RESUMO
Morphine is among the most powerful analgesics and pain-relieving agents. However, its addictive properties limit their medical use because patients may be susceptible to abuse and reinstatement. Morphine addiction occurs because of dopamine release in the mesolimbic brain area, implying in an increase in oxidative stress. Ferulic acid (FA), a phenolic phytochemical found in a variety of foods, has been reported to exert antioxidant and neuroprotective effects; however, its low bioavailability makes its nano-encapsulated form a promising alternative. This study aimed to evaluate the protective effects of a novel nanosystem with FA on morphine reinstatement and the consequent molecular neuroadaptations and oxidative status in the mesolimbic region. Rats previously exposed to morphine in conditioned place preference (CPP) paradigm were treated with ferulic acid-loaded nanocapsules (FA-Nc) or nonencapsulated FA during morphine-preference extinction. Following the treatments, animals were re-exposed to morphine to induce the reinstatement. While morphine-preference extinction was comparable among all experimental groups, FA-Nc treatment prevented morphine reinstatement. In the dorsal striatum, while morphine exposure increased lipid peroxidation (LP) and reactive species (RS), FA-Nc decreased LP and FA decreased RS levels. Morphine exposure increased the dopaminergic markers (D1R, D3R, DAT) and ΔFosB immunoreactivity in the ventral striatum; however, FA-Nc treatment decreased D1R, D3R, and ΔFosB and increased D2R, DAT, and NRF2. In conclusion, FA-Nc treatment prevented the morphine reinstatement, promoted antioxidant activity, and modified the dopaminergic neurotransmission, NRF2, and ΔFosB, what may indicate a neuroprotective and antioxidant role of this nanoformulation.
Assuntos
Dopamina , Morfina , Ratos , Animais , Morfina/farmacologia , Fator 2 Relacionado a NF-E2 , Antioxidantes/farmacologia , EncéfaloRESUMO
In recent years, interesterified fat (IF) has largely replaced trans fat in industrialized food. Studies of our research group showed that IF consumption may not be safe for central nervous system (CNS) functions. Our current aim was to evaluate IF maternal consumption before conception on cognitive performance of adult rat offspring. Female Wistar rats were fed with standard chow plus 20% soybean and fish oil mix (control group) or plus 20% IF from weaning until adulthood (before mating), when the diets were replaced by standard chow only. Following the gestation and pups' development, locomotion and memory performance followed by neurotrophin immunocontent and fatty acids (FA) profile in the hippocampus of the adulthood male offspring were quantified. Maternal IF consumption before conception decreased hippocampal palmitoleic acid incorporation, proBDNF and BDNF levels, decreasing both exploratory activity and memory performance in adult offspring. Considering that, the adult male offspring did not consume IF directly, further studies are needed to understand the molecular mechanisms and if the IF maternal preconception consumption could induce the epigenetic changes observed here. Our outcomes reinforce an immediate necessity to monitor and / or question the replacement of trans fat by IF with further studies involving CNS functions.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Ácidos Graxos trans , Animais , Ácidos Graxos/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Aprendizagem , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Ácidos Graxos trans/metabolismoRESUMO
Besides their clinical application, chronic misuse of opioids has often been associated to drug addiction due to their addictive properties, underlying neuroadaptations of AMPA glutamate-receptor-dependent synaptic plasticity. Topiramate (TPM), an AMPAR antagonist, has been used to treat psychostimulants addiction, despite its harmful effects on memory. This study aimed to evaluate the effects of a novel topiramate nanosystem on molecular changes related to morphine reinstatement. Rats were previously exposed to morphine in conditioned place preference (CPP) paradigm and treated with topiramate-chitosan nanoparticles (TPM-CS-NP) or non-encapsulated topiramate in solution (S-TPM) during CPP extinction; following memory performance evaluation, they were re-exposed to morphine reinstatement. While morphine-CPP extinction was comparable among all experimental groups, TPM-CS-NP treatment prevented morphine reinstatement, preserving memory performance, which was impaired by both morphine-conditioning and S-TPM treatment. In the NAc, morphine increased D1R, D2R, D3R, DAT, GluA1 and MOR immunoreactivity. It also increased D1R, DAT, GluA1 and MOR in the dorsal hippocampus. TPM-CS-NP treatment decreased D1R, D3R and GluA1 and increased DAT in the NAc, decreasing GluA1 and increasing D2 and DAT in the dorsal hippocampus. Taken together, we may infer that TPM-CS-NP treatment was able to prevent the morphine reinstatement without memory impairment. Therefore, TPM-CS-NP may be considered an innovative therapeutic tool due to its property to prevent opioid reinstatement because it acts modifying both dopaminergic and glutamatergic neurotransmission, which are commonly related to morphine addiction.
Assuntos
Quitosana/administração & dosagem , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Dependência de Morfina/metabolismo , Nanopartículas/administração & dosagem , Topiramato/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Quimioterapia Combinada , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Morfina/farmacologia , Dependência de Morfina/prevenção & controle , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMO
Interesterified fat (IF) currently substitutes the hydrogenated vegetable fat (HVF) in processed foods. However, the IF consumption impact on the central nervous system (CNS) has been poorly studied. The current study investigated connections between IF chronic consumption and locomotor impairments in early life period and adulthood of rats and access brain molecular targets related to behavior changes in adulthood offspring. During pregnancy and lactation, female rats received soybean oil (SO) or IF and their male pups received the same maternal supplementation from weaning until adulthood. Pups' motor ability and locomotor activity in adulthood were evaluated. In the adult offspring striatum, dopaminergic targets, glial cell line-derived neurotrophic factor (GDFN) and lipid profile were quantified. Pups from IF supplementation group presented impaired learning concerning complex motor skill and sensorimotor behavior. The same animals showed decreased locomotion in adulthood. Moreover, IF group showed decreased immunoreactivity of all dopaminergic targets evaluated and GDNF, along with important changes in FA composition in striatum. This study shows that the brain modifications induce by IF consumption resulted in impaired motor control in pups and decreased locomotion in adult animals. Other studies about health damages induced by IF consumption may have a contribution from our current outcomes.
Assuntos
Encéfalo/metabolismo , Gorduras na Dieta/efeitos adversos , Locomoção/fisiologia , Atividade Motora/fisiologia , Sistema Nervoso/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ácidos Graxos trans/efeitos adversos , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Gorduras na Dieta/metabolismo , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Modelos Animais , Fenômenos Fisiológicos do Sistema Nervoso , Gravidez , Ratos , Ácidos Graxos trans/metabolismoRESUMO
Opioids are addictive drugs, whose misuse evoke withdrawal and relapse. Mediterranean-based diet (MBD) is rich in n-3 polyunsaturated fatty acids (PUFA), while Western based diets (WBDs) contain saturated fatty acids including interesterified fat (IF) and palm oil (PO), influencing neural functions. We compared MBD and WBDs on morphine-induced addiction parameters. Rats fed with MBD (chow plus 20% soybean- and fish-oil- n-6/n-3 PUFA 1:1) or WBD (WBD- PO or WBD-IF: chow plus 20% of palm oil or interesterified fat, respectively; high n-6/n-3 PUFA ratio) were exposed to morphine in conditioned place preference (CPP) paradigm. Anxiety-like behavior, locomotion and thermal sensitivity were evaluated during withdrawal. After morphine-CPP extinction, animals were challenged to morphine-reinstatement to induce relapse. All groups showed morphine-CPP, WBDs favored anxiety-like behaviors per se, locomotor sensitization and thermal hipersensitivity during withdrawal, resulting in increased morphine-reinstatement in comparison to MBD, which did not show relapse. WBDs increased glucocorticoid receptor immunoreactivity in the pre-frontal cortex, increasing corticosterone (CORT) and adrenocorticotrophic hormone (ACTH) per se and after morphine-reinstatement. In the nucleus accumbens, WBDs increased dopamine transporter (DAT) and dopamine receptor-2 (D2R) immunoreactivity and decreased dopamine receptor-1 (D1R). These findings indicate that WBDs facilitate morphine-reinstatement, unlike MBD, preserving the DA system mesolimbic neuroplasticity.
Assuntos
Dieta Mediterrânea , Dieta Ocidental/efeitos adversos , Dependência de Morfina/dietoterapia , Síndrome de Abstinência a Substâncias/prevenção & controle , Animais , Ansiedade/prevenção & controle , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Dieta Mediterrânea/psicologia , Dieta Ocidental/psicologia , Modelos Animais de Doenças , Hipersensibilidade/prevenção & controle , Hipersensibilidade/psicologia , Masculino , Morfina/administração & dosagem , Dependência de Morfina/psicologia , Atividade Motora/efeitos dos fármacos , Ratos Wistar , RecidivaRESUMO
Drug abuse and addiction are overwhelming health problems mainly during adolescence. Based on a previous study of our research group, the rats that received modafinil (MD) during the adolescence showed less preference for amphetamine (AMPH) in adulthood. Our current hypothesis is that MD will show beneficial effects against AMPH preference and abstinence symptoms during adolescence, a critical lifetime period when drug hedonic effects are more pronounced. We investigated the influence of MD pretreatment on AMPH preference in conditioned place preference (CPP) paradigm in adolescent rats and anxiety-like symptoms during drug withdrawal (48â¯h after the last AMPH dose) in elevated plus maze (EPM) task. Besides that, oxidative and molecular status were evaluated in the ventral tegmental area (VTA) and striatum. Our findings showed, as it was expected, that adolescent animals developed AMPH preference together with anxiety-like symptoms during the drug withdrawal while the MD pretreatment prevented those behaviors. Besides promoting benefits on reward parameters, MD was able to preserve VTA and striatum from oxidative damages. This was observed by the increased catalase activity and reduced generation of reactive species and lipid peroxidation, which were inversely modified by AMPH exposure. At molecular level, MD exerted an interesting modulatory activity on the VTA and induced an up-regulation in striatal dopaminergic targets (TH, DAT, D1R and D2R). So far, during the adolescence, MD presented beneficial behavioral outcomes that could be attributed to its modulatory activity on the striatal dopaminergic system in an attempt to maintain the adequate dopamine levels.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Ansiedade/prevenção & controle , Estimulantes do Sistema Nervoso Central/farmacologia , Modafinila/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Anfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Ratos Wistar , Maturidade Sexual , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/crescimento & desenvolvimento , Área Tegmentar Ventral/metabolismoRESUMO
Addiction is a serious health problem which leads to general social impairment. The period of adolescence plays a significant role in drug abuse liability. Psychostimulants, such as modafinil (MOD), are majorly used by teenagers seeking improvements in cognition, which contributes to its indiscriminate use. This study aimed to investigate the influence of MOD (64 mg/kg by gavage, once a day) treatment during adolescence [post-natal day (PND) 28-42] on amphetamine (AMPH, 4 mg/kg i.p.)-conditioned place preference (CPP) in early adulthood (PND 60). Our findings showed that AMPH increased CPP for the drug and anxiety-like behaviours; on the other hand, AMPH decreased the number of crossings and recognition index. In addition, AMPH decreased catalase activity and increased reactive species, malondialdehyde and carbonyl protein levels in the hippocampus. AMPH also increased pro-brain derived neurotrophic factor (BDNF), tyrosine kinase receptor B, dopamine transporter, D1R and decreased BDNF and D2R immunoreactivity. Contrarily, animals pre-exposed to MOD showed reduced AMPH-CPP, no locomotor impairment, less anxiety-like behaviours and no memory deficits. In addition, MOD showed antioxidant activity by preventing AMPH-induced oxidative damage in the hippocampus. Moreover, molecular analysis showed that MOD was able to modulate the hippocampal dopaminergic system, thus preventing AMPH-induced impairments. Animals that received MOD during adolescence showed reduced AMPH-CPP in early adulthood. These unexpected behavioural effects of MOD on CPP could be due to its hippocampal dopaminergic system modulation, mainly by its action on D1R, which is closely linked to drug addiction. Nevertheless, further studies are necessary.
Assuntos
Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Fatores Etários , Anfetamina/toxicidade , Transtornos Relacionados ao Uso de Anfetaminas/prevenção & controle , Animais , Antioxidantes/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Condicionamento Psicológico/efeitos dos fármacos , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Modafinila , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Promotores da Vigília/farmacologiaRESUMO
In recent years, interesterified fat (IF) has been used to replace hydrogenated vegetable fat (HVF), rich in trans isomers, being found in processed foods. Studies involving IF have shown deleterious influences on the metabolic system, similarly to HVF, whereas no studies regarding its influence on the central nervous system (CNS) were performed. Rats from first generation born and maintained under supplementation (3g/Kg, p.o.) of soybean-oil or IF until adulthood were assessed on memory, biochemical and molecular markers in the hippocampus. IF group showed higher saturated fatty acids and linoleic acid and lower docosahexaenoic acid incorporation in the hippocampus. In addition, IF supplementation impaired short and long-term memory, which were related to increased reactive species generation and protein carbonyl levels, decreased catalase activity, BDNF and TrkB levels in the hippocampus. To the best of our knowledge, this is the first study to show that lifelong IF consumption may be related to brain oxidative damage, memory impairments and neurotrophins modifications, which collectively may be present indifferent neurological disorders. In fact, the use of IF in foods was intended to avoid damage from HVF consumption; however this substitute should be urgently reviewed, since this fat can be as harmful as trans fat.