting bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, preincubation with a low concentration of bupropion that mimics therapeutic drug conditions inhibits 5-HT-induced currents in 5-HT3A and 5-HT3AB receptors considerably. In summary, we demonstrate that bupropion inhibits heteromeric 5-HT3ABRs as well as homomeric 5-HT3ARs. This inhibition occurs at clinically relevant concentrations and may contribute to bupropion's clinical effects. SIGNIFICANCE STATEMENT: Clinical studies indicate that antagonizing serotonin (5-HT) type 3AB (5-HT3AB) receptors in brain areas involved in mood regulation is successful in treating mood and anxiety disorders. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT type 3A receptors. The present work provides novel insights into the pharmacological effects that bupropion exerts on heteromeric 5-HT3AB receptors, in particular when constantly present at low, clinically attainable concentrations. The results advance the knowledge on the clinical effects of bupropion as an antidepressant.


Assuntos
Bupropiona/metabolismo , Bupropiona/farmacologia , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sequência de Aminoácidos , Animais , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Camundongos , Receptores 5-HT3 de Serotonina/genética , Estereoisomerismo , Xenopus laevis
10.
Neuron ; 104(5): 916-930.e5, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31759807

RESUMO

Drugs of abuse elicit powerful experiences that engage populations of neurons broadly distributed throughout the brain. To determine how synaptic connectivity is organized to enable robust communication between populations of drug-activated neurons, we developed a complementary targeting system for monosynaptic rabies virus (RV) tracing that identifies direct inputs to activated versus nonactivated neuronal populations. Analysis of over 100,000 synaptic input neurons demonstrated that cocaine-activated neurons comprise selectively connected but broadly distributed corticostriatal networks. Electrophysiological assays using optogenetics to stimulate activated versus nonactivated inputs revealed stronger synapses between coactivated cortical pyramidal neurons and neurons in the dorsal striatum (DS). Repeated cocaine exposure further enhanced the connectivity specifically between drug-activated neurons in the orbitofrontal cortex (OFC) and coactive DS neurons. Selective chemogenetic silencing of cocaine-activated OFC neurons or their terminals in the DS disrupted behavioral sensitization, demonstrating the utility of this methodology for identifying novel circuit elements that contribute to behavioral plasticity.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Vias Neurais/efeitos dos fármacos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Optogenética/métodos
11.
Sci Rep ; 9(1): 15294, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653935

RESUMO

Previous evidence pointed out a role for the striatal-enriched protein Rhes in modulating dopaminergic transmission. Based on the knowledge that cocaine induces both addiction and motor stimulation, through its ability to enhance dopaminergic signaling in the corpus striatum, we have now explored the involvement of Rhes in the effects associated with this psychostimulant. Our behavioral data showed that a lack of Rhes in knockout animals caused profound alterations in motor stimulation following cocaine exposure, eliciting a significant leftward shift in the dose-response curve and triggering a dramatic hyperactivity. We also found that Rhes modulated either short- or long-term motor sensitization induced by cocaine, since lack of this protein prevents both of them in mutants. Consistent with this in vivo observation, we found that lack of Rhes in mice caused a greater increase in striatal cocaine-dependent D1R/cAMP/PKA signaling, along with considerable enhancement of Arc, zif268, and Homer1 mRNA expression. We also documented that lack of Rhes in mice produced cocaine-related striatal alterations in proteomic profiling, with a differential expression of proteins clustering in calcium homeostasis and cytoskeletal protein binding categories. Despite dramatic striatal alterations associated to cocaine exposure, our data did not reveal any significant changes in midbrain dopaminergic neurons as a lack of Rhes did not affect: (i) DAT activity; (ii) D2R-dependent regulation of GIRK; and (iii) D2R-dependent regulation of dopamine release. Collectively, our results strengthen the view that Rhes acts as a pivotal physiological "molecular brake" for striatal dopaminergic system overactivation induced by psychostimulants, thus making this protein of interest in regulating the molecular mechanism underpinning cocaine-dependent motor stimulatory effects.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Proteínas de Ligação ao GTP/genética , Atividade Motora/efeitos dos fármacos , Proteoma/metabolismo , Proteômica/métodos , Animais , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Proteoma/genética , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
eNeuro ; 6(5)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31541002

RESUMO

The GABAergic medium-size spiny neuron (MSN), the striatal output neuron, may be classified into striosome, also known as patch, and matrix, based on neurochemical differences between the two compartments. At this time, little is known regarding the regulation of the development of the two compartments. Nr4a1, primarily described as a nuclear receptor/immediate early gene involved in the homeostasis of the dopaminergic system, is a striosomal marker. Using Nr4a1-overexpressing and Nr4a1-null mice, we sought to determine whether Nr4a1 is necessary and/or sufficient for striosome development. We report that in vivo and in vitro, Nr4a1 and Oprm1 mRNA levels are correlated. In the absence of Nr4a, there is a decrease in the percentage of striatal surface area occupied by striosomes. Alterations in Nr4a1 expression leads to dysregulation of multiple mRNAs of members of the dopamine receptor D1 signal transduction system. Constitutive overexpression of Nr4a1 decreases both the induction of phosphorylation of ERK after a single cocaine exposure and locomotor sensitization following chronic cocaine exposure. Nr4a1 overexpression increases MSN excitability but reduces MSN long-term potentiation. In the resting state, type 5 adenylyl cyclase (AC5) activity is normal, but the ability of AC5 to be activated by Drd1 G-protein-coupled receptor inputs is decreased. Our results support a role for Nr4a1 in determination of striatal patch/matrix structure and in regulation of dopaminoceptive neuronal function.


Assuntos
Corpo Estriado/metabolismo , Neurônios/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Receptores de Dopamina D1/biossíntese , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Cocaína/farmacologia , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Humanos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Transdução de Sinais/efeitos dos fármacos
13.
J Proteome Res ; 18(11): 3999-4012, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550894

RESUMO

Cocaine addiction afflicts nearly 1 million adults in the United States, and to date, there are no known treatments approved for this psychiatric condition. Women are particularly vulnerable to developing a cocaine use disorder and suffer from more serious cardiac consequences than men when using cocaine. Estrogen is one biological factor contributing to the increased risk for females to develop problematic cocaine use. Animal studies have demonstrated that estrogen (17ß-estradiol or E2) enhances the rewarding properties of cocaine. Although E2 affects the dopamine system, the molecular and cellular mechanisms of E2-enhanced cocaine reward have not been characterized. In this study, quantitative top-down proteomics was used to measure intact proteins in specific regions of the female mouse brain after mice were trained for cocaine-conditioned place preference, a behavioral test of cocaine reward. Several proteoform changes occurred in the ventral tegmental area after combined cocaine and E2 treatments, with the most numerous proteoform alterations on myelin basic protein, indicating possible changes in white matter structure. There were also changes in histone H4, protein phosphatase inhibitors, cholecystokinin, and calmodulin proteoforms. These observations provide insight into estrogen signaling in the brain and may guide new approaches to treating women with cocaine use disorder.


Assuntos
Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Estradiol/farmacologia , Proteoma/metabolismo , Proteômica/métodos , Animais , Encéfalo/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Estrogênios/farmacologia , Feminino , Camundongos Endogâmicos C57BL , Ovariectomia , Recompensa , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
14.
Nat Commun ; 10(1): 3934, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477694

RESUMO

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress-rather than promote-relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is, in part, driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Neurônios/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Alcoolismo/fisiopatologia , Alcoolismo/prevenção & controle , Animais , Cocaína/administração & dosagem , Comportamento Compulsivo/fisiopatologia , Comportamento Compulsivo/prevenção & controle , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Masculino , Córtex Pré-Frontal/fisiopatologia , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Transgênicos , Recidiva , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
15.
ACS Chem Neurosci ; 10(10): 4213-4220, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31479229

RESUMO

Addiction to psychostimulants is a major public health crisis that leads to significant morbidity and mortality, for which there are currently no FDA-approved pharmacotherapies. Female subjects have increased propensity to develop pathological substance use disorders after initial use, suggesting the possibility of different pathophysiological mechanisms between males and females. Recently, we identified the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) as a key mediator of neuronal and behavioral plasticity in response to cocaine in male mice. Here, we found that G-CSF potentiated the rewarding effects of cocaine in female mice as well; however, the dopaminergic mechanism linked to these effects was highly dependent on the ovarian hormone cycle. G-CSF treatment enhanced the ability of cocaine to inhibit dopamine clearance; however, this effect was observed specifically during pro/estrus, when circulating ovarian hormone levels were high. These findings demonstrate important sex differences in the synaptic effects of this translationally relevant neuroimmune modulator.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Ciclo Estral/fisiologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Recompensa
16.
Brain Res ; 1724: 146435, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491421

RESUMO

The combination of metyrapone and oxazepam (Met-Ox) has recently shown promise as a pharmacotherapy for cocaine use disorder. Metyrapone is available clinically and is typically used to diagnose adrenal insufficiency, while oxazepam is often prescribed to treat anxiety. The combination of low doses of metyrapone and oxazepam has been shown to significantly attenuate cocaine self-administration and cue-reactivity in rats, as well as decrease the number of subjects that used cocaine in a pilot clinical trial. Previous studies in rats suggest that the combination of these two drugs may decrease drug-related behaviors by reducing corticosterone synthesis in the medial prefrontal cortex. Since corticosterone has been associated with increased brain dopamine, these reductions in central corticosterone produced by Met-Ox might be accompanied by a concomitant decrease in dopamine to thereby attenuate drug taking and seeking. Thus, these studies were designed to determine the effects of Met-Ox on dopamine in rats. In vivo microdialysis studies in the medial prefrontal cortex and nucleus accumbens revealed that Met-Ox produced no measurable effects on cocaine-induced increases in dopamine. Further, the combination of these two drugs produced no effect on dopamine in the absence of cocaine. Together, these studies demonstrate that Met-Ox does not exert its effects by altering dopamine, suggesting that it might be possible to treat cocaine use disorder without affecting dopamine, which would lead to reduced side effects and increased compliance.


Assuntos
Dopamina/metabolismo , Metirapona/farmacologia , Oxazepam/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Corticosterona/farmacologia , Dopamina/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Autoadministração
17.
Neurosci Lett ; 712: 134499, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536752

RESUMO

The psychoactive drug methylenedioxypyrovalerone (MDPV) elicits feelings of euphoria and hyperexcitability, but can also result in paranoia, agitation, and depression by unknown mechanisms. We identified molecular networks in the rat striatum that were affected by single or repeated exposure to MDPV. Male Long Evans rats were injected with either saline or MDPV (1 mg/kg) (single or repeated MDPV) over 5 days. To distinguish the effects of repeated MDPV from a single exposure, an additional group received saline over 4 days and then MDPV on the 5th day. Twenty-four hours after the final injection, the left dorsal striatum was processed for transcriptomics. The transcriptome response was subtle after 24 h, and a single gene passed an FDR correction (LOC103691845) following repeated MDPV treatment. Gene set and subnetwork enrichment analyses were conducted to improve data interpretation from a network perspective. Consistent with the mode of action of MDPV, networks related to the nigrostriatal dopaminergic system were altered in the rat striatum. Transcriptional networks related to cognition, short and long-term memory, and synaptic transmission were over-represented in the striatum of rats repeatedly injected with MDPV. This study identifies potential transcriptional networks altered by single or repeated MDPV exposure, which can be interrogated further to elucidate molecular mechanisms underlying cathinone abuse.


Assuntos
Benzodioxóis/farmacologia , Corpo Estriado/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Pirrolidinas/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Vias de Administração de Medicamentos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Long-Evans , Comportamento Estereotipado/efeitos dos fármacos
18.
Nat Commun ; 10(1): 4263, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537790

RESUMO

Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short-term plasticity of dopamine release, using fast-scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short-term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+-gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short-term plasticity, governing the balance between release-dependent and independent mechanisms that also show region-specific gating.


Assuntos
Axônios/metabolismo , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Animais , Transporte Biológico , Inibidores da Captação de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia
19.
PLoS Negl Trop Dis ; 13(8): e0007573, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31408466

RESUMO

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct.


Assuntos
Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Fasciola hepatica/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Ácido Cólico , Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , FMRFamida/farmacologia , Fluorenos/farmacologia , Neuropeptídeo Y/farmacologia , Peptídeo YY/farmacologia , Piperazinas/farmacologia , Serotoninérgicos/farmacologia , Compostos de Espiro/farmacologia , Sulpirida/farmacologia
20.
Cell Rep ; 28(9): 2256-2263.e3, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461643

RESUMO

We examine synaptic connectivity and cocaine-evoked plasticity at specific networks within the nucleus accumbens (NAc). We identify distinct subpopulations of D1+ medium spiny neurons (MSNs) that project to either the ventral pallidum (D1+VP) or the ventral tegmental area (D1+VTA). We show that inputs from the ventral hippocampus (vHPC), but not the basolateral amygdala (BLA), are initially biased onto D1+VTA MSNs. However, repeated cocaine exposure eliminates the bias of vHPC inputs onto D1+VTA MSNs, while strengthening BLA inputs onto D1+VP MSNs. Our results reveal that connectivity and plasticity depend on the specific inputs and outputs of D1+ MSNs and highlight the complexity of cocaine-evoked circuit level adaptations in the NAc.


Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Núcleo Accumbens/citologia , Animais , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia
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