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1.
Clin Nucl Med ; 45(11): 919-920, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32969905

RESUMO

F-FDG is the most widely used PET tracer worldwide. Before the examination, recommendations are given to patients to avoid muscular activities, with the goal to limit F-FDG uptake in muscles. Here, we report the case of a 36-year-old man with Hodgkin disease referred to our department to perform an F-FDG PET/CT for immunotherapy assessment. The PET images showed a homogeneous, symmetric, and very intense uptake of the masticatory muscles. The medical examination exhibited a trismus, and the patient revealed to have been using cocaine 15 minutes before injection of F-FDG.


Assuntos
Cocaína/farmacologia , Fluordesoxiglucose F18/metabolismo , Músculos da Mastigação/metabolismo , Adulto , Artefatos , Transporte Biológico/efeitos dos fármacos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/metabolismo , Humanos , Masculino , Músculos da Mastigação/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
2.
Nat Commun ; 11(1): 3996, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778725

RESUMO

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipercinese/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Dopamina , Feminino , Hipercinese/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética
3.
Proc Natl Acad Sci U S A ; 117(18): 9991-10002, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312805

RESUMO

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.


Assuntos
Comportamento Aditivo/genética , Comportamento Animal/efeitos dos fármacos , Canabinoides/efeitos adversos , Cocaína/efeitos adversos , Adolescente , Animais , Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/patologia , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Canabinoides/farmacologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Cocaína/farmacologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona/genética , Humanos , Proteínas de Membrana/farmacologia , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Fosfoproteínas/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Córtex Pré-Frontal/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Ratos , Transcriptoma/efeitos dos fármacos
4.
Cell Mol Life Sci ; 77(19): 3745-3768, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32172301

RESUMO

Risk of relapse is a major challenge in the treatment of substance use disorders. Several types of learning and memory mechanisms are involved in substance use and have implications for relapse. Associative memories form between the effects of drugs and the surrounding environmental stimuli, and exposure to these stimuli during abstinence causes stress and triggers drug craving, which can lead to relapse. Understanding the neural underpinnings of how these associations are formed and maintained will inform future advances in treatment practices. A large body of research has expanded our knowledge of how associative memories are acquired and consolidated, how they are updated through reactivation and reconsolidation, and how competing extinction memories are formed. This review will focus on the vast literature examining the mechanisms of cocaine Pavlovian associative memories with an emphasis on the molecular memory mechanisms and circuits involved in the consolidation, reconsolidation, and extinction of these memories. Additional research elucidating the specific signaling pathways, mechanisms of synaptic plasticity, and epigenetic regulation of gene expression in the circuits involved in associative learning will reveal more distinctions between consolidation, reconsolidation, and extinction learning that can be applied to the treatment of substance use disorders.


Assuntos
Cocaína/farmacologia , Memória/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/patologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interocepção/efeitos dos fármacos , Memória/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo
5.
Pharmacol Rep ; 72(2): 332-339, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32124388

RESUMO

BACKGROUND: Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor-receptor interactions have previously been demonstrated in A2AR-D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR-D2R interaction disappeared in the dorsal striatum. METHODS: In the current experiments, it was tested whether such modifications in the antagonistic A2AR-D2R receptor-receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc). RESULTS: Microdialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group. CONCLUSIONS: The molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR-D2R receptor-receptor interactions may be an increased formation of higher-order complexes A2AR-D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR-D2R interaction in this receptor complex.


Assuntos
Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/metabolismo , Regulação Alostérica , Sítio Alostérico , Animais , Ligação Competitiva , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Masculino , Microdiálise , Ligação Proteica , Ratos Wistar , Autoadministração
6.
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
7.
Psychopharmacology (Berl) ; 237(4): 1043-1053, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912191

RESUMO

RATIONALE AND OBJECTIVE: Alcohol is a recreational substance that is generally socially acceptable and legal in most areas worldwide. An alcohol overdose will produce an inhibitory effect on the brain and impair cognition and memory. In this study, we examined the effect of alcohol on the acquisition, consolidation, and reconsolidation of drug reward memory induced by morphine and cocaine in rats. METHODS: Rats were trained to acquire morphine sulfate (10 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) conditioned place preference (CPP) via an unbiased CPP paradigm. Vehicle or alcohol (0.25, 0.75, 1.5 g/kg, i.p.) was administered at various time-points, including 30 min before each CPP conditioning session (acquisition), immediately after each CPP conditioning session (consolidation), immediately after the reactivation of CPP (reconsolidation with re-exposure), or without reactivation to the drug-paired context (reconsolidation without re-exposure). Conditioning scores were recorded before or after each conditioning session or memory reactivation. RESULTS: Alcohol at a dose of 1.5 g/kg but not 0.25 g/kg or 0.75 g/kg significantly inhibited the acquisition and reconsolidation of morphine- and cocaine-associated memory. In contrast, alcohol had no effect on the consolidation of morphine- or cocaine-induced CPP. CONCLUSIONS: The results suggested that pre-exposure alcohol dose-dependently attenuated morphine- or cocaine-induced place preference and prevented drug reinstatement in rats by disrupting memory reconsolidation, which may be explained by the inhibitory effect of alcohol on dopaminergic and glutamatergic neurotransmission.


Assuntos
Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Memória/efeitos dos fármacos , Morfina/farmacologia , Recompensa , Animais , Condicionamento Clássico/fisiologia , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Memória/fisiologia , Ratos , Ratos Sprague-Dawley
8.
Nat Commun ; 11(1): 504, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980629

RESUMO

Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrated the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Epigênese Genética , Homeostase/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Cocaína/administração & dosagem , Epigênese Genética/efeitos dos fármacos , Feminino , Histonas/metabolismo , Homeostase/genética , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenilacetatos/farmacologia , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional , Sinapsinas/metabolismo
9.
Nat Commun ; 11(1): 306, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949158

RESUMO

With the rise of e-cigarette use, teen nicotine exposure is becoming more widespread. Findings from clinical and preclinical studies show that the adolescent brain is particularly sensitive to nicotine. Animal studies have demonstrated that adolescent nicotine exposure increases reinforcement for cocaine and other drugs. However, the mechanisms that underlie these behaviors are poorly understood. Here, we report reactive microglia are critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has dichotomous, age-dependent effects on microglial morphology and immune transcript profiles. A multistep signaling mechanism involving D2 receptors and CX3CL1 mediates nicotine-induced increases in cocaine self-administration and microglial activation. Moreover, nicotine depletes presynaptic markers in a manner that is microglia-, D2- and CX3CL1-dependent. Taken together, we demonstrate that adolescent microglia are uniquely susceptible to perturbations by nicotine, necessary for nicotine-induced increases in cocaine-seeking, and that D2 receptors and CX3CL1 play a mechanistic role in these phenomena.


Assuntos
Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Nicotina/farmacologia , Aminopiridinas/farmacologia , Animais , Quimiocina CX3CL1/metabolismo , Modelos Animais de Doenças , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Minociclina/farmacologia , Fenótipo , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos , Reforço Psicológico , Recompensa , Autoadministração , Sinaptofisina
10.
J Neurosci ; 40(6): 1321-1331, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31836660

RESUMO

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VPGABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.SIGNIFICANCE STATEMENT The ventral pallidum consists mainly of GABAergic reward-promoting neurons, but it also encloses a subgroup of aversion-promoting glutamatergic neurons. Dynorphin, an opioid neuropeptide abundant in the ventral pallidum, shows differential modulation of GABA input to GABAergic and glutamatergic pallidal neurons and may therefore affect both the rewarding and aversive aspects of withdrawal. Indeed, abstinence after repeated exposure to cocaine alters dynorphin actions in a cell-type-specific manner; after abstinence dynorphin suppresses the inhibitory drive on the "rewarding" GABAergic neurons but ceases to modulate the inhibitory drive on the "aversive" glutamatergic neurons. This reflects a complex role for dynorphin in cocaine reward and abstinence.


Assuntos
Prosencéfalo Basal/metabolismo , Cocaína/farmacologia , Dinorfinas/metabolismo , Neurônios/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Transmissão Sináptica/fisiologia , Animais , Prosencéfalo Basal/citologia , Prosencéfalo Basal/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Recompensa , Transmissão Sináptica/efeitos dos fármacos
11.
J Pharmacol Exp Ther ; 372(2): 205-215, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31748404

RESUMO

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the µ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at µ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.


Assuntos
Buprenorfina/uso terapêutico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos Opioides/metabolismo , Animais , Técnicas de Observação do Comportamento , Pressão Sanguínea/efeitos dos fármacos , Buprenorfina/efeitos adversos , Buprenorfina/farmacocinética , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Interações Alimento-Droga , Frequência Cardíaca/efeitos dos fármacos , Heroína/metabolismo , Humanos , Macaca mulatta , Masculino , Morfina/metabolismo , Naltrexona/efeitos adversos , Naltrexona/farmacocinética , Canais de Potássio/metabolismo , Receptores Opioides mu/metabolismo , Remifentanil/farmacologia , Prevenção Secundária , Autoadministração , Resultado do Tratamento
12.
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
13.
Proc Natl Acad Sci U S A ; 117(38): 23304-23310, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31636216

RESUMO

The induction of immediate-early gene (IEG) expression in brain nuclei in response to an experience is necessary for the formation of long-term memories. Additionally, the rapid dynamics of IEG induction and decay motivates the common use of IEG expression as markers for identification of neuronal assemblies ("ensembles") encoding recent experience. However, major gaps remain in understanding the rules governing the distribution of IEGs within neuronal assemblies. Thus, the extent of correlation between coexpressed IEGs, the cell specificity of IEG expression, and the spatial distribution of IEG expression have not been comprehensively studied. To address these gaps, we utilized quantitative multiplexed single-molecule fluorescence in situ hybridization (smFISH) and measured the expression of IEGs (Arc, Egr2, and Nr4a1) within spiny projection neurons (SPNs) in the dorsal striatum of mice following acute exposure to cocaine. Exploring the relevance of our observations to other brain structures and stimuli, we also analyzed data from a study of single-cell RNA sequencing of mouse cortical neurons. We found that while IEG expression is graded, the expression of multiple IEGs is tightly correlated at the level of individual neurons. Interestingly, we observed that region-specific rules govern the induction of IEGs in SPN subtypes within striatal subdomains. We further observed that IEG-expressing assemblies form spatially defined clusters within which the extent of IEG expression correlates with cluster size. Together, our results suggest the existence of IEG-expressing neuronal "superensembles," which are associated in spatial clusters and characterized by coherent and robust expression of multiple IEGs.


Assuntos
Encéfalo/metabolismo , Genes Precoces , Neurônios/metabolismo , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cocaína/farmacologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Expressão Gênica , Genes Precoces/efeitos dos fármacos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Imagem Individual de Molécula
14.
Psychopharmacology (Berl) ; 237(2): 385-394, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31667531

RESUMO

RATIONALE: Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction. OBJECTIVES: Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation. METHODS: Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3-10 mg/kg) or JWH133 (CB2R agonist; 1-10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus. RESULTS: AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals. CONCLUSIONS: CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.


Assuntos
Cocaína/farmacologia , Condicionamento Clássico/fisiologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/fisiologia , Animais , Canabinoides/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Piperidinas/farmacologia , Pirazóis/farmacologia
15.
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
16.
Acta Pharmacol Sin ; 41(2): 163-172, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31399700

RESUMO

Cocaine is one of the most abused illicit drugs worldwide. It is well known that the dopamine (DA) transporter is its major target; but cocaine also acts on other targets including nicotinic acetylcholine receptors (nAChRs). In this study, we investigated the effects of cocaine on a special subtype of neuronal nAChR, α3ß4-nAChR expressed in native SH-SY5Y cells. α3ß4-nAChR-mediated currents were recorded using whole-cell recordings. Drugs were applied using a computer-controlled U-tube drug perfusion system. We showed that bath application of nicotine induced inward currents in a concentration-dependent manner with an EC50 value of 20 µM. Pre-treatment with cocaine concentration-dependently inhibited nicotine-induced current with an IC50 of 1.5 µM. Kinetic analysis showed that cocaine accelerated α3ß4-nAChR desensitization, which caused a reduction of the amplitude of nicotine-induced currents. Co-application of nicotine and cocaine (1.5 µM) depressed the maximum response on the nicotine concentration-response curve without changing the EC50 value, suggesting a non-competitive mechanism. The cocaine-induced inhibition of nicotine response exhibited both voltage- and use-dependence, suggesting an open-channel blocking mechanism. Furthermore, intracellular application of GDP-ßS (via recording electrode) did not affect cocaine-induced inhibition, suggesting that cocaine did not alter receptor internalization. Moreover, intracellular application of cocaine (30 µM) failed to alter the nicotine response. Finally, cocaine (1.5 µM) was unable to inhibit the nicotine-induced inward current in heterologous expressed α6/α3ß2ß3-nAChRs and α4ß2-nAChRs expressed in human SH-EP1 cells. Collectively, our results suggest that cocaine is a potent blocker for native α3ß4-nAChRs expressed in SH-SY5Y cells.


Assuntos
Cocaína/farmacologia , Neurônios/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Linhagem Celular Tumoral , Cocaína/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Neuroblastoma/metabolismo , Neurônios/metabolismo , Nicotina/farmacologia , Técnicas de Patch-Clamp , Receptores Nicotínicos/metabolismo
17.
Mol Neurobiol ; 57(1): 346-357, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31359322

RESUMO

Cocaine addiction remains a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to yoked saline controls. By contrast, cued reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug-seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.


Assuntos
Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Canais de Cálcio Tipo N/metabolismo , Cocaína/administração & dosagem , Sinais (Psicologia) , Modelos Animais de Doenças , Masculino , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Autoadministração
18.
Mol Neurobiol ; 57(1): 450-460, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31378002

RESUMO

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.


Assuntos
Cocaína/farmacologia , Hipocampo/enzimologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Animal , Cocaína/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Indazóis/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos Wistar
19.
Psychopharmacology (Berl) ; 237(1): 55-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31463541

RESUMO

RATIONALE: Comorbid use of heroin and cocaine is highly prevalent among drug users and can greatly increase addiction risk. Nonetheless, little is known regarding how a multi-drug history impacts motivation and cue responsivity to individual drugs. OBJECTIVE: We used behavioral-economic procedures to examine motivation to maintain drug consumption and tests of drug-seeking to drug-associated cues to assess sensitivity to heroin and cocaine-associated cues in rats that had a self-administration history of heroin, cocaine, or both drugs. RESULTS: Unexpectedly, we found that groups with a polydrug history of heroin and cocaine did not have higher levels of motivation or cue-induced reinstatement of drug-seeking for either cocaine or heroin compared to single drug groups. Nonetheless, we did find drug-specific differences in both economic price and cue sensitivity. Specifically, demand elasticity was lower for cocaine compared to heroin in animals with a single drug history, but not with polydrug groups. In addition, cocaine demand was predictive of the degree of cue-induced reinstatement of drug-seeking for cocaine following extinction, whereas heroin demand was predictive of the degree of reactivity to a heroin-associated cue. Furthermore, although cue reactivity following the initial self-administration phase did not differ across cues and drug history, reactivity to both heroin and cocaine cues was greater during subsequent heroin use compared to cocaine use, and this enhanced reactivity to heroin cues persisted during forced abstinence. CONCLUSIONS: These results indicate that there is a greater motivation to maintain cocaine consumption, but higher sensitivity to drug-associated cues with a history of heroin use, suggesting that cocaine and heroin may drive continued drug use through different behavioral processes.


Assuntos
Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Heroína/farmacologia , Motivação/efeitos dos fármacos , Animais , Comportamento Aditivo/psicologia , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Psicológico , Sinais (Psicologia) , Economia Comportamental , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração/métodos
20.
Int J Mol Sci ; 22(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396297

RESUMO

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Recompensa , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , AMP Cíclico/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley
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