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1.
Nat Commun ; 11(1): 1957, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327644

RESUMO

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.


Assuntos
Neostriado/citologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D2/metabolismo , Anfetamina/farmacologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopaminérgicos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/metabolismo , Neostriado/fisiologia , Vias Neurais , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/genética
2.
Am J Physiol Regul Integr Comp Physiol ; 318(3): R649-R656, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32048863

RESUMO

Psychomotor stimulants are prescribed for many medical conditions, including obesity, sleep disorders, and attention-deficit/hyperactivity disorder. However, despite their acknowledged therapeutic utility, these stimulants are frequently abused, and their use can have both short- and long-term negative consequences. Although stimulants such as amphetamines acutely elevate blood pressure, it is unclear whether they cause any long-term effects on cardiovascular function after use has been discontinued. Previous work in our laboratory has demonstrated that physiological and psychosocial stressors will produce sensitization of the hypertensive response, a heightened pressor response to a hypertensinogenic stimulus delivered after stressor exposure. Here, we tested whether pretreatment with amphetamine for 1 wk can sensitize the hypertensive response in rats. We found that repeated amphetamine administration induced and maintained sensitization of the pressor response to angiotensin II following a 7-day delay after amphetamine injections were terminated. We also found that amphetamine pretreatment altered mRNA expression for molecular markers associated with neuroinflammation and renin-angiotensin-aldosterone system (RAAS) activation in the lamina terminalis, a brain region implicated in the control of sympathetic nervous system tone and blood pressure. The results indicated amphetamine upregulated mRNA expression underlying neuroinflammation and, to a lesser degree, message for components of the RAAS in the lamina terminalis. However, we found no changes in mRNA expression in the paraventricular nucleus. These results suggest that a history of stimulant use may predispose individuals to developing hypertension by promoting neuroinflammation and upregulating activity of the RAAS in the lamina terminalis.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Hipertensão/fisiopatologia , Hipotálamo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipotálamo/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos
3.
Neuron ; 105(6): 1036-1047.e5, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954621

RESUMO

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.


Assuntos
Astrócitos/fisiologia , Dopamina/fisiologia , Núcleo Accumbens/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Anfetamina/farmacologia , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/fisiologia , Optogenética , Receptores de Dopamina D1/genética , Recompensa
4.
Obesity (Silver Spring) ; 27(11): 1874-1882, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31562706

RESUMO

OBJECTIVE: Amphetamine was formerly used as a treatment to combat obesity, but amphetamine's use as an appetite suppressant was discontinued because of its significant abuse potential. Most of the rewarding and reinforcing effects of amphetamine differ by sex, with females showing higher levels of drug intake and amphetamine-induced motivation, relapse, and locomotion, but it is unknown whether amphetamine's effects on feeding also differ by sex. Furthermore, previous research on the anorectic effects of amphetamine has been focused primarily on its effects on baseline homeostatic feeding, but it is unknown whether amphetamine also affects hedonic, reward-related feeding, which is an important factor driving the rise in obesity levels. METHODS: This study tested whether amphetamine alters food intake in a sex-dependent manner in two reward-related feeding paradigms: a sucrose two-bottle choice test and a high-fat/high-sugar binge intake model. RESULTS: Amphetamine altered food intake equally in males and females in both paradigms, with higher doses significantly inhibiting feeding and low doses of amphetamine increasing feeding at later time points. CONCLUSIONS: Amphetamine's effects on feeding and drug reward may be mediated by distinct mechanisms, which could allow for the development of new approaches to combat obesity with limited abuse and addiction-related side effects.


Assuntos
Anfetamina/farmacologia , Bulimia , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Ingestão de Energia/efeitos dos fármacos , Sacarose/administração & dosagem , Animais , Depressores do Apetite/farmacologia , Bulimia/induzido quimicamente , Bulimia/metabolismo , Bulimia/prevenção & controle , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais
5.
Synapse ; 73(12): e22129, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31449701

RESUMO

Published behavioral experiments document that amphetamine-induced increases in locomotor activity are preserved or enhanced in animals with major depletions of stored dopamine but intact dopamine synthesis. Conversely, amphetamine effects are substantially attenuated after inhibition of dopamine synthesis when most of the dopamine stores are preserved. Such data suggest that amphetamine mobilizes newly synthesized dopamine into extracellular signaling space. The first goal of this project is to determine kinetic parameters of dopamine secretion into and removal from extracellular space compatible with the majority of amphetamine-elicited increases in extracellular dopamine deriving from newly synthesized dopamine. The strategy uses a computational model of extracellular space surrounding a single dopamine varicosity. Model output was compared to published micro-dialysis data for effects of amphetamine on levels of extracellular dopamine. A family of solutions was found, characterized by a biphasic dose-response relationship for rate of dopamine release. Maximum rates of dopamine release occurred at doses of 0.5-1.0 mg/kg amphetamine. The second goal is to develop a hypothesis by which newly synthesized dopamine gains access to extracellular space. The model chosen involves amphetamine-induced shunting of DOPAC secretion to dopamine secretion into extracellular space. The quality of the hypothesis was evaluated by goodness of match of model output to published data for amphetamine alone and after inhibition of dopamine synthesis or storage. In summary, the results provide conditions required for and a potential mechanism for newly synthesized dopamine to be a major fraction of amphetamine-elicited increases in extracellular dopamine.


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Animais , Simulação por Computador , Neurônios Dopaminérgicos/metabolismo , Modelos Teóricos
6.
Neuron ; 103(5): 891-908.e6, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277924

RESUMO

Motivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheral→central pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Etanol/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Recompensa , Proteína Relacionada com Agouti/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Hipotálamo/metabolismo , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nicotina/farmacologia , Pró-Opiomelanocortina/metabolismo , Vagotomia , Nervo Vago/fisiologia
7.
Behav Neurosci ; 133(5): 478-488, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343201

RESUMO

Substance use disorder is driven by complex gene-environment interactions. Epigenetic histone regulation is a significant contributor to several behavioral phenotypes of drug abuse. The primary epigenetic mechanisms that drive drug taking and drug seeking are still being investigated, and it is unclear how environmental conditions alter epigenetic histone acetylation to change behaviors geared toward drug reward. This study examined the effects of environmental condition on amphetamine self-administration, and whether drug-taking and drug-seeking behaviors could be influenced through inhibition of an epigenetic regulator, histone deacetylase (HDAC). Male rats reared for 30 days in enriched (EC), isolated (IC), or standard conditions (SC) prior to amphetamine (0.03, 0.05, 0.1 mg/kg/infusion, IV) self-administration, extinction, and reinstatement sessions. The HDAC inhibitor, Trichostatin A (TsA; 0.3 mg/kg, IV), was injected 30 min prior to operant sessions. After amphetamine-induced reinstatement (0.25 mg/kg, subcutaneous [s.c.]), tissue was extracted for Western blot analyses of acetylated histone H3 lysine 9 (acH3K9) in the nucleus accumbens (NAc) and dorsal striatum (DSt). While TsA did not significantly affect amphetamine self-administration or extinction, TsA decreased cue-, but not drug-induced reinstatement in IC rats only. In the DSt, but not in the NAc, IC rats exhibited significantly less acH3K9 expression than EC and SC rats, irrespective of TsA treatment. HDAC inhibition decreases cue-induced reinstatement of amphetamine seeking in IC rats. While IC rats exhibit less acH3K9 expression in the DSt, future studies are needed to elucidate the critical epigenetic factors that drive substance abuse, particularly in vulnerable populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Comportamento de Procura de Droga/efeitos dos fármacos , Inibidores de Histona Desacetilases/metabolismo , Transtornos Relacionados ao Uso de Substâncias/genética , Acetilação , Anfetamina/farmacologia , Animais , Condicionamento Operante/fisiologia , Corpo Estriado/fisiologia , Sinais (Psicologia) , Comportamento de Procura de Droga/fisiologia , Meio Ambiente , Epigênese Genética/genética , Epigenômica/métodos , Extinção Psicológica/fisiologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Masculino , Núcleo Accumbens/fisiologia , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração
8.
Neuron ; 103(6): 1056-1072.e6, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31324539

RESUMO

Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3DTR/+ diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson's disease (PD). VIDEO ABSTRACT.


Assuntos
Acetilcolina/metabolismo , Neurônios Colinérgicos/metabolismo , Dopamina/deficiência , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Interneurônios/metabolismo , Neostriado/metabolismo , Doença de Parkinson/metabolismo , Anfetamina/farmacologia , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Camundongos , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neostriado/fisiopatologia , Doença de Parkinson/fisiopatologia , Técnicas de Patch-Clamp , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transcrição Genética
9.
Behav Neurosci ; 133(4): 428-436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31294591

RESUMO

Previous work from our laboratory has indicated that temporary inactivation of the basolateral amygdala (BLA) with bupivacaine blocks acquisition, consolidation, and retrieval of an amphetamine conditioned place preference (CPP). The present study was designed to extend this line of investigation by examining whether N-methyl-D-aspartate (NMDA) receptors in the BLA mediate acquisition and extinction of an amphetamine CPP. Adult male Long-Evans rats received bilateral intra-BLA injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1.25 µg, 2.5 µg, or 5.0 µg) or saline prior to each session of CPP acquisition (Experiment 1). In addition, separate groups of rats received intra-BLA injections of the sodium channel blocker bupivacaine (Experiment 2), AP5 (1.25 µg, 2.5 µg, or 5.0 µg; Experiment 3), or saline prior to each session of CPP extinction training. Results indicated that intra-BLA injection of bupivacaine or AP5 (2.5 or 5.0 µg) disrupted acquisition of an amphetamine CPP. In addition, neural inactivation of the BLA with bupivacaine blocked extinction of CPP. Finally, intra-BLA AP5 injections (2.5 or 5.0 µg) were sufficient to block CPP extinction. The present findings indicate that NMDA receptor activity in the BLA is critical for acquisition and extinction of an amphetamine CPP and may be relevant to understanding the neural mechanisms underlying some aspects of drug seeking and addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Anfetamina/metabolismo , Anfetamina/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Bupivacaína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Extinção Psicológica/fisiologia , Masculino , Memória/fisiologia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Behav Pharmacol ; 30(7): 588-595, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31206370

RESUMO

Does the effect of amphetamine on behavior (wheel running) differ depending on the functional role (operant, reinforcement) of that behavior? This study addressed this question using a multiple schedule of reinforcement in which wheel running served as reinforcement for lever pressing in one component and as operant behavior for sucrose reinforcement in the other component. Seven female Long-Evans rats were exposed to a multiple schedule in which pressing a lever on a variable ratio 10 schedule produced the opportunity to run for 15 revolutions in one component and running 15 revolutions produced a drop of 15% sucrose solution in the other component. Doses of 0.5, 1.0, and 2.0 mg/kg D-amphetamine were administered by intraperitoneal injection 20 min prior to a session. As amphetamine dose increased, wheel running decreased in both components - showing no evidence that the effect of the drug on wheel running depended on the function of wheel activity. Notably, lever pressing for wheel-running reinforcement also decreased with amphetamine dose. Drug dose increased the initiation of operant lever pressing, but not the initiation of operant wheel running. We propose that amphetamine dose had common effects on wheel running regardless of its function (reinforcement vs. operant) because wheel-running generates automatic reinforcement and the automatic-reinforcement value of wheel activity is modulated by drug dose.


Assuntos
Anfetamina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Animais , Feminino , Ratos , Ratos Long-Evans , Esquema de Reforço , Reforço Psicológico , Sacarose/farmacologia
11.
Neurochem Int ; 129: 104487, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176680

RESUMO

Repeated exposure to classical psychomotor stimulants, like amphetamine (AMPH), produces locomotor sensitization and accompanied structural plasticity of dendritic spines in the nucleus accumbens (NAcc). Following our previous report that repeated administration of methiopropamine (MPA), a structural analog to meth-AMPH, produces locomotor sensitization, it was examined in the present study whether this behavioral change also accompanies with structural plasticity in the NAcc in a similar way to AMPH. A week after adeno-associated viral vectors containing enhanced green fluorescent protein (eGFP) were microinjected into the NAcc core, rats were repeatedly injected with saline, AMPH (1 mg/kg, IP), or MPA (5 mg/kg, IP) once every 2-3 days for a total of 4 times. Two weeks after last injection, all rats were perfused and their brains were processed for immunohistochemical staining. The image stacks for dendrite segments of medium spiny neuronal cells in the NAcc core were obtained and dendritic spines were quantitatively analyzed. Interestingly, it was found that the number of total spine density, with thin spine as a major contributor, was significantly increased in MPA compared to saline pre-exposed group, in a similar way to AMPH. These results indicate that MPA, a novel psychoactive substance, has similar characteristics with AMPH in that they both produce structural as well as behavioral changes, further supporting MPA's dependence and abuse potential.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Metanfetamina/análogos & derivados , Núcleo Accumbens/efeitos dos fármacos , Tiofenos/farmacologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Espinhas Dendríticas/ultraestrutura , Genes Reporter , Masculino , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/ultraestrutura , Ratos , Ratos Sprague-Dawley
12.
Neurobiol Dis ; 130: 104494, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176715

RESUMO

Attention deficit hyperactivity disorder is a pervasive developmental disorder characterized by inattention, impulsivity, and hyperactivity and is 75-90% heritable. Latrophilin-3 (LPHN3; or ADGRL(3)) is associated with a subtype of ADHD, but how it translates to symptoms is unknown. LPHN3 is a synaptic adhesion G protein coupled receptor that binds to fibronectin leucine rich transmembrane protein 3 and teneurin-3 (FLRT3 and TEN-3). We created a null mutation of Lphn3 (KO) in Sprague-Dawley rats using CRISPR/Cas9 to delete exon-3. The KO rats had no effects on reproduction or survival but reduced growth. KO females showed catch-up weight gain whereas KO males did not. We tested WT and KO littermates for home-cage activity, anxiety-like behavior, acoustic startle response, and activity after amphetamine challenge. Expression of Lphn3-related genes, monoamines, and receptors were determined. Lphn3 KO rats showed persistent hyperactivity, increased acoustic startle, reduced activity in response to amphetamine relative to baseline, and female-specific reduced anxiety-like behavior. Expression of Lphn1, Lphn2, and Flrt3 by qPCR and their protein products by western-blot analysis showed no compensatory upregulation. Striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase (AADC), and the dopamine transporter were increased and dopamine D1 receptor (DRD1) and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) decreased with no changes in DRD2, DRD4, vesicular monoamine transporter-2, N-methyl-d-aspartate (NMDA)-NR1, -NR2A, or -NR2B. LPHN3 is expressed in many brain regions but its function is largely unknown. Data from human, mouse, zebrafish, Drosophila and our new Lphn3 KO rat data collectively show that its disruption is significantly correlated with hyperactivity and associated striatal changes in dopamine markers.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Corpo Estriado/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Feminino , Técnicas de Inativação de Genes , Masculino , Ratos , Ratos Sprague-Dawley
13.
Artigo em Inglês | MEDLINE | ID: mdl-31022425

RESUMO

The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMPH)-related appetitive 50-kHz ultrasonic vocalisations (USVs) in rats differing in freezing duration in a contextual fear test (CFT), i.e. HR (high-anxiety responsive) and LR (low-anxiety responsive) rats. The LR and the HR rats, previously exposed to an AMPH binge experience, differed in sensitivity to AMPH's rewarding effects, measured as appetitive vocalisations. Moreover, chronic restraint stress attenuated AMPH-related appetitive vocalisations in the LR rats but had no influence on the HR rats' behaviour. To specify, the restraint LR rats vocalised appetitively less in the AMPH-associated context and after an AMPH challenge than the control LR rats. This phenomenon was associated with a decrease in the mRNA level for D2 dopamine receptor in the amygdala and its protein expression in the basal amygdala (BA) and opposite changes in the nucleus accumbens (NAc) - an increase in the mRNA level for D2 dopamine receptor and its protein expression in the NAc shell, compared to control conditions. Moreover, we observed that chronic restraint stress influenced epigenetic regulation in the LR and the HR rats differently. The contrasting changes were observed in the dentate gyrus (DG) of the hippocampus - the LR rats presented a decrease, but the HR rats showed an increase in H3K9 trimethylation. The restraint LR rats also showed higher miR-494 and miR-34c levels in the NAc than the control LR group. Our study provides behavioural and biochemical data concerning the role of differences in fear-conditioned response in stress vulnerability and AMPH-associated appetitive behaviour. The LR rats were less sensitive to the rewarding effects of AMPH when previously exposed to chronic stress that was accompanied by changes in D2 dopamine receptor expression and epigenetic regulation in mesolimbic areas.


Assuntos
Anfetamina/farmacologia , Epigênese Genética , Receptores de Dopamina D2/metabolismo , Estresse Psicológico/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Giro Denteado/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Estresse Psicológico/fisiopatologia
14.
Physiol Behav ; 204: 355-363, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30831183

RESUMO

Despite generally being a reinforcing drug of abuse, amphetamine (amph) also produces effects such as hypophagia and conditioned taste avoidance (CTA), which may indicate that amph acts as an aversive homeostatic stressor. Stress-responsive prolactin-releasing peptide (PrRP)-positive noradrenergic and glucagon-like peptide-1 (GLP-1)-positive neurons in the caudal nucleus of the solitary tract (cNTS) are modulated by metabolic state, and are prime candidates for mediating amph-induced hypophagia and CTA. The present study used dual immunolabeling and fluorescent in situ hybridization (RNAscope) to examine acute amph-induced activation of cFos expression in phenotypically-identified cNTS neurons in ad lib-fed vs. overnight-fasted male Sprague Dawley rats. We also examined the impact of food deprivation on amph-induced CTA. Compared to control saline treatment, amph activated significantly more cNTS neurons, including PrRP-negative noradrenergic (NA) neurons, GABAergic neurons, and glutamatergic neurons, but not PrRP or GLP-1 neurons. Amph also increased neural activation within a subset of central cNTS projection targets, including the lateral parabrachial nucleus and central amygdala, but not the paraventricular hypothalamus. Food deprivation did not alter amph-induced neural activation or impact the ability of amph to support CTA. These findings indicate that PrRP-negative NA and other cNTS neurons are recruited by acute amph treatment regardless of metabolic state, and may participate in amph-induced hypophagia and CTA.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Privação de Alimentos , Hibridização in Situ Fluorescente , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Transl Psychiatry ; 9(1): 81, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30745563

RESUMO

Abnormal levels of dopamine (DA) are thought to contribute to several neurological and psychiatric disorders including drug addiction. Extracellular DA levels are regulated primarily via reuptake by the DA transporter (DAT). Amphetamine, a potent psychostimulant, increases extracellular DA by inducing efflux through DAT. Recently, we discovered that G protein ßγ subunits (Gßγ) interact with DAT, and that in vitro activation of Gßγ promotes DAT-mediated efflux. Here, we investigated the role of Gßγ in the actions of amphetamine in DA neurons in culture, ex vivo nucleus accumbens (NAc), and freely moving rats. Activation of Gßγ with the peptide myr-Ser-Ile-Arg-Lys-Ala-Leu-Asn-Ile-Leu-Gly-Tyr-Pro-Asp-Tyr-Asp (mSIRK) in the NAc potentiated amphetamine-induced hyperlocomotion, but not cocaine-induced hyperlocomotion, and systemic or intra-accumbal administration of the Gßγ inhibitor gallein attenuated amphetamine-induced, but not cocaine-induced hyperlocomotion. Infusion into the NAc of a TAT-fused peptide that targets the Gßγ-binding site on DAT (TAT-DATct1) also attenuated amphetamine-induced but not cocaine-induced hyperlocomotion. In DA neurons in culture, inhibition of Gßγ with gallein or blockade of the Gßγ-DAT interaction with the TAT-DATct1 peptide decreased amphetamine-induced DA efflux. Furthermore, activation of Gßγ with mSIRK potentiated and inhibition of Gßγ with gallein reduced amphetamine-induced increases of extracellular DA in the NAc in vitro and in freely moving rats. Finally, systemic or intra-accumbal inhibition of Gßγ with gallein blocked the development of amphetamine-induced, but not cocaine-induced place preference. Collectively, these results suggest that interaction between Gßγ and DAT plays a critical role in the actions of amphetamine and presents a novel target for modulating the actions of amphetamine in vivo.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Anfetamina/efeitos adversos , Animais , Estimulantes do Sistema Nervoso Central/efeitos adversos , Cocaína/administração & dosagem , Neurônios Dopaminérgicos/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley
16.
PLoS One ; 14(2): e0210273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30779732

RESUMO

This work extends the understanding of how toxic exposures to amphetamine (AMPH) adversely affect the immune system and lead to tissue damage. Importantly, it determines which effects of AMPH are and are not due to pronounced hyperthermia. Whole blood messenger RNA (mRNA) and whole blood and serum microRNA (miRNA) transcripts were identified in adult male Sprague-Dawley rats after exposure to toxic AMPH under normothermic conditions, AMPH when it produces pronounced hyperthermia, or environmentally-induced hyperthermia (EIH). mRNA transcripts with large increases in fold-change in treated relative to control rats and very low expression in the control group were a rich source of organ-specific transcripts in blood. When severe hyperthermia was produced by either EIH or AMPH, significant increases in circulating organ-specific transcripts for liver (Alb, Fbg, F2), pancreas (Spink1), bronchi/lungs (F3, Cyp4b1), bone marrow (Np4, RatNP-3b), and kidney (Cesl1, Slc22a8) were observed. Liver damage was suggested also by increased miR-122 levels in the serum. Increases in muscle/heart-enriched transcripts were produced by AMPH even in the absence of hyperthermia. Expression increases in immune-related transcripts, particularly Cd14 and Vcan, indicate that AMPH can activate the innate immune system in the absence of hyperthermia. Most transcripts specific for T-cells decreased 50-70% after AMPH exposure or EIH, with the noted exception of Ccr5 and Chst12. This is probably due to T-cells leaving the circulation and down-regulation of these genes. Transcript changes specific for B-cells or B-lymphoblasts in the AMPH and EIH groups ranged widely from decreasing ≈ 40% (Cd19, Cd180) to increasing 30 to 100% (Tk1, Ahsa1) to increasing ≥500% (Stip1, Ackr3). The marked increases in Ccr2, Ccr5, Pld1, and Ackr3 produced by either AMPH or EIH observed in vivo provide further insight into the initial immune system alterations that result from methamphetamine and AMPH abuse and could modify risk for HIV and other viral infections.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/sangue , Anfetamina/administração & dosagem , Febre/sangue , Golpe de Calor/sangue , MicroRNAs/sangue , RNA Mensageiro/sangue , Anfetamina/farmacologia , Animais , Biomarcadores/sangue , Febre/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley
17.
J Affect Disord ; 245: 1079-1088, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699850

RESUMO

BACKGROUND: Genetic and physiological studies have implicated the striatum in bipolar disorder (BD). Although Glycogen synthase kinase 3 beta (GSK3ß) has been suggested to play a role in the pathophysiology of BD since it is inhibited by lithium, it remains unknown how GSK3ß activity might be involved. Therefore we examined the functional roles of GSK3ß and one of its substrates, CRMP2, within the striatum. METHODS: Using CRISPR-Cas9 system, we specifically ablated GSK3ß in the striatal neurons in vivo and in vitro. Sholl analysis was performed for the structural studies of medium spiny neurons (MSNs) and amphetamine-induced hyperlocomotion was measured to investigate the effects of gene ablations on the mania-like symptom of BD. RESULTS: GSK3ß deficiency in cultured neurons and in neurons of adult mouse brain caused opposite patterns of neurite changes. Furthermore, specific knockout of GSK3ß in the MSNs of the indirect pathway significantly suppressed amphetamine-induced hyperlocomotion. We demonstrated that these phenotypes of GSK3ß ablation were mediated by CRMP2, a major substrate of GSK3ß. LIMITATIONS: Amphetamine-induced hyperlocomotion only partially recapitulate the symptoms of BD. It requires further study to examine whether abnormality in GSK3ß or CRMP2 is also involved in depression phase of BD. Additionally, we could not confirm whether the behavioral changes observed in GSK3ß-ablated mice were indeed caused by the cellular structural changes observed in the striatal neurons. CONCLUSION: Our results demonstrate that GSK3ß and its substrate CRMP2 critically regulate the neurite structure of MSNs and their functions specifically within the indirect pathway of the basal ganglia network play a critical role in manifesting mania-like behavior of BD. Moreover, our data also suggest lithium may exert its effect on BD through a GSK3ß-independent mechanism, in addition to the GSK3ß inhibition-mediated mechanism.


Assuntos
Transtorno Bipolar/patologia , Corpo Estriado/patologia , Dendritos/ultraestrutura , Glicogênio Sintase Quinase 3 beta/deficiência , Locomoção/genética , Anfetamina/farmacologia , Animais , Transtorno Bipolar/tratamento farmacológico , Células Cultivadas , Corpo Estriado/metabolismo , Depressão , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/fisiologia , Humanos , Lítio/farmacologia , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neostriado/patologia , Neurônios/citologia
18.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30766916

RESUMO

Estradiol potentiates behavioral sensitization to cocaine as well as self-administration of cocaine and other drugs of abuse in female rodents. Furthermore, stimulated dopamine (DA) in the dorsolateral striatum (DLS) is rapidly enhanced by estradiol, and it is hypothesized that this enhanced DA release mediates the more rapid escalation of drug taking seen in females, compared with males. The mechanisms mediating the effect of estradiol to enhance stimulated DA release were investigated in this study. Using in vivo microdialysis and high performance liquid chromatography coupled with electrochemical detection, we first examined the effect of estradiol on amphetamine-induced DA increase in the DLS of ovariectomized rats. We then tested whether the potentiation of this DA increase could be blocked by the estradiol receptor antagonist, ICI 182,780 (ICI), or an antagonist to the metabotropic glutamate receptor subtype 5 (mGlu5), 2-methyl-6-(phenylethynyl)pyridine (MPEP). There is evidence that estradiol receptors collaborate with mGlu5 within caveoli in DLS and mGlu5 is hypothesized to mediate many of the effects of estradiol in the addiction processes in females. Our data show that estradiol enhances the DA response to amphetamine. Either ICI or MPEP prevented the effect of estradiol to enhance DA release. Importantly, our results also showed that neither ICI or MPEP alone is able to influence the DA response to amphetamine when estradiol is not administrated, suggesting that ICI and MPEP act via estradiol receptors. Together, our findings demonstrate that estradiol potentiates amphetamine-stimulated DA release in the DLS and this effect requires both estradiol receptors and mGlu5.


Assuntos
Anfetamina/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Estradiol/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Estradiol/farmacologia , Feminino , Fulvestranto/farmacologia , Piridinas/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Estradiol/antagonistas & inibidores , Receptores de Estradiol/metabolismo
19.
Psychopharmacology (Berl) ; 236(6): 1959-1972, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30798404

RESUMO

RATIONALE: Stop signal reaction time procedures are used to investigate behavioral and neurobiological processes that contribute to behavioral inhibition and to evaluate potential therapeutics for disorders characterized by disinhibition and impulsivity. The current study examined effects of amphetamine, methylphenidate, atomoxetine, and morphine in rats responding under an adjusting stop signal reaction time task that measures behavioral inhibition, as well as motor impulsivity. METHODS: Rats (n = 8) completed a two-response sequence to earn food. During most trials, responses following presentation of a visual stimulus (go signal) delivered food. Occasionally, a tone (stop signal) was presented signifying that food would be presented only if the second response was withheld. Responding after the stop signal measured inhibition and responding prior to the start of the trial (premature) measured motor impulsivity. Delay to presentation of the stop signal was adjusted for individual subjects based on performance. RESULTS: Amphetamine and methylphenidate increased responding after presentation of the stop signal and markedly increased premature responding. Atomoxetine modestly improved accuracy on stop trials and decreased premature responding. Morphine did not alter stop trial accuracy or premature responding up to doses that decreased the number of trials initiated. CONCLUSIONS: These data demonstrate the sensitivity of an adjusting stop signal reaction time task to a range of drug effects and shows that some drugs that enhance dopaminergic transmission, such as amphetamine, can differentially alter various types of impulsive behavior.


Assuntos
Anfetamina/farmacologia , Cloridrato de Atomoxetina/farmacologia , Metilfenidato/farmacologia , Morfina/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Masculino , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-30664970

RESUMO

Drug abuse and addiction are overwhelming health problems mainly during adolescence. Based on a previous study of our research group, the rats that received modafinil (MD) during the adolescence showed less preference for amphetamine (AMPH) in adulthood. Our current hypothesis is that MD will show beneficial effects against AMPH preference and abstinence symptoms during adolescence, a critical lifetime period when drug hedonic effects are more pronounced. We investigated the influence of MD pretreatment on AMPH preference in conditioned place preference (CPP) paradigm in adolescent rats and anxiety-like symptoms during drug withdrawal (48 h after the last AMPH dose) in elevated plus maze (EPM) task. Besides that, oxidative and molecular status were evaluated in the ventral tegmental area (VTA) and striatum. Our findings showed, as it was expected, that adolescent animals developed AMPH preference together with anxiety-like symptoms during the drug withdrawal while the MD pretreatment prevented those behaviors. Besides promoting benefits on reward parameters, MD was able to preserve VTA and striatum from oxidative damages. This was observed by the increased catalase activity and reduced generation of reactive species and lipid peroxidation, which were inversely modified by AMPH exposure. At molecular level, MD exerted an interesting modulatory activity on the VTA and induced an up-regulation in striatal dopaminergic targets (TH, DAT, D1R and D2R). So far, during the adolescence, MD presented beneficial behavioral outcomes that could be attributed to its modulatory activity on the striatal dopaminergic system in an attempt to maintain the adequate dopamine levels.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Ansiedade/prevenção & controle , Estimulantes do Sistema Nervoso Central/farmacologia , Modafinila/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Anfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Ratos Wistar , Maturidade Sexual , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/crescimento & desenvolvimento , Área Tegmentar Ventral/metabolismo
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