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1.
Dev Neurosci ; 40(1): 84-92, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29216635

RESUMO

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20). In adulthood, DTI scans were performed and brain WMI was determined using voxelwise tract-based spatial statistics (TBSS). Postmortem fatty acid composition, peripheral (plasma IL-1ß, IL-6, and C-reactive protein [CRP]) and central (IL-1ß and CD11b mRNA) proinflammatory markers, and myelin basic protein (MBP) mRNA expression were determined. Compared with CON rats, forebrain DHA levels were lower in DEF rats and higher in FO rats. Compared with CON rats, DEF rats exhibited greater radial diffusivity (RD) and mean diffusivity in the right external capsule, and greater axial diffusivity in the corpus callosum genu and left external capsule. DEF rats also exhibited greater RD than FO rats in the right external capsule. Forebrain MBP expression did not differ between groups. Compared with CON rats, central (IL-1ß and CD11b) and peripheral (IL-1ß and IL-6) proinflammatory markers were not different in DEF rats, and DEF rats exhibited lower CRP levels. These findings demonstrate that deficits in adolescent DHA accrual negatively impact forebrain WMI, independently of elevated proinflammatory signaling.


Assuntos
Ácidos Docosa-Hexaenoicos/deficiência , Neurogênese/fisiologia , Prosencéfalo/patologia , Substância Branca/patologia , Animais , Imagem de Tensor de Difusão , Masculino , Ratos , Ratos Long-Evans
2.
Nutr Neurosci ; : 1-9, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29286866

RESUMO

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40-60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naïve rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH-pretreated DEF rats was similar to AMPH-naïve DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH-pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response.

3.
Psychiatry Res Neuroimaging ; 270: 39-45, 2017 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-29049903

RESUMO

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20). In adulthood 1H MRS scans were performed with voxels in the prefrontal cortex (PFC) and thalamus. Compared with controls, erythrocyte, PFC, and thalamus DHA levels were significantly lower in DEF rats and significantly higher in FO rats. In the PFC, but not the thalamus, glutamate was significantly elevated in DEF rats compared with controls and FO rats. Glutamine did not differ between groups and the glutamine/glutamate ratio was lower in DEF rats. No differences were observed for markers of excitotoxicity (NAA, GFAP), or astrocyte glutamate transporter (GLAST, GLT-1) or glutamine synthetase expression. Across diet groups, PFC DHA levels were inversely correlated with PFC glutamate levels and positively correlated with GLAST expression. Together these findings demonstrate that rat cortical DHA accrual during adolescence impacts glutamate homeostasis in the adult PFC.


Assuntos
Envelhecimento/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Glutâmico/metabolismo , Homeostase , Córtex Pré-Frontal/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Astrócitos/metabolismo , Dieta , Ácidos Docosa-Hexaenoicos/deficiência , Glutamato-Amônia Ligase/metabolismo , Glutamina/metabolismo , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Long-Evans
4.
J Psychiatr Res ; 95: 143-146, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28846858

RESUMO

Evidence from 31P magnetic resonance spectroscopy (31P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using 31P MRS. During the peri-adolescent period (P21-P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n = 20). On P90, 31P MRS was performed under isoflurane anesthetic using a 7 T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (-17%, p ≤ 0.0001) and significantly higher in rats fed the FO diet (+14%, p ≤ 0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present 31P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism.


Assuntos
Trifosfato de Adenosina/metabolismo , Encéfalo/metabolismo , Dieta , Ácidos Docosa-Hexaenoicos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Mitocôndrias/metabolismo , Fosfolipídeos/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Metabolismo Energético/fisiologia , Masculino , Fósforo , Ratos , Ratos Long-Evans
5.
Physiol Behav ; 161: 140-144, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27072507

RESUMO

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders.


Assuntos
Comportamento Aditivo/genética , Transdução de Sinais/fisiologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Anfetamina/farmacologia , Animais , Comportamento Aditivo/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dieta , Modelos Animais de Doenças , Exenatida , Comportamento Alimentar/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/deficiência , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nestina/metabolismo , Peptídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Peçonhas/uso terapêutico
6.
Obesity (Silver Spring) ; 24(3): 606-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26833633

RESUMO

OBJECTIVE: Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes. METHODS: In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured. RESULTS: Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased. CONCLUSIONS: While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.


Assuntos
Adjuvantes Imunológicos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Cloreto de Lítio/administração & dosagem , Paladar/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cloreto de Lítio/toxicidade , Ratos
7.
Obes Surg ; 23(7): 920-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23440511

RESUMO

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.


Assuntos
Consumo de Bebidas Alcoólicas , Comportamento de Escolha , Etanol/metabolismo , Derivação Gástrica/efeitos adversos , Grelina/sangue , Hipocampo/fisiopatologia , Vias Neurais/fisiopatologia , Obesidade/cirurgia , Animais , Comportamento Animal , Peso Corporal , Etanol/administração & dosagem , Etanol/sangue , Masculino , Período Pós-Operatório , Ratos , Ratos Long-Evans , Recompensa , Perda de Peso
8.
Biol Psychiatry ; 72(5): 354-60, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22444202

RESUMO

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective weight loss strategy employed to treat obesity and associated complications. Importantly, the RYGB procedure has been reported to attenuate reward-related consummatory behaviors. The present work examined the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption. METHODS: To do this, self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we utilized a rodent model of RYGB and examined ethanol consumption and ethanol reward in male ethanol-preferring (P) rats, which are selectively bred to consume large volumes of ethanol. RESULTS: Patients that reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. Notably, the attenuating effect of RYGB surgery on ethanol consumption was associated with ethanol-induced increases in the gut hormone glucagon-like peptide-1 (GLP-1). Pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. In addition, pharmacologic replacement of the gut hormone ghrelin restored drinking behavior in P rats following RYGB. CONCLUSIONS: Collectively, these findings unveil the potential of RYGB surgery to attenuate ethanol consumption in some humans and rats. Furthermore, our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Etanol/farmacologia , Derivação Gástrica , Grelina/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/agonistas , Obesidade/terapia , Perda de Peso/fisiologia , Análise de Variância , Animais , Etanol/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Masculino , Modelos Animais , Estudos Prospectivos , Ratos , Ratos Endogâmicos
9.
Biol Psychiatry ; 69(7): 668-74, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21035790

RESUMO

BACKGROUND: Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine. METHODS: The contribution of endogenous leptin signaling for food motivation and mesolimbic dopamine tone was examined after viral-mediated reduction of the leptin receptor within LH and midbrain neurons in male rats. RESULTS: Knockdown of leptin receptors selectively in the LH caused increased body weight, caloric consumption, and body fat in rats maintained on a calorically dense diet. Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens. CONCLUSIONS: In summary, endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods and the consequent increase in body mass, whereas leptin action in the midbrain regulates effort-based responding for food rewards and mesolimbic dopamine tone. These data highlight the ability of leptin to regulate overconsumption of palatable foods and food motivation through pathways that mediate energy homeostasis and reward, respectively.


Assuntos
Encéfalo/metabolismo , Metabolismo Energético/efeitos dos fármacos , Proteínas de Fluorescência Verde/efeitos dos fármacos , Leptina/farmacologia , Motivação/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Gorduras na Dieta/administração & dosagem , Dopamina/metabolismo , Metabolismo Energético/fisiologia , Proteínas de Fluorescência Verde/genética , Masculino , Vias Neurais/fisiologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Long-Evans , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo
10.
Behav Neurosci ; 122(6): 1257-63, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19045945

RESUMO

Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Gorduras na Dieta/administração & dosagem , Dopamina/metabolismo , Sistema Límbico/efeitos dos fármacos , Recompensa , Análise de Variância , Animais , Comportamento Animal , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Sistema Límbico/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Long-Evans , Esquema de Reforço , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem
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