RESUMO
Caffeine is a psychostimulant commonly consumed with high levels of sugar. The increased availability of highly caffeinated, high sugar energy drinks could put some consumers at risk of being exposed to high doses of caffeine and sugar. Notably, research that has examined the consequences of this combination is limited. Here, we explored the effect of chronic exposure to caffeine and/or sugar on behavior and protein levels in the orbitofrontal cortex (OFC) of rats. The OFC brain region has been implicated in neuropsychiatric conditions, including obesity and addiction behaviors. Adult male Sprague-Dawley rats were treated for 26 days with control, caffeine (0.6 g/L), 10% sugar, or combination of both. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label-free quantitative shotgun analysis revealed that 21, 12, and 23% of proteins identified in the OFC were differentially expressed by sugar and/or caffeine. The results demonstrate that the intake of high levels of sugar and/or low to moderate levels of caffeine has different behavioral consequences. Moreover, each treatment results in a unique proteomic profile with different implications for neural health.
Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Carboidratos da Dieta/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Proteoma/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Bebidas/efeitos adversos , Cafeína/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Locomoção/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/fisiologia , Proteoma/análise , Proteômica , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
In most Westernized societies, there has been an alarming increase in the consumption of sugar-sweetened drinks. For many adults these drinks represent a substantial proportion of their total daily caloric intake. Here we investigated whether extended exposure to sugar changes behavior and protein expression in the orbitofrontal cortex (OFC). Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 10% sucrose solution. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Following the 1-week period free from treatment, sucrose treated rats were significantly more active than the control. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free quantitative shotgun proteomic analyses of three rats from each group found 290 proteins were differentially expressed in the sucrose treated group when compared to the control group. Major changes in the proteome were seen in proteins related to energy metabolism, mitochondrial function and the cellular response to stress. This research does not seek to suggest that sugar will cause specific neurological disorders, however similar changes in proteins have been seen in neurological disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia.
Assuntos
Córtex Pré-Frontal/metabolismo , Proteoma/metabolismo , Sacarose/metabolismo , Animais , Metabolismo dos Carboidratos , Bebidas Gaseificadas/efeitos adversos , Ingestão de Energia , Metabolismo Energético , Glucose/metabolismo , Masculino , Mitocôndrias/metabolismo , Atividade Motora , Estresse Oxidativo , Córtex Pré-Frontal/fisiologia , Proteoma/análise , Proteômica , Ratos , Ratos Sprague-Dawley , Sacarose/efeitos adversos , Aumento de PesoRESUMO
Caffeine is a plant-derived psychostimulant and a common additive found in a wide range of foods and pharmaceuticals. The orbitofrontal cortex (OFC) is rapidly activated by flavours, integrates gustatory and olfactory information, and plays a critical role in decision-making, with dysfunction contributing to psychopathologies and neurodegenerative conditions. This study investigated whether long-term consumption of caffeine causes changes to behavior and protein expression in the OFC. Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 0.6 g/L caffeine solution. Locomotor behavior was measured on the first and last day of treatment, then again after 9 days treatment free following exposure to a mild stressor. When tested drug free, caffeine-treated animals were hyperactive compared to controls. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free shotgun proteomics found 157 proteins differentially expressed in the caffeine-drinking rats compared to control. Major proteomic effects were seen for cell-to-cell communication, cytoskeletal regulation, and mitochondrial function. Similar changes have been observed in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia.
Assuntos
Cafeína/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Córtex Pré-Frontal/química , Proteômica/métodos , Animais , Comunicação Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Perfilação da Expressão Gênica , Masculino , Mitocôndrias/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Doenças do Sistema Nervoso/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
KEY POINTS: Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood. Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non-shivering thermogenesis contributes to the well-described hyperthermia. In animals that showed METH-induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH-evoked effects in these parameters were similar to those seen in saline-treated or drug naïve animals. Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH. These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose. Methamphetamine (METH) is known to promote cardiovascular failure or life-threatening hyperthermia; however, there is still limited understanding of the mechanisms responsible for evoking the physiological changes. In this study, we systematically determined the effects on both autonomic and respiratory outflows, as well as reflex function, following acute and repeated administration of METH, which enhances behavioural responses. Arterial pressure, heart rate, phrenic nerve discharge amplitude and frequency, lumbar and splanchnic sympathetic nerve discharge, interscapular brown adipose tissue and core temperatures, and expired CO2 were measured in urethane-anaesthetised male Sprague-Dawley rats. Novel findings include potent increases in central inspiratory drive and frequency that are not dependent on METH-evoked increases in expired CO2 levels. Increases in non-shivering thermogenesis correlate with well-described increases in body temperature and heart rate. Unexpectedly, METH evoked minor effects on both sympathetic outflows and mean arterial pressure. METH modified cardiorespiratory reflex function in response to hypoxia, hypercapnia and baroreceptor unloading. Chronically METH-treated rats failed to exhibit changes in baseline sympathetic, cardiovascular, respiratory and metabolic parameters. The tonic and reflex cardiovascular, respiratory and metabolic responses to METH challenge were similar to those seen in saline-treated and drug naive animals. Overall, these findings describe independent and compound associations between physiological systems evoked by METH and serve to highlight that a single dose of METH can significantly impact basic homeostatic systems and protective functions. These effects of METH persist even following chronic METH treatment.
Assuntos
Metanfetamina/farmacologia , Tecido Adiposo Marrom/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Região Lombossacral/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Nervo Frênico/fisiologia , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Respiração/efeitos dos fármacos , Nervos Esplâncnicos/fisiologia , Sistema Nervoso Simpático/fisiologia , Termogênese/efeitos dos fármacosRESUMO
Repeat administration of psychostimulants, such as methamphetamine, produces a progressive increase in locomotor activity (behavioral sensitization) in rodents that is believed to represent the underlying neurochemical changes driving psychoses. Alterations to the prefrontal cortex (PFC) are suggested to mediate the etiology and maintenance of these behavioral changes. As such, the aim of the current study was to investigate changes to protein expression in the PFC in male rats sensitized to methamphetamine using quantitative label-free shotgun proteomics. A methamphetamine challenge resulted in a significant sensitized locomotor response in methamphetamine pretreated animals compared to saline controls. Proteomic analysis revealed 96 proteins that were differentially expressed in the PFC of methamphetamine treated rats, with 20% of these being previously implicated in the neurobiology of schizophrenia in the PFC. We identified multiple biological functions in the PFC that appear to be commonly altered across methamphetamine-induced sensitization and schizophrenia, and these include synaptic regulation, protein phosphatase signaling, mitochondrial function, and alterations to the inhibitory GABAergic network. These changes could inform how alterations to the PFC could underlie the cognitive and behavioral dysfunction commonly seen across psychoses and places such biological changes as potential mediators in the maintenance of psychosis vulnerability.
Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Metanfetamina/efeitos adversos , Córtex Pré-Frontal/metabolismo , Proteoma/metabolismo , Transtornos Psicóticos/fisiopatologia , Sinapses/metabolismo , Animais , Cromatografia Líquida , Bases de Dados de Proteínas , Eletroforese em Gel de Poliacrilamida , Masculino , Modelos Neurológicos , Córtex Pré-Frontal/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Transtornos Psicóticos/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Espectrometria de Massas em TandemRESUMO
Objective: Despite being common following a brain injury, post-concussive symptoms (PCS) are highly prevalent in healthy and non-concussed individuals. Psychosocial factors likely subserve the maintenance of symptoms, and numerous studies have identified prominent risk factors associated with post-concussive symptom reporting (e.g. history of depression). However, few studies have investigated protective factors in this context. The aim of the current study was to examine the relationship between resilience and PCS, and to identify the factors subserving resilience within this relationship. Method: Healthy and non-concussed participants (n = 283, Mage = 22.70 years) completed questionnaires examining PCS (Rivermead Post-Concussion Symptom Questionnaire) and resilience (Resilience Scale for Adults), together with a screener of background demographic/clinical factors. Results: Resilience negatively predicted PCS above and beyond the effect of demographic and clinical factors previously implicated in the reporting of PCS. Interestingly, heightened "perception of self" was the resilience factor uniquely associated with PCS symptoms. The final model accounted for 33% of the variance in PCS. Overall, female gender, a history of headaches, and diagnoses of ADHD and depression, and reduced "perception of self" were all predictive of greater PCS (ps < .05). Conclusion: Resilience, particularly perception of self, is a positive protective factor in the reporting of PCS. These findings highlight the importance of early identification of less resilient individuals following trauma-such as an mTBI and provide a potential rationale for the incorporation of resilience-based rehabilitation programs into the recovery process, particularly those that promote greater self-efficacy and self-competency.
Assuntos
Concussão Encefálica , Lesões Encefálicas , Síndrome Pós-Concussão , Resiliência Psicológica , Adulto , Humanos , Feminino , Adulto Jovem , Síndrome Pós-Concussão/psicologia , Testes Neuropsicológicos , Lesões Encefálicas/complicações , Fatores de Risco , Concussão Encefálica/diagnósticoRESUMO
Deficits in interpersonal and social functioning are well established in females with Anorexia Nervosa (AN), and are thought to be key features involved in the onset and maintenance of the disease. Growing literature suggests these may be attributed to poor social cognitive processes. This systematic review evaluates whether differences in social cognition exist in adult females with AN. A total of 32 studies that compared females with AN against a healthy control group using social cognitive measures and/or questionnaires were analysed. The majority of studies were deemed to have a low or moderate risk of bias. Overall, empathy appears to be intact in AN, however greater emotion regulation difficulties, elevated alexithymia and reduced emotional awareness are evident in AN. Findings relating to emotion recognition and emotional Theory of Mind were inconsistent. The nature of the task appeared to influence the domains of cognitive ToM and social perception, warranting further research. These findings are discussed within the broader context of social cognitive models and AN rehabilitation.
Assuntos
Anorexia Nervosa , Teoria da Mente , Adulto , Anorexia Nervosa/complicações , Anorexia Nervosa/psicologia , Cognição , Emoções , Empatia , Feminino , Humanos , Cognição Social , Percepção SocialRESUMO
OBJECTIVE: The aim of this study was to use various measures of emotion recognition, such as sensitivity to emotional intensity, accuracy-based emotion labeling, and the ability to differentiate among emotional displays, to examine whether these abilities are associated with emotional and cognitive empathy. We also sought to determine whether these relationships differ between individuals with traumatic brain injury (TBI) and healthy adults. METHOD: TBI participants (n = 28) and healthy adults (n = 29) matched for age, biological sex, and education, were tested on an emotion intensity rating and recognition task. Self-reported emotional and cognitive empathy questionnaires, together with a neuropsychological battery, were also completed. RESULTS: Participants with TBI reported reduced emotional and cognitive empathy. TBI participants also had reduced overall accuracy in recognizing emotion, specifically for happy and sad emotions, although they had no difficulty identifying the intensity or differentiating among emotional displays. Intensity labeling and sensitivity to differentiate among emotions positively correlated with emotional empathy for healthy adults but not for TBI participants. No facet of emotion recognition correlated with cognitive empathy for healthy adults or TBI participants. CONCLUSIONS: The ability to identify the intensity and differentiate among emotions is associated with emotional empathy. Although individuals with severe TBI may be able to differentiate emotions, they may be unable to utilize this information to share and understand the emotions of others, or vice versa. These results could have implications for understanding poor interpersonal relationships and impaired social functioning following TBI. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Assuntos
Lesões Encefálicas Traumáticas/psicologia , Emoções , Empatia , Reconhecimento Psicológico , Adulto , Estudos de Casos e Controles , Escolaridade , Feminino , Felicidade , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Desempenho Psicomotor , Tristeza , Caracteres Sexuais , Comportamento Social , Percepção SocialRESUMO
Behavioral sensitization to repeated psychostimulant administration has been proposed to reflect many of the neurochemical and behavioral changes that are characteristic of a range of disorders, including drug addiction and psychoses. While previous studies have examined the role of dopamine and glutamate neurotransmission in mediating sensitization, particularly within the prefrontal cortex (PFC), the role of inhibitory GABAergic processing of the PFC in the expression of sensitization is not well understood. Recent research, however, has proposed an emerging role of GABA synthesis, reuptake, ionotropic and metabotropic receptor regulation, and interneuronal changes following sensitization to methamphetamine and/or amphetamine within the PFC. The aim of this review, therefore, is to synthesize research findings on changes to the GABAergic network following sensitization induced by amphetamines (i.e., amphetamine and/or methamphetamine) in the PFC. In addition to providing an overview of global PFC changes, we also provide evidence of regional specific inhibitory influences on sensitized circuitry, focusing on the prelimbic and orbitofrontal cortices. We propose a neural circuit through which inhibitory PFC GABA changes mediate sensitized disease states, focusing on the interaction between the prelimbic and orbitofrontal cortices with subcortical brain structures and the mesolimbic system. Methodological considerations and avenues for future research are also discussed.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Neurônios GABAérgicos/metabolismo , Metanfetamina/farmacologia , Inibição Neural/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Córtex Pré-Frontal/metabolismoRESUMO
The ability to regulate emotional reactions is a complex process that incorporates both physiological and psychological components. Anxiety sensitivity is a construct associated with the negative and often misinterpretation of bodily sensations, with previous findings suggesting that anxiety sensitivity may regulate an individual's physiological response to an acute stress response. The aim of the current study, therefore, was to identify whether anxiety sensitivity moderates the physiological and subjective experience of acute psychosocial stress. Fifty-eight undergraduate students high and low on anxiety sensitivity (as indexed by the Anxiety Sensitivity Index - Third Edition) had their physiology recorded during a widely-used psychosocial stress induction procedure; the Trier Social Stress Test (TSST). Heart rate and skin conductance, together with self-reported anger and tension on the Profile of Mood States questionnaire, significantly increased in response to the TSST. Conversely, high-frequency heart rate variability (HF-HRV) decreased in response to the TSST. We found that anxiety sensitivity moderated the subjective experience of the TSST, such that those who had greater anxiety sensitivity self-reported elevated tension in response to the TSST compared to those with low anxiety sensitivity. Anxiety sensitivity did not moderate any of the physiological outcomes of the TSST. Consequently, this study provides a physiological profile on how the autonomic nervous system responds to stress. Additionally, these findings suggest that beliefs about body sensations specifically affects the interpretation of stressful experiences rather than augmenting physiological reactions themselves. This may provide insights into how biases subserve the development and maintenance of dysregulated emotional experience.
Assuntos
Ansiedade/psicologia , Autoavaliação Diagnóstica , Emoções/fisiologia , Frequência Cardíaca/fisiologia , Testes Neuropsicológicos , Estresse Psicológico/psicologia , Adolescente , Adulto , Ansiedade/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/fisiopatologia , Adulto JovemRESUMO
Methamphetamine is a potent psychostimulant that can induce psychosis among recreational and chronic users, with some users developing a persistent psychotic syndrome that shows similarities to schizophrenia. This review provides a comprehensive critique of research that has directly compared schizophrenia with acute and chronic METH psychosis, with particular focus on psychiatric and neurocognitive symptomatology. We conclude that while there is considerable overlap in the behavioral and cognitive symptoms between METH psychosis and schizophrenia, there appears to be some evidence that suggests there are divergent aspects to each condition, particularly with acute METH psychosis. Schizophrenia appears to be associated with pronounced thought disorder, negative symptoms more generally and cognitive deficits mediated by the parietal cortex, such as difficulties with selective visual attention, while visual and tactile hallucinations appear to be more prevalent in acute METH-induced psychosis. As such, acute METH psychosis may represent a distinct psychotic disorder to schizophrenia and could be clinically distinguished from a primary psychotic disorder based on the aforementioned behavioral and cognitive sequelae. Preliminary evidence, on the other hand, suggests that chronic METH psychosis may be clinically similar to that of primary psychotic disorders, particularly with respect to positive and cognitive symptomatology, although negative symptoms appear to be more pronounced in schizophrenia. Limitations of the literature and avenues for future research are also discussed.
RESUMO
Caffeine is a psychostimulant frequently consumed by adults and children, often in combination with high levels of sugar. Chronic pretreatment with either substance can amplify both amphetamine and cocaine-induced hyperactivity in rodents. The present study sought to elucidate whether age at the time of exposure to sugar and/or caffeine alters sensitivity to an acute illicit psychostimulant (methamphetamine, [METH]) challenge in adulthood. Adult and adolescent (Postnatal Day 35 on first day of treatment) male Sprague-Dawley rats were treated for 26 days with water, caffeine (0.6 g/L), 10% sucrose or their combination. Locomotor behavior was measured on the first and last day of treatment. Following 9-days treatment free, animals were challenged with saline (1 ml/kg, i.p.) or METH (1 mg/kg, i.p.) and locomotor activity was measured. During the treatment period, adolescent rats maintained a higher caffeine (mg/kg) dose than their adult counterparts. Adding sugar to caffeine increased adolescent consumption and the highest caffeine dose consumed was measured in these animals. Drinking sugar-sweetened caffeinated water or combination did not produce cross-sensitization to METH administration in either age group. Nevertheless, the finding that regular exposure through adolescence to caffeinated sugar-sweetened beverages could increase consumption of caffeine and sugar later in life is important, as there is a large body of evidence that has linked excess consumption of sugar-sweetened beverages to a broad range of other negative physical and mental health outcomes. (PsycINFO Database Record
Assuntos
Cafeína/efeitos adversos , Açúcares/efeitos adversos , Fatores Etários , Animais , Cafeína/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Sacarose Alimentar/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/metabolismo , Metanfetamina/farmacologia , Ratos , Ratos Sprague-Dawley , Açúcares/metabolismo , Edulcorantes/farmacologiaRESUMO
Schizophrenia is associated with significant pathophysiological changes to interneurons within the prefrontal cortex (PFC), with mRNA and protein changes associated with the GABA network localized to specific interneuron subtypes. Methamphetamine is a commonly abused psychostimulant that can induce chronic psychosis and symptoms that are similar to schizophrenia, suggesting that chronic METH induced psychosis may be associated with similar brain pathology to schizophrenia in the PFC. The aim of this study, therefore, was to examine mRNA expression of interneuron markers across two regions of the PFC (prelimbic (PRL) and orbitofrontal cortices (OFC)) following METH sensitization, an animal model of METH psychosis. We also studied the association between GABA mRNA expression and interneuronal mRNA expression to identify whether particular changes to the GABA network could be localized to a specific inhibitory cellular phenotype. METH sensitization increased the transcriptional expression of calbindin, calretinin, somatostatin, cholecyctokinin and vasoactive intestinal peptide in the PRL while parvalbumin, calbindin, cholectokinin and vasoactive intestinal peptide were upregulated in the OFC. Based on our previous findings, we also found significant correlations between GAD67, GAT1 and parvalbumin while GAD67, GAD65 and GAT1 were positively correlated with cholecystokinin in the PRL of METH sensitized rats. Within the OFC, the expression of GABAAα1 was positively correlated with somatostatin while GABAAα5 was negatively associated with somatostatin and calbindin. These findings suggest that METH sensitization differentially changes the expression of mRNAs encoding for multiple peptides and calcium binding proteins across the PRL and the OFC. Furthermore, these findings support that changes to the GABA network may also occur within specific cell types. These results, therefore, provide the first evidence that METH sensitization mediates differential interneuronal pathology across the PRL and OFC and such changes could have profound consequences on behavior and cognitive output.
Assuntos
Sensibilização do Sistema Nervoso Central , Interneurônios/metabolismo , Interneurônios/patologia , Lobo Límbico/metabolismo , Metanfetamina/farmacologia , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Glutamato Descarboxilase/metabolismo , Lobo Límbico/patologia , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Receptores de GABA-A/biossíntese , Ácido gama-Aminobutírico/metabolismoRESUMO
Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed.
Assuntos
Bulbo/citologia , Neuroquímica , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Catecolaminas/metabolismo , Desoxiglucose/farmacologia , Encefalinas/genética , Encefalinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Hidralazina/farmacologia , Hipotensão/metabolismo , Hipotensão/patologia , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Taquicininas/genética , Taquicininas/metabolismoRESUMO
Inhibitory gamma-aminobutyric acid (GABA)-mediated neurotransmission plays an important role in the regulation of the prefrontal cortex (PFC), with increasing evidence suggesting that dysfunctional GABAergic processing of the PFC may underlie certain deficits reported across psychotic disorders. Methamphetamine (METH) is a psychostimulant that induces chronic psychosis in a subset of users, with repeat administration producing a progressively increased vulnerability to psychotic relapse following subsequent drug administration (sensitization). The aim here was to investigate changes to GABAergic mRNA expression in the PFC of rats sensitized to METH using quantitative polymerase chain reaction (qPCR). Male Sprague-Dawley rats (n=12) underwent repeated methamphetamine (intraperitoneal (i.p.) or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute methamphetamine (1mg/kg i.p.) and RNA was isolated from the PFC to compare the relative mRNA expression of a range of GABA enzymes, transporters and receptors subunits. METH challenge resulted in a significant sensitized behavioral (locomotor) response in METH pre-treated animals compared with saline pre-treated controls. The mRNAs of transporters (GAT1 and GAT3), ionotropic GABAA receptor subunits (α3 and ß1), together with the metabotropic GABAB1 receptor, were upregulated in the PFC of sensitized rats compared with saline controls. These findings indicate that GABAergic mRNA expression is significantly altered at the pre and postsynaptic level following sensitization to METH, with sensitization resulting in the transcriptional upregulation of several inhibitory genes. These changes likely have significant consequences on GABA-mediated neurotransmission in the PFC and may underlie certain symptoms conserved across psychotic disorders, such as executive dysfunction.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Metanfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Reação em Cadeia da Polimerase , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Psychotic disorders, such as schizophrenia, are characterized by prevalent and persistent executive deficits that are believed to be the result of dysfunctional inhibitory gamma-aminobutyric acid (GABA) processing of the prefrontal cortex (PFC). Methamphetamine (METH) is a commonly used psychostimulant that can induce psychotic and cognitive symptoms that are indistinguishable to schizophrenia, suggesting that METH-induced psychosis may have a similar GABAergic profile of the PFC. As the PFC consists of multiple subregions, the aim of the current study was to investigate changes to GABAergic mRNA expression in the prelimbic (PRL) and orbitofrontal (OFC) cortices of the PFC in rats sensitized to repeated METH administration. Male Sprague Dawley rats underwent daily METH or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute METH administration, RNA was isolated from the PRL and OFC and quantitative PCR was used to compare the relative expression of GABA enzymes, transporters, metabolites and receptor subunits. GAD67, GAD65, GAT1, GAT3, VGAT and GABAT mRNA expression were upregulated in the PRL. Ionotropic GABAA receptor subunits α1, α3, α5 and ß2 were specifically upregulated in the OFC. These findings suggest that alterations to GABAergic mRNA expression following sensitization to METH are biologically dissociated between the OFC and PRL, suggesting that GABAergic gene expression is significantly altered following chronic METH exposure in a brain-region and GABA-specific manner. These changes may lead to profound consequences on central inhibitory mechanisms of localized regions of the PFC and may underpin common behavioral phenotypes seen across psychotic disorders.