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1.
J Proteome Res ; 18(9): 3492-3502, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31329447

RESUMO

Chronic binge alcohol drinking is known to increase risky decision through pathological impulsive behaviors. Recently, we established a novel rodent model of ethanol-induced waiting impulsivity using 5-choice serial reaction time task (5-CSRTT) in mice. However, molecular mechanisms underlying the chronic binge ethanol-induced waiting impulsivity is not well characterized. Among brain regions involved in impulsivity, the anterior cingulate cortex (ACC) is a major neural substrate for mediating the 5-CSRTT-based waiting impulsivity. Thus, we sought to determine the ACC proteomic profile using label-free proteomics of mice exhibiting ethanol-induced impulsivity. Ingenuity pathway analysis revealed that impulsivity-related proteins involved in ion channel complexes such as KCNIP3 (potassium voltage-gated channel interacting protein 3) and CACNG2 (calcium voltage-gated channel auxiliary subunit gamma 2) are downregulated in the ACC. We identified significant protein expression changes in the mechanistic target of rapamycin (mTOR) canonical pathway between control and ethanol-induced impulsive mice. Impulsive mice showed over 60% of proteins involved in the mTOR canonical pathway have been altered. This pathway has been previously implicated in the neuroadaptation in drugs of abuse and impulsivity. We found substantial changes in the protein levels involved in neurological disorders such as schizophrenia and Alzheimer's disease. Our findings provide a neuroproteomic profile of ethanol-induced impulsive mice.

2.
Behav Brain Res ; 370: 111943, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095992

RESUMO

Adolescent's consumption of caffeine and caffeinated beverage is increasing, yet little is known about the consequences of chronic caffeine exposure during the critical development period of adolescence. In the present study, we investigated the effect of beginning chronic caffeine consumption in adolescence on locomotor, mood, sensorimotor gating, and reward seeking behaviors through adolescence and in adulthood. During the light cycle, caffeine exposed mice exhibited hypoactivity in a novel open-field box and increased anxiety-like and depressive-like behaviors, while maintaining normal home cage locomotor activity. In contrast, during the dark cycle caffeine exposed mice displayed normal locomotor activity in a novel open-field box with hyperactive home cage activity. Interestingly, we found that caffeine exposed mice also showed enhanced prepulse inhibition during the light cycle whereas they displayed a deficit of prepulse inhibition during the dark cycle. Reward seeking for sucrose was higher in caffeine exposed than control mice during the light cycle. Additionally, when granted 24 -h access to ethanol as adults, caffeine exposed mice consumed more ethanol in the absence of acute caffeine use. Altogether, mice that consumed chronic caffeine beginning in adolescence had increased reward seeking and exhibited a circadian-dependent pattern of mood fluctuations in adulthood.

3.
Neurosci Lett ; 706: 169-175, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31116969

RESUMO

Impulsivity is defined as a predisposition toward rapid, unplanned reactions in response to internal or external stimuli, often yielding negative consequences. Accordingly, impulsivity is considered a significant risk factor for developing addictive behaviors. The hippocampus is involved in regulating behavioral adaptability and learned behaviors. Consequently, abnormal hippocampal function has been demonstrated to contribute to impulsive and addictive behaviors. Furthermore, differential reinforcement of low rates of behavior (DRL) has shown that the hippocampus is implicated in reward acquisition and impulsivity in humans and rodent models. We have previously shown that impulsive behavior potentiates hippocampal neuroblast proliferation. However, the fate of these precursor cells produced during impulsive reward seeking remains unknown. Here, we demonstrate that DRL-mediated impulsive reward seeking with the 2-choice reaction time task (2-CRTT) increases the number of BrdU labeled cells in the dentate gyrus region of the hippocampus. Importantly, our results also show a significant increase in BrdU+ and NeuN+ colocalized mature newborn neurons in mice exhibiting impulsivity compared to non-impulsive control mice. These results suggest that operant reward seeking during unpredictable schedules of reinforcement contributes to adult hippocampal neurogenesis.


Assuntos
Hipocampo/fisiologia , Comportamento Impulsivo/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Comportamento Animal/fisiologia , Proliferação de Células/fisiologia , Comportamento de Escolha/fisiologia , Condicionamento Operante/fisiologia , Hipocampo/citologia , Masculino , Camundongos , Neurônios/citologia , Tempo de Reação/fisiologia , Recompensa
4.
Addict Biol ; : e12754, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31012186

RESUMO

Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge-like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5-choice serial reaction time task (5-CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5-CSRTT sessions. We further characterized our ethanol-induced impulsive mice using Open Field, y-maze, two-bottle choice, and an action-outcome task. Our results indicate that continuous binge-like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol-induced impulsive mice exhibited anxiety-like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol-treated mice were less motivated for a sucrose reward compared with air-exposed control mice, while also demonstrating reduced responding during action-outcome testing. Overall, ethanol-treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice.

5.
Int Neurourol J ; 23(Suppl 1): S5-10, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30832462

RESUMO

Synapses are sites of high energy demand which are dependent on high levels of mitochondrial derived adenosine triphosphate. Mitochondria within synaptic structures are key for maintenance of functional neurotransmission and this critical biological process is modulated by energy metabolism, mitochondrial distribution, mitochondrial trafficking, and cellular synaptic calcium flux. Synapse loss is presumed to be an early yet progressive pathological event in Alzheimer disease (AD), resulting in impaired cognitive function and memory loss which is particularly prevalent at later stages of disease. Supporting evidence from AD patients and animal models suggests that pathological mitochondrial dynamics indeed occurs early and is highly associated with synaptic lesions and degeneration in AD neurons. This review comprehensively highlights recent findings that describe how synaptic mitochondria pathology involves dysfunctional trafficking of this organelle, to maladaptive epigenetic contributions affecting mitochondrial function in AD. We further discuss how these negative, dynamic alterations impact synaptic function associated with AD. Finally, this review explores how antioxidant therapeutic approaches targeting mitochondria in AD can further clinical research and basic science investigations to advance our in-depth understanding of the pathogenesis of AD.

6.
Aging Cell ; 18(2): e12899, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30609266

RESUMO

Wnt signaling is a well-known molecular pathway in age-related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

7.
Int Neurourol J ; 22(Suppl 3): S122-130, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30396261

RESUMO

PURPOSE: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. METHODS: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. RESULTS: We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. CONCLUSION: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.

8.
Proteomics ; 18(7): e1700417, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29437267

RESUMO

Acamprosate is an FDA-approved medication for the treatment of alcoholism that is unfortunately only effective in certain patients. Although acamprosate is known to stabilize the hyper-glutamatergic state in alcoholism, pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of alcoholism, type 1 equilibrative nucleoside transporter (ENT1) null mice. The results demonstrate that acamprosate treatment significantly decreased both ethanol drinking and preference in ENT1 null mice compared to that of wild-type mice. Then, to elucidate acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label-free quantification proteomics comparing both genotype and acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040 protein expression changes are identified in the NAc among 3634 total proteins detected. The proteomics and Western blot result demonstrate that acamprosate treatment decreased EAAT expression implicating stabilization of the hyper-glutamatergic condition in ENT1 null mice. Pathway analysis suggests that acamprosate treatment in ENT1 null mice seems to rescue glutamate toxicity through restoring of RTN4 and NF-κB medicated neuroimmune signaling compared to wild-type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the acamprosate treatment of certain sub-populations of alcohol dependent subjects.


Assuntos
Acamprosato/uso terapêutico , Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Modelos Animais de Doenças , Alcoolismo/genética , Alcoolismo/metabolismo , Animais , Transportador Equilibrativo 1 de Nucleosídeo/genética , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Nogo/genética , Proteínas Nogo/metabolismo , Proteômica , Transdução de Sinais , Resultado do Tratamento
9.
Neuropharmacology ; 131: 58-67, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29225043

RESUMO

Dysfunction of N-methyl-d-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng-/- mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng-/- mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng-/- mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng-/- mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng-/- mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Motivação/fisiologia , Neurogranina/metabolismo , Núcleo Accumbens/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Dependovirus/genética , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Motivação/efeitos dos fármacos , Neurogranina/genética , Núcleo Accumbens/ultraestrutura , Autoadministração , Sacarose/administração & dosagem , Fatores de Tempo
11.
J Proteome Res ; 16(4): 1445-1459, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-27998058

RESUMO

The neural circuit of the dorsal hippocampus (dHip) and nucleus accumbens (NAc) contributes to cue-induced learning and addictive behaviors, as demonstrated by the escalation of ethanol-seeking behaviors observed following deletion of the adenosine equilibrative nucleoside transporter 1 (ENT1-/-) in mice. Here we perform quantitative LC-MS/MS neuroproteomics in the dHip and NAc of ENT1-/- mice. Using Ingenuity Pathway Analysis, we identified proteins associated with increased long-term potentiation, ARP2/3-mediated actin cytoskeleton signaling and protein expression patterns suggesting deficits in glutamate degradation, GABAergic signaling, as well as significant changes in bioenergetics and energy homeostasis (oxidative phosphorylation, TCA cycle, and glycolysis). These pathways are consistent with previously reported behavioral and biochemical phenotypes that typify mice lacking ENT1. Moreover, we validated decreased expression of the SNARE complex protein VAMP1 (synaptobrevin-1) in the dHip as well as decreased expression of pro-dynorphin (PDYN), neuroendocrine convertase (PCSK1), and Leu-Enkephalin (dynorphin-A) in the NAc. Taken together, our proteomic approach provides novel pathways indicating that ENT1-regulated signaling is essential for neurotransmitter release and neuropeptide processing, both of which underlie learning and reward-seeking behaviors.


Assuntos
Encefalinas/genética , Transportador Equilibrativo 1 de Nucleosídeo/genética , Pró-Proteína Convertase 1/genética , Precursores de Proteínas/genética , Proteômica , Proteína 1 Associada à Membrana da Vesícula/genética , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/patologia , Animais , Etanol/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Potenciação de Longa Duração/genética , Camundongos , Neuropeptídeos/biossíntese , Neuropeptídeos/genética , Neurotransmissores/biossíntese , Neurotransmissores/genética , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Transdução de Sinais/genética , Espectrometria de Massas em Tandem
12.
Front Behav Neurosci ; 10: 46, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27014007

RESUMO

The molecular mechanisms underlying the neuronal signaling changes in alcohol addiction and withdrawal are complex and multifaceted. The cortico-striatal circuit is highly implicated in these processes, and the striatum plays a significant role not only in the early stages of addiction, but in the developed-addictive state as well, including withdrawal symptoms. Transcriptional analysis is a useful method for determining changes in gene expression, however, the results do not always accurately correlate with protein levels. In this study, we employ label-free proteomic analysis to determine changes in protein expression within the striatum during chronic ethanol use and early withdrawal. The striatum, composed primarily of medium spiny GABAergic neurons, glutamatergic and dopaminergic nerve terminals and astrocytes, is relatively homogeneous for proteomic analysis. We were able to analyze more than 5000 proteins from both the dorsal (caudate and putamen) and ventral (nucleus accumbens) striatum and identified significant changes following chronic intermittent ethanol exposure and acute (8 h) withdrawal compared to ethanol naïve and ethanol exposure groups respectively. Our results showed significant changes in proteins involved in glutamate and opioid peptide signaling, and also uncovered novel pathways including mitochondrial function and lipid/cholesterol metabolism, as revealed by changes in electron transport chain proteins and RXR activation pathways. These results will be useful in the development of novel treatments for alcohol withdrawal and thereby aid in recovery from alcohol use disorder.

13.
Behav Brain Res ; 305: 8-17, 2016 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-26909848

RESUMO

Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3α and GSK-3ß in a dose- and time-dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic.


Assuntos
Antipsicóticos/uso terapêutico , Neurotensina/análogos & derivados , Agitação Psicomotora/tratamento farmacológico , Anfetamina/toxicidade , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotensina/uso terapêutico , Fosforilação/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Agitação Psicomotora/etiologia , Serina/metabolismo , Fatores de Tempo
14.
J Affect Disord ; 165: 151-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24882193

RESUMO

BACKGROUND: Bipolar disorder (BD) is a highly heritable disease. While genome-wide association (GWA) studies have identified several genetic risk factors for BD, few of these studies have investigated the genetic etiology of specific disease subtypes. In particular, BD is positively associated with eating dysregulation traits such as binge eating behavior (BE), yet the genetic risk factors underlying BD with comorbid BE have not been investigated. METHODS: Utilizing data from the Genetic Association Information Network study of BD, which included 729,454 single nucleotide polymorphisms (SNPs) genotyped in 1001 European American bipolar cases and 1034 controls, we performed GWA analyses of bipolar subtypes defined by the presence or absence of BE history, and performed a case-only analysis comparing BD subjects with and without BE history. Association signals were refined using imputation, and network analysis was performed with Ingenuity Pathway Analysis software. Based on these results, candidate SNPs were selected for replication in an independent sample of 855 cases and 857 controls. RESULTS: Top ranking SNPs in the discovery set included rs6006893 in PRR5, rs17045162 in ANK2, rs13233490 near PER4, rs4665788 and rs10198175 downstream of APOB, rs2367911 in CACNA2D1, and rs7249968 near ZNF536. Rs10198175 in APOB also demonstrated evidence of association in the replication sample and a meta-analysis of the two samples. LIMITATIONS: Without information of BE history in controls, it is not possible to determine whether the observed association with APOB reflects a risk factor for BE behavior in general or a risk factor for a subtype of BD with BE. Further longitudinal and functional studies are needed to determine the causal pathways underlying the observed associations. CONCLUSIONS: This study identified new potential BD-susceptibility genes, highlighting the advantages of phenotypic sub-classification in genetic research and clinical practice.


Assuntos
Apolipoproteínas B/genética , Transtorno Bipolar/complicações , Bulimia/complicações , Estudo de Associação Genômica Ampla , Transtorno Bipolar/genética , Bulimia/genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Neuropharmacology ; 85: 482-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24929110

RESUMO

Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF-81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Atividade Motora/efeitos dos fármacos , Neurotensina/análogos & derivados , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Neurotensina/agonistas , Animais , Benzazepinas/farmacologia , Bromocriptina/farmacologia , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Meio Ambiente , Abrigo para Animais , Masculino , Camundongos Endogâmicos C57BL , Microinjeções , Atividade Motora/fisiologia , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Neurotensina/farmacologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Distribuição Aleatória , Receptores Dopaminérgicos/metabolismo , Receptores de Neurotensina/metabolismo , Teste de Desempenho do Rota-Rod
16.
Behav Brain Funct ; 9(1): 35, 2013 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-23971729

RESUMO

BACKGROUND: There is significant interest in the generation of improved assays to clearly identify experimental mice possessing functional vision, a property that could qualify mice for inclusion in behavioral and neuroscience studies. Widely employed current methods rely on mouse responses to visual cues in assays of reflexes, depth perception, or cognitive memory. However, commonly assessed mouse reflexes can sometimes be ambiguous in their expression, while depth perception assays are sometimes confounded by variation in anxiety responses and exploratory conduct. Furthermore, in situations where experimental groups vary in their cognitive memory capacity, memory assays may not be ideal for assessing differences in vision. RESULTS: We have optimized a non-invasive behavioral assay that relies on an untrained, innate response to identify individual experimental mice possessing functional vision: slow angled-descent forepaw grasping (SLAG). First, we verified that SLAG performance depends on vision and not olfaction. Next, all members of an age-ranged cohort of 158 C57BL/6 mice (57 wild-type, 101 knockout, age range 44-241 days) were assessed for functional vision using the SLAG test without training or conditioning. Subjecting the population to a second innate behavioral test, Dark Chamber preference, corroborated that the functional vision assessment of SLAG was valid. CONCLUSIONS: We propose that the SLAG assay is immediately useful to quickly and clearly identify experimental mice possessing functional vision. SLAG is based on a behavioral readout with a significant innate component with no requirement for training. This will facilitate the selection of mice of known sighted status in vision-dependent experiments that focus on other types of behavior, neuroscience, and/or cognitive memory.


Assuntos
Pesquisa Comportamental/métodos , Membro Anterior/fisiologia , Força da Mão/fisiologia , Visão Ocular/fisiologia , Animais , Comportamento Animal/fisiologia , Camundongos
17.
PLoS One ; 8(5): e52147, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23690912

RESUMO

BACKGROUND: Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level. HYPOTHESIS: Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement. METHODS: Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry. RESULTS: Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation. CONCLUSIONS: Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs.


Assuntos
Afeto/efeitos dos fármacos , Antipsicóticos/farmacologia , Fosfoproteínas/metabolismo , Córtex Pré-Frontal/citologia , Proteoma/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Isoxazóis/farmacologia , Lítio/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Palmitato de Paliperidona , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Ácido Valproico/farmacologia
18.
J Neurosci ; 33(10): 4329-38, 2013 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23467349

RESUMO

Adenosine signaling has been implicated in the pathophysiology of many psychiatric disorders including alcoholism. Striatal adenosine A2A receptors (A2AR) play an essential role in both ethanol drinking and the shift from goal-directed action to habitual behavior. However, direct evidence for a role of striatal A2AR signaling in ethanol drinking and habit development has not been established. In the present study, we found that decreased A2AR-mediated CREB activity in the dorsomedial striatum (DMS) enhanced initial behavioral acquisition of goal-directed behaviors and the vulnerability to progress to excessive ethanol drinking during operant conditioning in mice lacking ethanol-sensitive adenosine transporter ENT1 (ENT1(-/-)). Using mice expressing ß-galactosidase (lacZ) under the control of seven repeated CRE sites in both genotypes (CRE-lacZ/ENT1(+/+) mice and CRE-lacZ/ENT1(-/-) mice) and the dominant-negative form of CREB, we found that reduced CREB activity in the DMS was causally associated with decreased A2AR signaling and increased goal-directed ethanol drinking. Finally, we have demonstrated that the A2AR antagonist ZM241385 dampened protein kinase A activity-mediated signaling in the DMS and promoted excessive ethanol drinking in ENT1(+/+) mice, but not in ENT1(-/-) mice. Our results indicate that A2AR-mediated CREB signaling in the DMS is a key determinant in enhancing the development of goal-directed ethanol drinking in mice.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Comportamento de Escolha/fisiologia , Corpo Estriado/fisiologia , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Metas , Receptor A2A de Adenosina/metabolismo , Consumo de Bebidas Alcoólicas/genética , Análise de Variância , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corpo Estriado/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esquema de Reforço , Transdução de Sinais/efeitos dos fármacos , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Triazinas/farmacologia , Triazóis/farmacologia , beta-Galactosidase/metabolismo
19.
Neuropeptides ; 45(1): 9-16, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21047685

RESUMO

NT69L is a neurotensin analog that blocks nicotine-induced locomotor activity and has sustained efficacy in a rat model of nicotine-induced sensitization when administered peripherally. Additionally, NT69L attenuates food-reinforcement in rats. The present study tested the effect of acute administration of NT69L on nicotine self-infusion in Sprague-Dawley rats. Rats were trained to self-infuse nicotine intravenously (0.03mg/kg per infusion) following operant training. Once the rats acquired stable responding to nicotine self-infusion they were pretreated with NT69L (1mg/kg, i.p.) or saline 30min before being assessed for nicotine self-infusion. Pretreatment with NT69L significantly attenuated nicotine self-infusion under FR1 (fixed ratio of 1) and FR5 schedule of reinforcement as compared to saline pretreatment. Control rats that were response-independent "yoked" as well as rats that self-infused saline or NT69L showed minimal responses, indicating that nicotine served as a reinforcer. Additionally, NT69L modulated serum corticosterone; brain norepinephrine serotonin; and dopamine receptors mRNA levels altered in the nicotine self-infused rats after a 24h withdrawal period. Pretreatment with NT69L significantly decreased the nicotine-induced increase in serum corticosterone levels and striatal norepinephrine and increased the nicotine-induced reduction in serotonin in both the striatum and the prefrontal cortex (PFC). NT69L might modulate dopamine neurotransmission implicated in the reinforcing effects of nicotine by modulating tyrosine hydroxylase and dopamine receptor mRNA levels in the PFC and striatum. These data support further study of the effects of NT analogs on attenuating the reinforcing effects of psychostimulants.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Neurotensina/análogos & derivados , Nicotina/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Autoadministração , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/sangue , Injeções Intraventriculares , Masculino , Neurotensina/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
20.
J Exp Biol ; 213(Pt 24): 4232-9, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21113004

RESUMO

Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg(-1)) and dizocilpine (1 mg kg(-1)). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1(-/-)) and NTS2 (NTS2(-/-)) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2(-/-) mice but not in NTS1(-/-) mice. In WT mice, clozapine (1 mg kg(-1)) and NT69L (1 mg kg(-1)) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2(-/-) mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Dextroanfetamina/farmacologia , Maleato de Dizocilpina/farmacologia , Neurotensina/análogos & derivados , Fragmentos de Peptídeos/farmacologia , Receptores de Neurotensina/fisiologia , Reflexo de Sobressalto/genética , Filtro Sensorial/genética , Animais , Deleção de Genes , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/fisiologia , Neurotensina/farmacologia , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos
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