RESUMO
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Analgésicos Opioides , Ratos , Masculino , Animais , Fatores de Crescimento Neural/farmacologia , Anfetamina , Encéfalo , Naloxona/farmacologia , Núcleo AccumbensRESUMO
Amphetamine (AMPH) is a psychostimulant drug frequently related to addiction, which is characterized by functional and molecular changes in the brain reward system, favoring relapse development, and pharmacotherapies have shown low effectiveness. Considering the beneficial influences of tactile stimulation (TS) in different diseases that affect the central nervous system (CNS), here we evaluated if TS applied in adult rats could prevent or minimize the AMPH-relapse behavior also accessing molecular neuroadaptations in the nucleus accumbens (NAc). Following AMPH conditioning in the conditioned place preference (CPP) paradigm, male rats were submitted to TS (15-min session, 3 times a day, for 8 days) during the drug abstinence period, which were re-exposed to the drug in the CPP paradigm for additional 3 days for relapse observation and molecular assessment. Our findings showed that besides AMPH relapse, TS prevented the dopamine transporter (DAT), dopamine 1 receptor (D1R), tyrosine hydroxylase (TH), mu opioid receptor (MOR) increase, and AMPH-induced delta FosB (ΔFosB). Based on these outcomes, we propose TS as a useful tool to treat psychostimulant addiction, which is subsequent to clinical studies; it could be included in detoxification programs together with pharmacotherapies and psychological treatments already conventionally established.
Assuntos
Anfetamina , Estimulantes do Sistema Nervoso Central , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina , Masculino , Núcleo Accumbens , Ratos , RecidivaRESUMO
Psychostimulant drugs addiction is a chronic public health problem and individuals remain susceptible to relapses increasing public expenses even after withdrawal and treatment. Our research group has focused on finding new therapies to be employed in drug addiction treatment, suggesting the physical exercise as a promising tool. This way, it is necessary to know the mechanisms involved in the beneficial influences of physical exercise observing the pathway that could be explored in drug addiction treatment. Male Wistar rats were conditioned with amphetamine (AMPH) following the conditioned place preference (CPP) protocol and subsequently submitted to swimming for 5 weeks (1 h per day, 5 days per week). Half of the animals were injected with Naloxone (0.3 mg/mL/kg body weight, i.p.) 5 min prior each physical exercise day. After AMPH-CPP re-exposure, our outcomes showed that physical exercise, in addition to minimizing the relapse behavior in the CPP, it increased D1R, D2R and DAT in the Ventral Tegmental Area (VTA), but not in the Nucleus accumbens (NAc). Interestingly, while naloxone inhibited the partial beneficial influence of the exercise on drug-relapse behavior, exercise-induced changes in the dopaminergic system were not observed in the group administered with naloxone as well. Based on these evidences, besides reinforcing the beneficial influence of the physical exercise on AMPH-induced drug addiction, we propose the involvement of endogenous opioid system activation, not as a single one, but as a possible mechanism of action resulting from the physical activity practice, thus characterizing an important therapeutic approach, which may contribute to drug withdrawal consequently preventing relapse.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/terapia , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Físico Animal/métodos , Animais , Condicionamento Clássico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Natação , Área Tegmentar Ventral/metabolismoRESUMO
Ketamine (KET) is a dissociative anesthetic for restrict medical use with high potential for abuse and neurotoxicity which does not prevent its recreational use. Gallic acid (GA) is a natural free radical "scavenger." We evaluated the GA protective role regarding binge or subchronic (SbChro) KET-induced toxicity in adolescent rats. In the binge protocol, animals were treated with GA (one dose of 13.5 mg/kg, p.o. every 2 h, totaling 3 doses) 12 h after KET exposure (one dose of 10 mg/kg, i.p., every 3 h, totaling 5 doses). In the SbChro, animals were treated with GA (one dose of 13.5 mg/kg/day, p.o., for 3 days) 48 h following KET exposure (one dose of 10 mg/kg/day, i.p) for 10 days. Our findings show that binge-KET impaired memory, increased pro-BDNF and TrkB levels in the hippocampus, and increased lipid peroxidation (LP) in the kidney and hippocampus, while SbChro-KET impaired memory, increased pro-BDNF, and decreased both BDNF and TrkB levels in the hippocampus, and increased LP in the kidney, liver, and hippocampus. GA treatment reversed the subchronically KET-induced harmful influences better. Interestingly, only memory impairment observed in the SbChro-KET protocol was reversed by GA. Memory impairments showed a positive correlation with hippocampal BDNF levels and negative with LP levels in the same brain area. This last hippocampal damage (LP) showed a negative correlation with BDNF levels in the hippocampus, indicating an interesting and close causal connection. Our outcomes show that the deleterious effects of SbChro-KET exposure can be attenuated or abolished with GA administration, a natural antioxidant that could be considered in KET abuse treatment.
Assuntos
Anestésicos Dissociativos/administração & dosagem , Antioxidantes/farmacologia , Ácido Gálico/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Anestésicos Dissociativos/toxicidade , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Hipocampo/metabolismo , Ketamina/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Receptor trkB/efeitos dos fármacos , Receptor trkB/metabolismo , Receptores de N-Metil-D-AspartatoRESUMO
Depression is a common psychiatric disease which pharmacological treatment relieves symptoms, but still far from ideal. Tactile stimulation (TS) has shown beneficial influences in neuropsychiatric disorders, but the mechanism of action is not clear. Here, we evaluated the TS influence when applied on adult female rats previously exposed to a reserpine-induced depression-like animal model. Immediately after reserpine model (1 mg/kg/mL, 1×/day, for 3 days), female Wistar rats were submitted to TS (15 min, 3×/day, for 8 days) or not (unhandled). Imipramine (10 mg/kg/mL) was used as positive control. After behavioral assessments, animals were euthanized to collect plasma and prefrontal cortex (PFC). Behavioral observations in the forced swimming test, splash test, and sucrose preference confirmed the reserpine-induced depression-like behavior, which was reversed by TS. Our findings showed that reserpine increased plasma levels of adrenocorticotropic hormone and corticosterone, decreased brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B, and increased proBDNF immunoreactivity in the PFC, which were also reversed by TS. Moreover, TS reestablished glial fibrillary acidic protein and glucocorticoid receptor levels, decreased by reserpine in PFC, while glial cell line-derived neurotrophic factor was increased by TS per se. Our outcomes are showing that TS applied in adulthood exerts a beneficial influence in depression-like behaviors, modulating the HPA axis and regulating neurotrophic factors more effectively than imipramine. Based on this, our proposal is that TS, in the long term, could be considered a new therapeutic strategy for neuropsychiatric disorders improvement in adult life, which may represent an interesting contribution to conventional pharmacological treatment.
Assuntos
Envelhecimento/fisiologia , Comportamento Animal , Depressão/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Fatores de Crescimento Neural/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Transdução de Sinais , Tato , Hormônio Adrenocorticotrópico/sangue , Animais , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Depressão/sangue , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos Wistar , Reserpina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sacarose , NataçãoRESUMO
OBJECTIVE: To investigate the combined effects of cryotherapy and pulsed ultrasound therapy (PUT) on oxidative stress parameters, tissue damage markers and systemic inflammation after musculoskeletal injury. DESIGN: Experimental animal study. SETTING: Research laboratory. PARTICIPANTS: Seventy male Wistar rats were divided into five groups: control, lesion, cryotherapy, PUT, and cryotherapy+PUT. INTERVENTIONS: The gastrocnemius muscle was injured by mechanical crushing. Cryotherapy was applied immediately after injury (immersion in water at 10°C for 20minutes). PUT was commenced 24hours after injury (1MHz, 0.4W/cm2SPTA, 20% duty cycle, 5minutes). All animals were treated every 8hours for 3 days. MAIN OUTCOME MEASURES: Oxidative stress in muscle was evaluated by concentration of reactive oxygen species (ROS), lipid peroxidation (LPO), anti-oxidant capacity against peroxyl radicals (ACAP) and catalase. Plasma levels of creatine kinase (CK), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were assessed. RESULTS: When applied individually, cryotherapy and PUT reduced CK, LDH, CRP and LPO caused by muscle damage. Cryotherapy+PUT in combination maintained the previous results, caused a reduction in ROS [P=0.005, mean difference -0.9×10-8 relative area, 95% confidence interval (CI) -0.2 to -1.9], and increased ACAP {P=0.007, mean difference 0.34 1/[relative area with/without 2,2-azobis(2-methylpropionamidine)dihydrochloride], 95% CI 0.07 to 0.61} and catalase (P=0.002, mean difference 0.41units/mg protein, 95% CI 0.09 to 0.73) compared with the lesion group. CONCLUSIONS: Cryotherapy+PUT in combination reduced oxidative stress in muscle, contributing to a reduction in adjacent damage and tissue repair.
Assuntos
Contusões/fisiopatologia , Contusões/reabilitação , Crioterapia/métodos , Músculo Esquelético/fisiopatologia , Estresse Oxidativo/fisiologia , Terapia por Ultrassom/métodos , Animais , Antioxidantes/fisiologia , Biomarcadores , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
Electroacupuncture (EA) has been used to treat many diseases, including heart failure (HF). This study aimed to evaluate the effects of chronic stimulation in the ST36 acupuncture point on haemodynamic parameters and baroreflex function in rats with HF. Cardiovascular parameters assessed were heart rate (HR), blood pressure (BP), and the reflex cardiovascular response of HR triggered by stimulation of baroreceptors in animals with HF subsequent to acute myocardial infarction (AMI). Male Wistar rats were divided into three groups: Sham Control - animals without HF and without EA; HF Control group - animals with HF and without EA; and HF EA group - animals with HF that received the EA protocol. Six weeks after surgical induction of AMI, the EA protocol (8 weeks, 5 times a week) was performed. The protocol was applied with EA at the ST36 point, frequency of 2 Hz, pulse of 0.3 ms and intensity of 1-3 mA for 30 min. Haemodynamic parameters and baroreceptor function were assessed. There was no difference between groups in the variables HR, systolic blood pressure (SBP) and diastolic blood pressure (DBP), which were evaluated with awake animals (p>0.05). There was an increase in the mean arterial pressure (MAP) in the HF EA group compared to the HF Control group (p<0.05). The maximum gain of the baroreflex heart rate response (Gain) was higher in the HF EA group than the HF Control and Sham Control groups. Chronic EA in the ST36 point increased the MAP and baroreflex sensitivity in rats with HF.
Assuntos
Barorreflexo , Eletroacupuntura/métodos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Hemodinâmica , Pontos de Acupuntura , Animais , Barorreflexo/fisiologia , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Masculino , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Ratos Wistar , Resultado do TratamentoRESUMO
Frogs have been used as an alternative model to study pain mechanisms. Since we did not find any reports on the effects of sciatic nerve transection (SNT) on the ultrastructure and pattern of metabolic substances in frog dorsal root ganglion (DRG) cells, in the present study, 18 adult male frogs (Rana catesbeiana) were divided into three experimental groups: naive (frogs not subjected to surgical manipulation), sham (frogs in which all surgical procedures to expose the sciatic nerve were used except transection of the nerve), and SNT (frogs in which the sciatic nerve was exposed and transected). After 3 days, the bilateral DRG of the sciatic nerve was collected and used for transmission electron microscopy. Immunohistochemistry was used to detect reactivity for glucose transporter (Glut) types 1 and 3, tyrosine hydroxylase, serotonin and c-Fos, as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase). SNT induced more mitochondria with vacuolation in neurons, satellite glial cells (SGCs) with more cytoplasmic extensions emerging from cell bodies, as well as more ribosomes, rough endoplasmic reticulum, intermediate filaments and mitochondria. c-Fos immunoreactivity was found in neuronal nuclei. More neurons and SGCs surrounded by tyrosine hydroxylase-like immunoreactivity were found. No change occurred in serotonin- and Glut1- and Glut3-like immunoreactivity. NADPH-diaphorase occurred in more neurons and SGCs. No sign of SGC proliferation was observed. Since the changes of frog DRG in response to nerve injury are similar to those of mammals, frogs should be a valid experimental model for the study of the effects of SNT, a condition that still has many unanswered questions.
Assuntos
Animais , Masculino , Gânglios Espinais/metabolismo , Gânglios Espinais/ultraestrutura , Oxirredutases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Nervo Isquiático/lesões , Serotonina/metabolismo , Microambiente Celular , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Imuno-Histoquímica , Microscopia Eletrônica de Transmissão , NADPH Desidrogenase/metabolismo , Neuralgia/metabolismo , Rana catesbeiana , /metabolismoRESUMO
Frogs have been used as an alternative model to study pain mechanisms. Since we did not find any reports on the effects of sciatic nerve transection (SNT) on the ultrastructure and pattern of metabolic substances in frog dorsal root ganglion (DRG) cells, in the present study, 18 adult male frogs (Rana catesbeiana) were divided into three experimental groups: naive (frogs not subjected to surgical manipulation), sham (frogs in which all surgical procedures to expose the sciatic nerve were used except transection of the nerve), and SNT (frogs in which the sciatic nerve was exposed and transected). After 3 days, the bilateral DRG of the sciatic nerve was collected and used for transmission electron microscopy. Immunohistochemistry was used to detect reactivity for glucose transporter (Glut) types 1 and 3, tyrosine hydroxylase, serotonin and c-Fos, as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase). SNT induced more mitochondria with vacuolation in neurons, satellite glial cells (SGCs) with more cytoplasmic extensions emerging from cell bodies, as well as more ribosomes, rough endoplasmic reticulum, intermediate filaments and mitochondria. c-Fos immunoreactivity was found in neuronal nuclei. More neurons and SGCs surrounded by tyrosine hydroxylase-like immunoreactivity were found. No change occurred in serotonin- and Glut1- and Glut3-like immunoreactivity. NADPH-diaphorase occurred in more neurons and SGCs. No sign of SGC proliferation was observed. Since the changes of frog DRG in response to nerve injury are similar to those of mammals, frogs should be a valid experimental model for the study of the effects of SNT, a condition that still has many unanswered questions.