RESUMO
PURPOSE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the µ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.
Assuntos
Fentanila , Camundongos Endogâmicos C57BL , Receptores Opioides mu , Caracteres Sexuais , Animais , Fentanila/farmacologia , Masculino , Feminino , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Camundongos , Metilação de DNA/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Naloxona/farmacologia , Comportamento Animal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Epigênese Genética/efeitos dos fármacosRESUMO
It has been well established that a consolidated memory can be updated during the plastic state induced by reactivation. This updating process opens the possibility to modify maladaptive memory. In the present study, we evaluated whether fear memory could be updated to less-aversive level by incorporating hedonic information during reactivation. Thus, male rats were fear conditioned and, during retrieval, a female was presented as a social rewarding stimulus. We found that memory reactivation with a female (but not a male) reduces fear expression within-session and in the test, without presenting reinstatement or spontaneous recovery. Interestingly, this intervention impaired extinction. Finally, we demonstrated that this emotional remodeling to eliminate fear expression requires the activation of dopamine and oxytocin receptors during retrieval. Hence, these results shed new lights on the memory updating process and suggests that the exposure to natural rewarding information such as a female during retrieval reduces a previously consolidated fear memory.
Assuntos
Medo , Receptores de Ocitocina , Interação Social , Animais , Medo/fisiologia , Masculino , Ratos , Receptores de Ocitocina/metabolismo , Feminino , Memória/fisiologia , Extinção Psicológica/fisiologia , Receptores Dopaminérgicos/metabolismo , Condicionamento Clássico/fisiologia , Recompensa , Ratos Wistar , Consolidação da Memória/fisiologiaRESUMO
1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.
Assuntos
Antidepressivos , Dopamina , Monoaminoxidase , Compostos Organosselênicos , Animais , Masculino , Camundongos , Antidepressivos/farmacologia , Compostos Organosselênicos/farmacologia , Monoaminoxidase/metabolismo , Monoaminoxidase/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Natação , Norepinefrina/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/metabolismo , Atividade Motora/efeitos dos fármacosRESUMO
Early stress can increase vulnerability to psychopathological disorders, including substance use disorders. The effects of stress in the juvenile period of the rat, that extends between weaning and the onset of adolescence (equivalent to late human childhood), have received little attention. This study assessed short and long-term behavioral effects of juvenile stress, with a focus on effects on ethanol intake. Male and female Wistar rats were exposed to variable stress (restraint, elevated platform, forced swimming, and social instability) or to restraint stress only, between postnatal days 26 to 29 (PDs 26-29). During adolescence, patterns of anxiety (PD 31) and depression (PD 33), ethanol intake (PDs 36-45) and behavioral sensitivity to the effects of acute stress (PD 47) were evaluated. In adulthood, alcohol ingestion was assessed through two-bottle ethanol intake tests (PDs 75-85). An additional experiment measured blood ethanol levels after a limited access intake session in adolescence. Exposure to juvenile variable stress exerted very mild effects in adolescence, but reduced ethanol ingestion in adulthood, in females only. Ethanol intake during the limited access session was significantly correlated to blood alcohol levels. The results indicate that a schedule of juvenile variable stress that did not significantly alter anxiety-related behaviors induced, nonetheless, sexually dimorphic effects on ethanol intake in adulthood. Early stress exposure that reduced alcohol intake in Wistar rats has been associated with changes on brain opioid and dopamine receptors. These results highlight the impact of early stress exposure on adult female ethanol consumption and its possible underlying neurobiological changes, involving opioid and dopamine receptors.
Assuntos
Analgésicos Opioides , Etanol , Humanos , Ratos , Masculino , Feminino , Animais , Criança , Etanol/toxicidade , Ratos Wistar , Consumo de Bebidas Alcoólicas/efeitos adversos , Receptores DopaminérgicosRESUMO
We employed the whole-cell patch-clamp method and ChAT-Cre mice to study the electrophysiological attributes of cholinergic neurons in the external globus pallidus. Most neurons were inactive, although approximately 20% displayed spontaneous firing, including burst firing. The resting membrane potential, the whole neuron input resistance, the membrane time constant and the total neuron membrane capacitance were also characterized. The current-voltage relationship showed time-independent inward rectification without a "sag". Firing induced by current injections had a brief initial fast adaptation followed by tonic firing with minimal accommodation. Intensity-frequency plots exhibited maximal average firing rates of about 10 Hz. These traits are similar to those of some cholinergic neurons in the basal forebrain. Also, we examined their dopamine sensitivity by acutely blocking dopamine receptors. This action demonstrated that the membrane potential, excitability, and firing pattern of pallidal cholinergic neurons rely on the constitutive activity of dopamine receptors, primarily D2-class receptors. The blockade of these receptors induced a resting membrane potential hyperpolarization, a decrease in firing for the same stimulus, the disappearance of fast adaptation, and the emergence of a depolarization block. This shift in physiological characteristics was evident even when the hyperpolarization was corrected with D.C. current. Neither the currents that generate the action potentials nor those from synaptic inputs were responsible. Instead, our findings suggest, that subthreshold slow ion currents, that require further investigation, are the target of this novel dopaminergic signaling.
Assuntos
Dopamina , Globo Pálido , Camundongos , Animais , Dopamina/fisiologia , Potenciais de Ação/fisiologia , Neurônios Colinérgicos , Receptores Dopaminérgicos , ColinérgicosRESUMO
Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.
Assuntos
Ansiolíticos , Dopamina , Ratos , Animais , Dopamina/metabolismo , Olfato , Receptores Dopaminérgicos/metabolismo , Núcleo Accumbens , Ansiedade , Ansiolíticos/farmacologia , Receptores de Dopamina D1/metabolismoRESUMO
OBJECTIVES: To test the association of 45 single nucleotide polymorphisms (SNPs) with transition to psychiatric disorders in a cohort of individuals at ultrahigh risk (UHR) mental state for psychosis. METHODS: Through general population screening, 88 non-help-seeking UHR subjects and 130 healthy control individuals were genotyped for 45 SNPs related to psychosis. They were followed for a mean of 2.5 years, and conversion to psychotic and to general psychiatric disorders was assessed. Genotype frequencies between controls, converters, and non-converters were analyzed. RESULTS: There were no differences in sociodemographics between controls and UHR. Also, UHR converters and non-converters had no differences in their baseline symptoms scores. The dopamine receptor D2 gene (DRD2) SNP rs6277 was significantly more common among UHR who transitioned to psychosis (p < 0.001) and to UHR who transitioned to any psychiatric disorders (p = 0.001) when compared to UHR who did not transition. The rs6277 T allele was related to psychiatric morbidity in a dose-response fashion, being significantly more frequent in UHR converters than UHR non-converters and control subjects (p = 0.003). CONCLUSION: Our findings suggest that rs6277 could potentially constitute a genetic marker of transition to psychiatric disorders in subjects with at-risk mental states, warranting further investigation in larger samples.
Assuntos
Transtornos Mentais , Transtornos Psicóticos , Receptores de Dopamina D2 , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/genética , Receptores Dopaminérgicos , Fatores de Risco , Receptores de Dopamina D2/genéticaRESUMO
Obesity is a pandemic caused by many factors, including a chronic excess in hypercaloric and high-palatable food intake. In addition, the global prevalence of obesity has increased in all age categories, such as children, adolescents, and adults. However, at the neurobiological level, how neural circuits regulate the hedonic consumption of food intake and how the reward circuit is modified under hypercaloric diet consumption are still being unraveled. We aimed to determine the molecular and functional changes of dopaminergic and glutamatergic modulation of nucleus accumbens (NAcc) in male rats exposed to chronic consumption of a high-fat diet (HFD). Male Sprague-Dawley rats were fed a chow diet or HFD from postnatal day (PND) 21 to 62, increasing obesity markers. In addition, in HFD rats, the frequency but not amplitude of the spontaneous excitatory postsynaptic current is increased in NAcc medium spiny neurons (MSNs). Moreover, only MSNs expressing dopamine (DA) receptor type 2 (D2) increase the amplitude and glutamate release in response to amphetamine, downregulating the indirect pathway. Furthermore, NAcc gene expression of inflammasome components is increased by chronic exposure to HFD. At the neurochemical level, DOPAC content and tonic dopamine (DA) release are reduced in NAcc, while phasic DA release is increased in HFD-fed rats. In conclusion, our model of childhood and adolescent obesity functionally affects the NAcc, a brain nucleus involved in the hedonic control of feeding, which might trigger addictive-like behaviors for obesogenic foods and, through positive feedback, maintain the obese phenotype.
Assuntos
Dopamina , Obesidade Infantil , Ratos , Masculino , Animais , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Dieta Hiperlipídica , Ratos Sprague-Dawley , Obesidade Infantil/metabolismo , Transmissão Sináptica/fisiologia , Receptores Dopaminérgicos/metabolismoRESUMO
Alzheimer's and Parkinson's are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals, due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, this review aimed to evaluate the anti-Alzheimer's and anti-Parkinson's activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds' pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citronellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1 receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. The compounds studied presented high probability of modulatory activity against the disease targets under study, and are potential candidates for future drugs.
Assuntos
Doença de Alzheimer , Doença de Parkinson , Humanos , Simulação de Acoplamento Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Qualidade de Vida , Doença de Alzheimer/metabolismo , Receptores DopaminérgicosRESUMO
The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal CaV conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV2.1, CaV2.3, or CaV3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.