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1.
Neuropharmacology ; 171: 108109, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32325064

RESUMO

Pituitary adenylyl cyclase activating polypeptide (PACAP) was originally isolated from the hypothalamus and found to stimulate adenylyl cyclase in the pituitary. Later studies showed that this peptide and its receptors (PAC1, VPAC1, and VPAC2) are widely expressed in the central nervous system (CNS). Consistent with its distribution in the CNS, the PACAP/PAC1 receptor system is involved in several physiological responses, such as mediation of the stress response, modulation of nociception, regulation of prolactin release, food intake, etc. This system is also implicated in different pathological states, e.g., affective component of nociceptive processing, anxiety, depression, schizophrenia, and post-traumatic stress disorders. A review of the literature on PubMed revealed that PACAP and its receptors also play a significant role in the actions of addictive drugs. The goal of this review is to discuss the literature regarding the involvements of PACAP and its receptors in the motivational effects of addictive drugs. We particularly focus on the role of this peptide in the motivational effects of morphine, alcohol, nicotine, amphetamine, methamphetamine, and cocaine. This article is part of the special issue on Neuropeptides.

2.
Clin Sci (Lond) ; 133(21): 2189-2202, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31696216

RESUMO

Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKO mice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11ß-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAcKO mice also had reduced fasting blood glucose levels, increased glucose tolerance, and increased insulin sensitivity. In addition, plasma free fatty acid (FFA) levels were decreased with a concomitant decrease in the expression of lipase adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in adipose tissue. These results indicate that inactivation of adipocyte H6PDH expression is sufficient to cause intra-adipose GC inactivation that leads to a favorable pattern of metabolic phenotypes. These data suggest that H6PDHAcKO mice may provide a good model for studying the potential contributions of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo. Our study suggests that suppression or inactivation of H6PDH expression in adipocytes could be an effective intervention for treating obesity and diabetes.

3.
Prog Mol Biol Transl Sci ; 167: 143-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31601402

RESUMO

Stress activates many brain nuclei and causes acute changes in several physiological and behavioral responses to restore homeostasis in affected organisms. While this response is protective, chronic stress exposure causes the sustained activation of these nuclei, leading to maladaptive physiological changes that underlie pathological mood and affective states. Hence, chronic stress may produce anxiety and mood disorders by promoting neuronal plasticity within these stress-responsive nuclei. A growing body of evidence attributes neuropeptide systems in mediating not only the physiological stress response but also pathological states that develop following chronic stress exposure. Recent preclinical data suggest that pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC1, and VPAC2) play an important role in the behavioral and endocrine responses to stress, as well as in mood and affective disorders. Human studies also point out the significance of the PACAP/PAC1 receptor system in these disorders. For instance, PACAP through PAC1 receptor up-regulates the expression of DISC1 (disrupted in schizophrenia 1) and impedes its association with its interacting protein. Interestingly, the DISC1 gene mutation is linked to schizophrenia and depression. Moreover, a link between PACAP blood titer and fear physiology, post-traumatic stress disorder (PTSD) diagnosis and symptoms has been reported in heavily traumatized female patients. Additionally, in the peripheral blood, methylation of the gene encoding the PAC1 receptor is also associated with PTSD. This book chapter describes the emerging evidence that entails PACAP in the stress response and stress-mediated neuropsychiatric disorders.

4.
Medicine (Baltimore) ; 98(40): e17375, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577741

RESUMO

Achieving abstinence in schizophrenic smokers using a combination of medications and cognitive behavioral therapy is feasible; however, abstinence rates are significantly lower compared to the general population and studies are scanty. Additionally, maintaining sustained abstinence and preventing relapse is a major limiting factor and represents key tasks in managing tobacco dependence in schizophrenic patients. Several theories have been postulated to explain the higher tendency of tobacco use among schizophrenic individuals. Schizophrenic patients may use nicotine as a "self-medication" strategy to improve negative symptoms of schizophrenia. However, studies suggest that although nicotine may act as an anxiolytic acutely, chronic use of nicotine may lead to increased anxiety with the possibility of increased catecholamines, which is confirmed with the prevalence of tachycardia and hypertension in smokers in general. On this basis, the main objective of our present study was to assess anxiety in schizophrenic smoking and nonsmoking patients by comparing the number of anxiety and agitation episodes and evaluating the amount of antianxiety/antiagitation medication used by each group. A separate objective was to document the unmet needs of smoking cessation programs in treating schizophrenic patients. Consequently, in the present retrospective cohort study, it was observed that schizophrenic smokers tend to have higher anxiety episodes and utilize as-needed medications at a higher frequency compared to nonsmokers for the relief of anxiety and agitation symptoms. Further research is warranted to examine these results on a larger scale.


Assuntos
Ansiedade/epidemiologia , Fumar Cigarros/epidemiologia , Esquizofrenia/epidemiologia , Ansiolíticos/uso terapêutico , Antipsicóticos/uso terapêutico , Ansiedade/tratamento farmacológico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Esquizofrenia/tratamento farmacológico , Fumantes , Abandono do Hábito de Fumar/métodos
5.
J Neurosci Methods ; 326: 108376, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361999

RESUMO

Electronic cigarettes (E-cig) use is increasing rapidly, particularly among youths. Animal models for E-cig exposure with pharmacokinetics resembling human E-cig users are lacking. We developed an E-cig aerosol exposure system for rodents and a chronic intermittent delivery method that simulates E-cig users who vape episodically during wakefulness and abstain during sleep. Mice were exposed to E-cig in a programmed schedule at very low, low, medium, or high doses defined by duration of each puff, number of puffs per delivery episode and frequency of episodes in the dark phase of a 12/12-h circadian cycle for 9 consecutive days. The plasma nicotine/cotinine levels and their time courses were determined using LC/MS-MS. We assessed the body weight, food intake and locomotor activity of Apolipoprotein E null (ApoE-/-) mice exposed to chronic intermittent E-cig aerosol. Plasma nicotine and cotinine levels were positively correlated with exposure doses. Nicotine and cotinine levels showed a circadian variation as they increased with time up to the maximum nicotine level of 21.8 ±â€¯7.1 ng/mL during the daily intermittent E-cig exposure in the 12-h dark phase and then declined during the light phase when there was no E-cig delivery. Chronic E-cig exposure to ApoE-/- mice decreased body weight, food intake and increased locomotion. Our rodent E-cig exposure system and chronic intermittent exposure method yield clinically relevant nicotine pharmacokinetics associated with behavioral and metabolic changes. The methodologies are essential tools for in vivo studies of the health impacts of E-cig exposure on CNS, cardiovascular, pulmonary, hepatic systems, metabolism and carcinogenesis.

6.
Pharmacol Biochem Behav ; 181: 46-52, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31028757

RESUMO

Pituitary adenylyl cyclase activating polypeptide (PACAP) and its receptors (PAC1, VPAC1, and VPAC2) are localized in brain regions implicated in stress response, reward seeking and aversive responses, raising the possibility that PACAP may be involved in motivational effects of nicotine. To test this hypothesis, we used two-bottle choice (TBC) and place conditioning paradigms and assessed if nicotine preference or conditioned place preference (CPP) or aversion (CPA) induced by nicotine would be altered in mice lacking PACAP compared to their wild-type controls. In the TBC paradigm, mice had access to two water bottles during the first week and then one of the water bottles was switched to nicotine solution (20, 40 and then 80 µg/mL). The volume of water and nicotine consumed was measured every day. In the place conditioning paradigm, mice were tested for baseline place preference on day 1, received conditioning with saline versus a low (0.25) or high (1 mg/kg) dose nicotine and, respectively, tested for CPP or CPA 24 h following the last conditioning. We discovered that mice lacking PACAP compared to their wild-type controls exhibited more preference for nicotine over water in the TBC paradigm, particularly at the two higher concentrations of nicotine. While the rewarding action of the low dose nicotine was not altered in mice lacking PACAP, the aversive effect of the high dose nicotine was blunted in these mice compared to their wild-type controls. The present results suggest that endogenous PACAP may play a functional role in nicotine preference and its aversive effect.


Assuntos
Agentes Aversivos/administração & dosagem , Agentes Aversivos/farmacologia , Nicotina/administração & dosagem , Nicotina/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Recompensa , Análise de Variância , Animais , Feminino , Técnicas de Inativação de Genes , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Autoadministração , Fumar/fisiopatologia , Fumar/psicologia , Água/administração & dosagem , Água/farmacologia
7.
Front Psychiatry ; 9: 638, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555362

RESUMO

Treatment of drug addiction remains an unmet medical need due to the dearth of approved pharmacotherapies. There are no approved treatments for cocaine addiction, whereas the current opioid crisis has revealed the stark reality of the limited options to treat prescription and illicit opioid abuse. Preclinical studies in rodents and nonhuman primates have shown that orphanin FQ/nociceptin (N/OFQ), the endogenous ligand for the nociceptin opioid receptor (NOP) reduces the rewarding effects of several abused substances, including opioids, psychostimulants and alcohol. A few nonpeptide small-molecule NOP agonists have also shown efficacy in attenuating the rewarding effects of various abused drugs. We previously demonstrated that a high affinity small-molecule NOP agonist AT-312 selectively reduced the rewarding effects of ethanol in the conditioned place preference paradigm in mice. In the present study, we examined if AT-312 (3 mg/kg, i.p. or s.c. respectively), would alter the rewarding action of morphine (7.5 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). The effect of AT-312 on morphine- and cocaine-induced motor stimulation was also assessed on the conditioning days. The role of the NOP receptor in the effects of AT-312 was further confirmed by conducting the place conditioning experiments in NOP knockout mice and compared to their wild-type controls. Our results showed that AT-312 significantly reduced the acquisition of morphine and cocaine CPP in wild-type mice but not in mice lacking NOP receptors. AT-312 also suppressed morphine-induced and completely abolished cocaine-induced motor stimulation in NOP wild-type mice, but not in NOP knockout mice. These results show that small-molecule NOP receptor agonists have promising efficacy for attenuating the rewarding effects of morphine and cocaine, and may have potential as pharmacotherapy for opioid and psychostimulant addiction or for treating polydrug addiction.

8.
Int J Obes (Lond) ; 42(12): 1999-2011, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29568102

RESUMO

BACKGROUND: Visceral fat accumulation increases the risk of developing type 2 diabetes and metabolic syndrome, and is associated with excessive glucocorticoids (GCs). Fat depot-specific GC action is tightly controlled by 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) coupled with the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Mice with inactivation or activation of H6PDH genes show altered adipose 11ß-HSD1 activity and lipid storage. We hypothesized that adipose tissue H6PDH activation is a leading cause for the visceral obesity and insulin resistance. Here, we explored the role and possible mechanism of enhancing adipose H6PDH in the development of visceral adiposity in vivo. METHODS: We investigated the potential contribution of adipose H6PDH activation to the accumulation of visceral fat by characterization of visceral fat obese gene expression profiles, fat distribution, adipocyte metabolic molecules, and abdominal fat-specific GC signaling mechanisms underlying the diet-induced visceral obesity and insulin resistance in H6PDH transgenic mice fed a standard of high-fat diet (HFD). RESULTS: Transgenic H6PDH mice display increased abdominal fat accumulation, which is paralleled by elevated lipid synthesis associated with induction of lipogenic transcriptor C/EBPα and PPARγ mRNA levels within adipose tissue. Transgenic H6PDH mice fed a high-fat diet (HFD) gained more abdominal visceral fat mass coupled with activation of GSK3ß and induction of XBP1/IRE1α, but reduced pThr308 Akt/PKB content and browning gene CD137 and GLUT4 mRNA levels within the visceral adipose tissue than WT controls. HFD-fed H6PDH transgenic mice also had impaired insulin sensitivity and exhibited elevated levels of intra-adipose GCs with induction of adipose 11ß-HSD1. CONCLUSION: These data provide the first in vivo mechanistic evidence for the adverse metabolic effects of adipose H6PDH activation on visceral fat distribution, fat metabolism, and adipocyte function through enhancing 11ß-HSD1-driven intra-adipose GC action.


Assuntos
Tecido Adiposo/enzimologia , Desidrogenases de Carboidrato/metabolismo , Obesidade Abdominal/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Desidrogenases de Carboidrato/análise , Desidrogenases de Carboidrato/genética , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Transgênicos , Obesidade Abdominal/genética , Transcriptoma/genética
9.
Endocrinology ; 159(2): 931-944, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29272360

RESUMO

α7-Nicotinic acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers.


Assuntos
Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Fígado Gorduroso/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Benzamidas/uso terapêutico , Compostos Bicíclicos com Pontes/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Nicotina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas
10.
Alcohol Clin Exp Res ; 42(2): 461-471, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29215139

RESUMO

BACKGROUND: Nociceptin/orphanin FQ, the endogenous peptide agonist for the opioid receptor-like receptor (also known as NOP or the nociceptin receptor), has been shown to block the acquisition and expression of ethanol (EtOH)-induced conditioned place preference (CPP). Here, we report the characterization of a novel small-molecule NOP ligand AT-312 (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol) in receptor binding and GTPγS functional assays in vitro. We then investigated the effect of AT-312 on the rewarding action of EtOH in mice using the CPP paradigm. Further, using mice lacking the NOP receptor and their wild-type controls, we also examined the involvement of NOP in the effect of AT-312. Motivational effects of AT-312 alone were also assessed in the CPP paradigm. METHODS: Female mice lacking NOP and/or their wild-type controls received conditioning in the presence or absence of the NOP agonist [AT-312 (1, 3, and 10 mg/kg) or the control NOP agonist SCH221510 (10 mg/kg)] followed by saline/EtOH for 3 consecutive days (twice daily) and tested for CPP in a drug-free state on the next day. RESULTS: Our in vitro data showed that AT-312 is a high-affinity, selective NOP full agonist with 17-fold selectivity over the mu opioid receptor and >200-fold selectivity over the kappa opioid receptor. The results of our in vivo studies showed that AT-312 reduced EtOH CPP at the lowest dose (1 mg/kg) tested but completely abolished EtOH CPP at higher doses (3 or 10 mg/kg) compared to their vehicle-treated control group. AT-312 (3 mg/kg) did not alter EtOH-induced CPP in mice lacking NOP, confirming that AT-312 reduced EtOH CPP through its action at the NOP receptor. AT-312 (3 mg/kg) did not induce reward or aversion when administered alone, showing that the novel small-molecule NOP agonist shows efficacy in blocking EtOH-induced CPP via the NOP receptor. CONCLUSIONS: Together, these data suggest that small-molecule NOP agonists have the potential to reduce alcohol reward and may be promising as medications to treat alcohol addiction.


Assuntos
Comportamento Animal/efeitos dos fármacos , Indóis/farmacologia , Piperidinas/farmacologia , Receptores Opioides/agonistas , Animais , Células CHO , Depressores do Sistema Nervoso Central/farmacologia , Cricetulus , Etanol/farmacologia , Humanos , Camundongos , Camundongos Knockout , Receptores Opioides/genética
11.
Glia ; 65(12): 2003-2023, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28906039

RESUMO

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Astrócitos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Peptídeos Opioides/metabolismo , Receptores Opioides/deficiência , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feto/citologia , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Hidroxilaminas/farmacologia , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peptídeos Opioides/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/genética , Retinal Desidrogenase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
12.
J Endocrinol ; 235(1): R13-R31, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28814527

RESUMO

Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Nicotina/farmacologia , Animais , Regulação do Apetite/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos
13.
Pharmacol Biochem Behav ; 159: 84-89, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28735686

RESUMO

Previous preclinical studies have shown that nicotine pretreatment during adolescence increases the reinforcing actions of cocaine. However, little is known about the effect of prior nicotine administration on cocaine-induced conditioned place preference (CPP) and its reinstatement in adult mice. Besides, little information is available regarding the role of sex in this cross-talk between nicotine and cocaine. Thus, we examined if nicotine administration during adulthood would differentially alter cocaine-induced CPP, its extinction and reinstatement in male versus female mice and if the dose of nicotine was important in this regard. To this end, mice were pretreated with saline or nicotine (0.25 or 1mg/kg; twice daily for seven days) and then tested for place preference before and after single and repeated conditioning with cocaine (15mg/kg). Mice were then exposed to extinction training and tested for reinstatement of CPP. Our results showed that male and female mice pretreated with saline and conditioned with cocaine each exhibited a robust CPP after a single cocaine conditioning. However, this response was blunted in mice pretreated with the lower but not higher dose of nicotine. Female mice pretreated with the lower dose nicotine also failed to show CPP after repeated conditioning. Reinstatement of cocaine-induced CPP was also blunted in these mice compared to their respective controls. Together, these results suggest that nicotine administration during adulthood exerts differential effects on cocaine-induced CPP and its reinstatement in male and female mice and the dose of nicotine is important in this regard.


Assuntos
Cocaína/antagonistas & inibidores , Condicionamento Operante/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Envelhecimento , Animais , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Caracteres Sexuais
14.
Prog Mol Biol Transl Sci ; 137: 203-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26810003

RESUMO

For centuries, opiate analgesics have had a considerable presence in the treatment of moderate to severe pain. While effective in providing analgesia, opiates are notorious in exerting many undesirable adverse reactions. The receptor targets and the intracellular effectors of opioids have largely been identified. Furthermore, much of the mechanisms underlying the development of tolerance, dependence, and withdrawal have been delineated. Thus, there is a focus on developing novel compounds or strategies in mitigating or avoiding the development of tolerance, dependence, and withdrawal. This review focuses on the adenylyl cyclase and cyclic adenosine 3,5-monophosphate (cAMP)/protein kinase A (AC/cAMP/PKA) system as the central player in mediating the acute and chronic effects of opioids. This chapter also reviews the neuronal adaptive changes in the locus coeruleus, amygdala, periaqueductal gray, and ventral tegmental area induced by acute and chronic actions of opioid because these neuronal adaptive changes in these regions may underlie the behavioral changes observed in opiate users and abusers.


Assuntos
Adenilil Ciclases/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Humanos
15.
Prog Mol Biol Transl Sci ; 137: 149-81, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26810001

RESUMO

Cocaine addiction is a global public health and socioeconomic issue that requires pharmacological and cognitive therapies. Currently there are no FDA-approved medications to treat cocaine addiction. However, in preclinical studies, interventions ranging from herbal medicine to deep-brain stimulation have shown promise for the therapy of cocaine addiction. Recent developments in molecular biology, pharmacology, and medicinal chemistry have enabled scientists to identify novel molecular targets along the pathways involved in drug addiction. In 1994, a receptor that showed a great deal of homology to the traditional opioid receptors was characterized. However, endogenous and exogenous opioids failed to bind to this receptor, which led scientists to name it opioid receptor-like receptor, now referred to as the nociceptin receptor. The endogenous ligand of NOPr was identified a year later and named orphanin FQ/nociceptin. Nociceptin and NOPr are widely distributed throughout the CNS and are involved in many physiological responses, such as food intake, nociceptive processing, neurotransmitter release, etc. Furthermore, exogenous nociceptin has been shown to regulate the activity of mesolimbic dopaminergic neurons, glutamate, and opioid systems, and the stress circuit. Importantly, exogenous nociceptin has been shown to reduce the rewarding and addictive actions of a number of drugs of abuse, such as psychostimulants, alcohol, and opioids. This paper reviews the existing literature on the role of endogenous nociceptin in the rewarding and addictive actions of cocaine. The effect of exogenous nociceptin on these processes is also reviewed. Furthermore, the effects of novel small-molecule NOPr ligands on these actions of cocaine are discussed. Overall, a review of the literature suggests that NOPr could be an emerging target for cocaine addiction pharmacotherapy.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Receptores Opioides/fisiologia , Humanos
16.
Stem Cell Res ; 15(3): 731-741, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26613348

RESUMO

Stem cell-based neuronal differentiation has provided a unique opportunity for disease modeling and regenerative medicine. Neurospheres are the most commonly used neuroprogenitors for neuronal differentiation, but they often clump in culture, which has always represented a challenge for neurodifferentiation. In this study, we report a novel method and defined culture conditions for generating sub-type or region-specific neurons from human embryonic and induced pluripotent stem cells derived neurosphere without any genetic manipulation. Round and bright-edged neurospheres were generated in a supplemented knockout serum replacement medium (SKSRM) with 10% CO2, which doubled the expression of the NESTIN, PAX6 and FOXG1 genes compared with those cultured with 5% CO2. Furthermore, an additional step (AdSTEP) was introduced to fragment the neurospheres and facilitate the formation of a neuroepithelial-type monolayer that we termed the "neurosphederm". The large neural tube-type rosette (NTTR) structure formed from the neurosphederm, and the NTTR expressed higher levels of the PAX6, SOX2 and NESTIN genes compared with the neuroectoderm-derived neuroprogenitors. Different layers of cortical, pyramidal, GABAergic, glutamatergic, cholinergic neurons appeared within 27 days using the neurosphederm, which is a shorter period than in traditional neurodifferentiation-protocols (42-60 days). With additional supplements and timeline dopaminergic and Purkinje neurons were also generated in culture too. Furthermore, our in vivo results indicated that the fragmented neurospheres facilitated significantly better neurogenesis in severe combined immunodeficiency (SCID) mouse brains compared with the non-fragmented neurospheres. Therefore, this neurosphere-based neurodifferentiation protocol is a valuable tool for studies of neurodifferentiation, neuronal transplantation and high throughput screening assays.


Assuntos
Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurogênese/imunologia , Neurônios/metabolismo , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Neurônios/citologia , Medicina Regenerativa
17.
Nature ; 519(7542): 242-6, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25533952

RESUMO

Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.


Assuntos
Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/imunologia , Imunidade Inata/imunologia , Linfócitos/fisiologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Metabolismo Energético/imunologia , Encefalina Metionina/biossíntese , Encefalina Metionina/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Humanos , Interleucinas/imunologia , Interleucinas/farmacologia , Canais Iônicos/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Masculino , Camundongos , Proteínas Mitocondriais/metabolismo , Obesidade/patologia , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-4/metabolismo , Proteína Desacopladora 1
18.
Am J Physiol Endocrinol Metab ; 308(1): E84-95, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25389364

RESUMO

Long-term glucocorticoid exposure increases the risk for developing type 2 diabetes. Prereceptor activation of glucocorticoid availability in target tissue by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH) is an important mediator of the metabolic syndrome. We explored whether the tissue-specific modulation of 11ß-HSD1 and H6PDH in adipose tissue mediates glucocorticoid-induced insulin resistance and lipolysis and analyzed the effects of 11ß-HSD1 inhibition on the key lipid metabolism genes and insulin-signaling cascade. We observed that corticosterone (CORT) treatment increased expression of 11ß-HSD1 and H6PDH and induced lipase HSL and ATGL with suppression of p-Thr(172) AMPK in adipose tissue of C57BL/6J mice. In contrast, CORT induced adipose insulin resistance, as reflected by a marked decrease in IR and IRS-1 gene expression with a reduction in p-Thr(308) Akt/PKB. Furthermore, 11ß-HSD1 shRNA attenuated CORT-induced 11ß-HSD1 and lipase expression and improved insulin sensitivity with a concomitant stimulation of pThr(308) Akt/PKB and p-Thr(172) AMPK within adipose tissue. Addition of CORT to 3T3-L1 adipocytes enhanced 11ß-HSD1 and H6PDH and impaired p-Thr(308) Akt/PKB, leading to lipolysis. Knockdown of 11ß-HSD1 by shRNA attenuated CORT-induced lipolysis and reversed CORT-mediated inhibition of pThr(172) AMPK, which was accompanied by a parallel improvement of insulin signaling response in these cells. These findings suggest that elevated adipose 11ß-HSD1 expression may contribute to glucocorticoid-induced insulin resistance and adipolysis.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Gordura Abdominal/efeitos dos fármacos , Gordura Abdominal/metabolismo , Glucocorticoides/farmacologia , Resistência à Insulina , Lipólise , RNA Interferente Pequeno/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Animais , Corticosterona/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Resistência à Insulina/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Interferência de RNA
19.
Am J Physiol Endocrinol Metab ; 306(5): E543-51, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24381005

RESUMO

The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has emerged as a potential mechanism in the pathogenesis of visceral obesity and metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) is an endoplasmic reticulum lumen-resident enzyme that generates cofactor NADPH and thus mediates 11ß-HSD1 activity. To determine the role of adipose H6PDH in the prereceptor modulation of 11ß-HSD1 and metabolic phenotypes, we generated a transgenic (Tg) mouse model overexpressing H6PDH under the control of the enhancer-promoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2/H6PDH Tg mice). Transgenic aP2/H6PDH mice exhibited relatively high expression of H6PDH and elevated corticosterone production with induction of 11ß-HSD1 activity in adipose tissue. This increase in corticosterone production in aP2-H6PDH Tg mice resulted in mild abdominal fat accumulation with induction of C/EBP mRNA expression and slight weight gain. Transgenic aP2/H6PDH mice also exhibited fasting hyperglycemia and glucose intolerance with insulin resistance. In addition, the aP2/H6PDH Tg mice have elevated circulating free fatty acid levels with a concomitant increased adipose lipolytic action associated with elevated HSL mRNA and Ser(660) HSL phosphorylation within abdominal fat. These results suggest that increased H6PDH expression specifically in adipose tissue is sufficient to cause intra-adipose glucocorticoid production and adverse metabolic phenotypes. These findings suggest that the aP2/H6PDH Tg mice may provide a favorable model for studying the potential impact of H6PDH in the pathogenesis of human metabolic syndrome.


Assuntos
Tecido Adiposo/metabolismo , Desidrogenases de Carboidrato/metabolismo , Glucocorticoides/biossíntese , Lipólise/fisiologia , Adiposidade , Animais , Desidrogenases de Carboidrato/genética , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos
20.
J Obes ; 2013: 764742, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24073333

RESUMO

BACKGROUND: Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. METHODS: Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. RESULTS: We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. CONCLUSION: The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight.


Assuntos
Analgésicos Opioides/administração & dosagem , Encéfalo/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Dependência de Morfina/metabolismo , Morfina/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Implantes de Medicamento , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dependência de Morfina/psicologia , Antagonistas de Entorpecentes/farmacologia , Limiar da Dor/efeitos dos fármacos , Fosforilação , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Fatores de Tempo
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