RESUMO
ß-caryophyllene (BCP) is a cannabinoid receptor CB2 agonist plant-derived terpenoid found in different essential oil plants, including rosemary, black pepper, copaiba and cannabis. It has GRAS (generally recognized as safe) status and is approved by the FDA (Food and Drug Administration) for food use. BCP displays agonist activity on the CB2 receptor and is a potential therapeutic target in several neuropsychiatric disorders, including anxiety and drug addiction. Unlike CB1 receptors, activation of the CB2 receptors is devoid of psychotomimetic and addictive properties. In this regard, this study aimed to evaluate the effects of BCP on incentive salience ("wanting") performance and motivational properties elicited by sweetened palatable foods in female Swiss mice. After 9 days of training for incentive salience performance for a sweet reward (hazelnut cream with chocolate), food-restricted mice received a systemic injection of BCP (50 and 100 mg/kg) before testing over 3 days. Moreover, independent groups of female mice were tested on sweet reward-induced conditioned place preference (CPP) for 22 consecutive days. To evaluate BCP effects on the expression of seeking behaviour for sweetened food, mice received a single intraperitoneal injection of BCP (50 mg/kg) 30 min before testing on the CPP task. BCP significantly decreased the incentive performance for a sweet reward compared with the control group in a CB2 receptor-dependent manner. Also, BCP suppressed the expression of sweet reward-CPP. Altogether, these preclinical data demonstrate the potential role of BCP in treating disorders associated with food addiction-like behaviour.
Assuntos
Sesquiterpenos , Camundongos , Animais , Sesquiterpenos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Motivação , Receptor CB2 de Canabinoide , Receptor CB1 de CanabinoideRESUMO
We demonstrate that the rate of extracellular signal-related kinase phosphorylation (P-ERK1,2/Total-ERK1,2) in the amygdala is negatively and independently associated with anxiety symptoms in 23 consecutive patients with drug-resistant mesial temporal lobe epilepsy that was surgically treated. In naive Wistar rats, the P-ERK1,2/Total-ERK1,2 ratio in the amygdala correlates negatively with innate anxiety-related behavior on the elevated plus maze (n = 20) but positively with expression of defensive-learned behavior (i.e., freezing) on Pavlovian aversive (fear) conditioning (n = 29). The microinfusion of ERK1/2 inhibitor (FR180204, n = 8-13/group) or MEK inhibitor (U0126, n = 8-9/group) into the basolateral amygdala did not affect anxiety-related behavior but impaired the evocation (anticipation) of conditioned-defensive behavior (n = 9-11/group). In conclusion, the P-ERK1,2/Total-ERK1,2 ratio in the amygdala predicts anxiety in humans and the innate anxiety- and conditioned freezing behaviors in rats. However, the ERK1/2 in the basolateral AMY is only required for the expression of defensive-learned behavior. These results support a dissociate ERK-dependent mechanism in the amygdala between innate anxiety-like responses and the anticipation of learned-defensive behavior. These findings have implications for understanding highly prevalent psychiatric disorders related to the defensive circuit manifested by anxiety and fear. HIGHLIGHTS: The P-ERK1,2/Total-ERK1,2 ratio in the amygdala (AMY) correlates negatively with anxiety symptoms in patients with mesial temporal lobe epilepsy. The P-ERK1,2/Total-ERK1,2 in the amygdala correlates negatively with the anxiety-like behavior and positively with freezing-learned behavior in naive rats. ERK1,2 in the basolateral amygdala is required for learned-defensive but not for the anxiety-like behavior expression in rats.
Assuntos
Tonsila do Cerebelo , Ansiedade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação , Ratos , Ratos WistarRESUMO
Ethanol exposure and early life stress during brain development are associated with an increased risk of developing psychiatric disorders. We used a third-trimester equivalent model of fetal alcohol spectrum disorders combined with a maternal separation (MS) protocol to evaluate whether these stressors cause sexually dimorphic behavioral and hippocampal dendritic arborization responses in adolescent rats. Wistar rat pups were divided into four experimental groups: 1) Control; 2) MS (MS, for 3 h/day from postnatal (PND) 2 to PND14); 3) EtOH (EtOH, 5 g/kg/day, i.p., PND2, 4, 6, 8, and 10); 4) EtOH + MS. All animals were divided into two cohorts and subjected to a battery of behavioral tests when they reached adolescence (PND37-44). Animals from cohort 1 were submitted to: 1) the open field test; 2) self-cleaning behavior (PND38); and 3) the motivation test (PND39-41). Animals from cohort 2 were submitted to: 1) the novel object recognition (PND37-39); 2) social investigation test (PND40); and 3) Morris water maze test (PND41-44). At PND45, the animals were euthanized, and the brains were collected for subsequent dendritic analysis. Postnatal ethanol exposure (PEE) caused anxiety-like behavior in females and reduced motivation, and increased hippocampal dendritic arborization in both sexes. MS reduced body weight, increased locomotor activity in females, and increased motivation, and hippocampal dendritic arborization in both sexes. We found that males from the EtOH + MS groups are more socially engaged than females, who were more interested in sweets than males. Altogether, these data suggest that early life adverse conditions may alter behavior in a sex-dependent manner in adolescent rats.
Assuntos
Etanol/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Afeto/fisiologia , Animais , Animais Recém-Nascidos , Ansiedade/etiologia , Ansiedade/metabolismo , Cognição/fisiologia , Dendritos , Modelos Animais de Doenças , Etanol/metabolismo , Etanol/farmacologia , Feminino , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Masculino , Privação Materna , Gravidez , Ratos , Ratos Wistar , Estresse PsicológicoRESUMO
The central autonomic network, which is connected to the limbic system structures including the amygdala (AMY) and anterior hippocampus (aHIP), regulates the sympathetic and parasympathetic modulation of visceromotor, neuroendocrine, pain, and behavior manifestations during stress responses. Heart rate variability (HRV) is useful to estimate the cardiac autonomic tone. The levels of phosphorylation on the Ser831 and Ser845 sites of the GluA1 subunit of the AMPAr (P-GluA1-Ser845 and P-GluA1-Ser831) are useful markers of synaptic plasticity. The relation between synaptic plasticity in the human limbic system structures and autonomic regulation in humans is unknown. This study investigated the association between HRV and neurochemistry biomarkers of synaptic plasticity in AMY and aHIP. HRV indices were obtained from the resting state electrocardiogram of patients with drug-resistant mesial temporal lobe epilepsy (MTLE, n = 18) and the levels of P-GluA1-Ser845 and P-GluA1-Ser831 in the AMY and aHIP resected during the epilepsy surgery. A backward stepwise multiple linear regression models were used to analyze the association between HRV and synaptic plasticity biomarkers controlling for imbalances in the distribution of sociodemographic, clinical, neuroimaging, and neurosurgical variables. P-GluA1-Ser845 levels in AMY show a negative association (p < 0.05) with the 3 investigated parasympathetic autonomic HRV indices (SDNN, rMSSD, and HF) predicting 24 to 40% of their variation. The final multiple linear regression models include disease duration and levels of P-GluA1-Ser845 and predict 24 to 56% of cardiac autonomic tone variation (p < 0.01). P-GluA1-Ser845 levels in AMY and aHIP are negatively associated with the resting HRV in MTLE-HS indicating that increased synaptic efficiency in amygdala is associated with a parasympathetic cardiac autonomic tone impairment. The results suggest that specific changes in synaptic plasticity may be involved in the brain-heart axis regulation by the limbic system.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Coração/inervação , Sistema Límbico/metabolismo , Fosfosserina/metabolismo , Receptores de AMPA/metabolismo , Tonsila do Cerebelo/metabolismo , Biomarcadores/metabolismo , Feminino , Frequência Cardíaca , Hipocampo/metabolismo , Humanos , Masculino , Plasticidade Neuronal , FosforilaçãoRESUMO
Interictal dysphoric disorder (IDD) is a poorly understood psychiatric disorder of epilepsy patients. Interictal dysphoric disorder is characterized by depressive, somatoform, and affective symptoms observed in up to 5.9% of drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). This study aimed to evaluate the association between ictal fear (IF) and the psychiatric symptoms and diagnosis in MTLE-HS patients. We included 116 (54.3% male) consecutive adult patients (36⯱â¯11â¯years) with MTLE-HS. Anxiety and depression symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS) and the psychiatric diagnosis were according to Fourth Edition of the Diagnosis and Statistical Manual of Mental Disorders (DSM-IV). The independent association between the occurrence of IF aura and the psychiatric diagnosis was determined by binary regression. When compared to those with other auras or without aura, patients reporting IF have higher HADS anxiety, but not HADS depression, scores. Ictal fear was independently associated with the diagnosis of interictal dysphoric disorder (OR, IC 95%â¯=â¯7.6, 1.3-43.2, pâ¯=â¯0.02), but not with the diagnosis of anxiety (OR, CI 95%â¯=â¯0.72, 0.08-6.0, pâ¯=â¯0.73), depression (OR, CI 95%â¯=â¯0.94, 0.19-4.8, pâ¯=â¯0.94) or psychotic disorders (pâ¯=â¯0.99). Only patients with drug-resistant MTLE-HS were included and the small number of cases with DD diagnosis in the sample. In MTLE-HS patients, the occurrence of IF is associated with higher levels of anxiety symptoms and IDD. The results provide insights about fear-related neural network connections with anxiety symptoms and the IDD in MTLE-HS.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Preparações Farmacêuticas , Adulto , Ansiedade/etiologia , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/patologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/patologia , Medo , Feminino , Hipocampo/patologia , Humanos , Masculino , Esclerose/patologiaRESUMO
Fear is a conscious state caused by exposure to real or imagined threats that trigger stress responses that affect the body and brain, particularly limbic structures. A sub-group of patients with mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) have seizures with fear, which is called ictal fear (IF), due to epileptic activity within the brain defensive survival circuit structures. Synaptic transmission efficacy can be bi-directionally modified through potentiation (long-term potentiation (LTP)) or depression (long-term depression (LTD)) as well as the phosphorylation state of Ser831 and Ser845 sites at the GluA1 subunit of the glutamate AMPA receptors, which has been characterized as a critical event for this synaptic plasticity. In this study, GluA1 levels and the phosphorylation at Ser845 and Ser831 in the amygdala (AMY), anterior hippocampus (aHIP) and middle gyrus of temporal neocortex (CX) were determined with western blots and compared between MTLE-HS patients who were showing (n = 06) or not showing (n = 25) IF. Patients with IF had an 11% decrease of AMY levels of the GluA1 subunit (p = 0.05) and a 21.5% decrease of aHIP levels of P-GluA1-Ser845 (p = 0.009) compared to patients not showing IF. The observed associations were not related to imbalances in the distribution of other concomitant types of aura, demographic, clinical or neurosurgical variables. The lower levels of P-GluA1-Ser845 in the aHIP of patients with IF were not related to changes in the levels of the serine/threonine-protein phosphatase PP1-alpha catalytic subunit or protein kinase A activation. Taken together, the GluA1 subunit levels in AMY and P-GluA1-Ser845 levels in the aHIP show an overall accuracy of 89.3% (specificity 95.5% and sensitivity 66.7%) to predict the presence of IF. AMY levels of the GluA1 subunit and aHIP levels of P-GluA1-Ser845 were not associated with the psychiatric diagnosis and symptoms of patients. Taken together with previous findings in MTLE-HS patients with IF who were evaluated by stereotactic implanted depth electrodes, we speculate our findings are consistent with the hypothesis that AMY is not a centre of fear but together with other sub-cortical and cortical structures integrates the defensive circuit that detect and respond to threats. This is the first report to address neuroplasticity features in human limbic structures connected to the defensive survival circuits, which has implications for the comprehension of highly prevalent psychiatric disorders and symptoms.
Assuntos
Medo/fisiologia , Receptores de Glutamato/genética , Convulsões/psicologia , Adulto , Tonsila do Cerebelo/metabolismo , Ansiedade/genética , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Biomarcadores/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração , Masculino , Plasticidade Neuronal/fisiologia , Fosforilação , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Convulsões/metabolismo , Serina/metabolismo , Transmissão SinápticaRESUMO
(1) Objectives: Epilepsy disorder is likely to increase with aging, leading to an increased incidence of comorbidities and mortality. In spite of that, there is a lack of information regarding this issue and little knowledge of cognitive and emotional responses in aging subjects following epileptogenesis. We investigated whether and how aging distress epilepsy-related behavioral and biochemical outcomes are associated with cognition and emotion. (2) Methods: Young and middle-aged Wistar rats (3 or 12 months old) were treated with pentylenetetrazol (PTZ, 35 mg/kg) and injected on alternated days for 20 (young rats) and 32 days (middle-aged rats). Kindling was reached after two consecutive stages 4 plus one stage 5 or 6 in Racine scale. Control and kindled rats were evaluated in the elevated plus-maze (EPM) and object-recognition tests and their hippocampus was collected 24 h later for mitogen-activated protein kinases (MAPK) dosage. (3) Results: Middle-aged rats presented a higher resistance to develop kindling, with a decrease in the seizure severity index observed following the 4th and 9th PTZ injections. Middle-aged rats displayed an increased duration of the first myoclonic seizure and an increased latency to the first generalized seizure when compared to younger rats. The induction of kindling did not impair the animals' performance (regardless of age) in the object-recognition task and the EPM test as well as it did not alter the hippocampal levels of MAPKs. (4) Significance: Our findings reveal that, despite age-related differences during epileptogenesis, middle-aged rats evaluated after kindling performed similarly during discriminative learning and emotional tasks in comparison to young animals, with no alteration of hippocampal MAPKs. Additional investigation must be carried out to explore the electrophysiological mechanisms underlying these responses, as well as the long-term effects displayed after kindling.
RESUMO
In addicts, craving and relapse are frequently induced by the recall of memories related to a drug experience. Several studies have demonstrated that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to the pathological cycle of addiction. Here we used drug-induced conditioned place preference (CPP) to investigate whether cannabidiol (CBD), a phytocannabinoid, given just after reactivation sessions, would affect reconsolidation of drug-reward memory, reinstatement of morphine-CPP, or conditioned place aversion precipitated by naltrexone in Wistar rats. We found that CBD impaired the reconsolidation of preference for the environment previously paired with both morphine and cocaine. This disruption seems to be persistent, as the preference did not return after further reinstatement induced by priming drug and stress reinstatement. Moreover, in an established morphine-CPP, an injection of CBD after the exposure to a conditioning session led to a significant reduction of both morphine-CPP and subsequent conditioned place aversion precipitated by naltrexone in the same context. Thus, established memories induced by a drug of abuse can be blocked after reactivation of the drug experience. Taken together, these results provide evidence for the disruptive effect of CBD on reconsolidation of contextual drug-related memories and highlight its therapeutic potential to attenuate contextual memories associated with drugs of abuse and consequently to reduce the risk of relapse.
Assuntos
Canabidiol/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Animais , Cocaína/administração & dosagem , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Naltrexona/administração & dosagem , Ratos , Ratos Wistar , RecompensaRESUMO
Epidemiological studies indicate that high midlife plasma cholesterol levels increases the risk of Alzheimer's disease. Moreover, middle-aged familial hypercholesterolemia (FH) subjects show a particularly high incidence of mild cognitive impairments (MCI). These evidence points to hypercholesterolemia as one of the modifiable risk factors focused on prevention/treatment of cognitive deterioration. The present study draws a comparison between pharmacological (lipid-lowering drug probucol) and non-pharmacological (voluntary running wheel, RW) approaches for the management of hypercholesterolemia and cognitive impairments associated with the low-density lipoprotein receptor-deficient (LDLr(-/-)) mice, a well-established rodent model of FH. We also investigated whether exposure to environmental enrichment (EE), a feasible option to increase physical activity in young mice cohort, from birth to adolescence (PN45) yields long-term behavioral changes in adult LDLr(-/-) mice (PN90). We observed that both probucol and RW significantly decreased total and non-HDL plasma cholesterol levels in LDLr(-/-) mice. Notably, only physical exercise mitigated the spatial memory deficits of LDLr(-/-) mice. In addition, we showed that exposure to EE from birth until the adolescence did not mitigate the spatial memory deficits of adult LDLr(-/-) mice in the object location task, although it induced persistent anxyolitic-like effects in the open field arena. Collectively, our results emphasize the advantages physical exercise, in comparison to lipid-lowering drugs, for the management of cognitive deficits associated with FH.
Assuntos
Transtornos Cognitivos/psicologia , Hiperlipoproteinemia Tipo II/psicologia , Condicionamento Físico Animal , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/terapia , Efeito Fundador , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Camundongos , Camundongos Knockout , Atividade Motora , Probucol/farmacologia , Probucol/uso terapêutico , Receptores de LDL/genética , Meio SocialRESUMO
OBJECTIVES: The aim of the present study was to evaluate the possible neurobehavioural effects in rats of the proanthocyanidin-rich fraction (PRF) isolated from the bark of Croton celtidifolius (Euphorbiaceae). METHODS: Adult Wistar rats were treated with the PRF (0.3-30 mg/kg) and evaluated in different behavioural paradigms classically used for the screening of drugs with psychoactive effects. KEY FINDINGS: Acute intraperitoneal (i.p.) administration of PRF decreased spontaneous locomotor activity (open field arena and activity cage), enhanced the duration of ethyl ether-induced hypnosis, increased the latency to the first convulsion induced by pentylenetetrazole (60 mg/kg, i.p.) and attenuated apomorphine-induced (0.5 mg/kg, i.p.) stereotyped behaviour. In lower doses, PRF (0.3 or 3 mg/kg, i.p.) increased the frequency of open arm entries in the elevated plus-maze test. CONCLUSIONS: The present findings suggest that the systemic administration of PRF induces a wide spectrum of behavioural alterations in rats, consistent with the putative existence of hypnosedative, anticonvulsant and anxiolytic compounds.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Croton , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia , Anestésicos Inalatórios/farmacologia , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Antipsicóticos/farmacologia , Apomorfina/farmacologia , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/isolamento & purificação , Estado de Consciência/efeitos dos fármacos , Croton/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éter/farmacologia , Hipnóticos e Sedativos/farmacologia , Injeções Intraperitoneais , Masculino , Atividade Motora/efeitos dos fármacos , Pentilenotetrazol , Casca de Planta , Extratos Vegetais/administração & dosagem , Proantocianidinas/administração & dosagem , Proantocianidinas/isolamento & purificação , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Comportamento Estereotipado/efeitos dos fármacosRESUMO
The present study investigated the consequences of environmental enrichment on the impact of novelty and motivational properties of ethanol in spontaneously hypertensive rats (SHR), a validated model of attention deficit hyperactivity disorder (ADHD). This rat strain displays increased sensitivity to distinct classes of abused drugs, which makes it an interesting model for the study of the association between ADHD and drug abuse. Female SHR reared from weaning to adulthood in standard (SE) or enriched (EE) environment were tested on novelty-induced locomotion, saccharin consumption, ethanol consumption (forced and free-choice schedules) and ethanol-induced conditioned place preference (CPP). SHR reared in an EE showed reduced novelty-induced locomotion, consumed less saccharin and ethanol in a forced schedule and showed less ethanol preference in a free-choice schedule compared to SE rats. Moreover, EE rats did not develop CPP, whereas SE rats developed preference for ethanol (1.2g/kg). These results show that exposure to stimuli mimicking positive life experiences (environmental enrichment) induces persistent changes in the reward/motivational system of female SHR, suggesting an important role of the familiar environment during early stages of the neurodevelopment on the co-morbidity of ADHD and drug abuse.