RESUMO
BACKGROUND: Syphilis is a sexually transmitted disease caused by Treponema pallidum. However, there are of hematogenic and vertical transmission. All health care professionals must be aware of the manifestations of this condition, such as oral lesions. OBJECTIVES: This study to analyze and compare four clinical cases of syphilis that were diagnosed based on lesions in the oral cavity with published literature. MATERIAL AND METHODS: Four patients with a confirmed sorologic and clinical diagnosis of syphilis were examined, confirmated from manifestation of oral lesions together with analysis of serological laboratory tests and histopathological analyses. RESULTS: Lesions were found in classic sites such as lips, tongue and skin. However, there were also lesions on the hard palate, and labial commissure, which correspond to less than 5% of the syphilis oral manifestations. CONCLUSIONS: The practice of unprotected oral sex may result in infection and development of syphilis. The acknowledgment of the oral manifestations of syphilis in all its period of training for health professionals is of basic importance, the association of clinical features, histopathological findings and serological tests are required to complete the diagnosis and correct treatment.
Assuntos
Doenças da Boca/diagnóstico , Doenças da Boca/microbiologia , Sífilis/complicações , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Dronabinol/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Anfetamina/administração & dosagem , Anfetamina/efeitos adversos , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Cicloexanóis/administração & dosagem , Cicloexanóis/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Injeções Intraperitoneais , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Morfina/administração & dosagem , Morfina/efeitos adversos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Ratos , Reforço Psicológico , Reprodutibilidade dos Testes , Automedicação , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/etiologiaRESUMO
We previously reported that both the high-carbohydrate diet (HCD) and high-fat diet (HFD) given for two months promote lipid deposition and inflammation in the liver and brain of mice. The results obtained indicate a tissue-specific response to both diets. Herein, we compared the effects of HCD and HFD on fatty acid (FA) composition and inflammation in the gastrocnemius muscle. Male Swiss mice were fed with HCD or HFD for 1 or 2 months. Saturated FA (SFA), monounsaturated FA (MUFA), n-3 polyunsaturated FA (n-3 PUFA), and n-6 PUFA were quantified. The activities of stearoyl-CoA desaturase 1 (SCD-1), Δ-6 desaturase (D6D), elongase 6, and de novo lipogenesis (DNL) were estimated. As for indicators of the inflammatory tissue state, we measured myeloperoxidase (MPO) activity and gene expression of F4/80, tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, and IL-10. The HCD led to a lower deposition of SFA, MUFA, n-3 PUFA, and n-6 PUFA compared to HFD. However, the HCD increased arachidonic acid levels, SFA/n-3 PUFA ratio, DNL, SCD-1, D6D, and MPO activities, and expression of IL-6, contrasting with the general idea that increased lipid deposition is associated with more intense inflammation. The HCD was more potent to induce skeletal muscle inflammation than the HFD, regardless of the lower lipid accumulation.
Assuntos
Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Inflamação/metabolismo , Músculo Esquelético/metabolismo , Animais , Peso Corporal , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/metabolismo , Ingestão de Energia , Expressão Gênica , Masculino , CamundongosRESUMO
The legume lectins from the subtribe Diocleinae, often referred to as concanavalin A-like lectins, are a typical example of highly similar proteins that show distinct biological activities. The pH-dependent oligomerization that some of these lectins undergo and the relative position of amino acids within the carbohydrate-binding site are factors that have been reported to contribute to these differences in the activities of Diocleinae lectins. In the present work, we determined the amino acid sequence and the crystal structure of the lectin of Dioclea rostrata seeds (DRL), with the aim of investigating the structural bases of the different behavior displayed by this lectin in comparison to other Diocleinae lectins and determining the reason for the distinct pH-dependent dimer-tetramer equilibrium. In addition, we discovered a novel multimeric arrangement for this lectin.
Assuntos
Carboidratos/química , Dioclea/química , Multimerização Proteica , Sequência de Aminoácidos , Cristalografia por Raios X , Concentração de Íons de Hidrogênio , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Ligação Proteica , Conformação Proteica , Sementes/químicaRESUMO
The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.
Assuntos
Proteínas de Transporte/genética , Cocaína/administração & dosagem , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Camundongos Knockout/genética , Camundongos Knockout/fisiologia , Proteínas do Tecido Nervoso , Animais , Sítios de Ligação/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/genética , Autoadministração , Serotonina/fisiologiaRESUMO
A lectin-like protein from the seeds of Acacia farnesiana was isolated from the albumin fraction, characterized, and sequenced by tandem mass spectrometry. The albumin fraction was extracted with 0.5 M NaCl, and the lectin-like protein of A. farnesiana (AFAL) was purified by ion-exchange chromatography (Mono-Q) followed by chromatofocusing. AFAL agglutinated rabbit erythrocytes and did not agglutinate human ABO erythrocytes either native or treated with proteolytic enzymes. In sodium dodecyl sulfate gel electrophoresis under reducing and nonreducing conditions, AFAL separated into two bands with a subunit molecular mass of 35 and 50 kDa. The homogeneity of purified protein was confirmed by chromatofocusing with a pI = 4.0 +/- 0.5. Molecular exclusion chromatography confirmed time-dependent oligomerization in AFAL, in accordance with mass spectrometry analysis, which confers an alteration in AFAL affinity for chitin. The protein sequence was obtained by a liquid chromatography quadrupole time-of-flight experiment and showed that AFAL has 68% and 63% sequence similarity with lectins of Phaseolus vulgaris and Dolichos biflorus, respectively.
Assuntos
Acacia/química , Lectinas de Plantas/isolamento & purificação , Sementes/química , Sequência de Aminoácidos , Quitina/química , Cromatografia de Afinidade , Cromatografia em Gel , Cromatografia por Troca Iônica , Fabaceae , Espectrometria de Massas , Dados de Sequência Molecular , Peso Molecular , Lectinas de Plantas/análise , Lectinas de Plantas/química , Alinhamento de Sequência , Análise de Sequência de Proteína , Espectrometria de Massas em TandemRESUMO
We previously reported that both the high-carbohydrate diet (HCD) and high-fat diet (HFD) given for two months promote lipid deposition and inflammation in the liver and brain of mice. The results obtained indicate a tissue-specific response to both diets. Herein, we compared the effects of HCD and HFD on fatty acid (FA) composition and inflammation in the gastrocnemius muscle. Male Swiss mice were fed with HCD or HFD for 1 or 2 months. Saturated FA (SFA), monounsaturated FA (MUFA), n-3 polyunsaturated FA (n-3 PUFA), and n-6 PUFA were quantified. The activities of stearoyl-CoA desaturase 1 (SCD-1), Δ-6 desaturase (D6D), elongase 6, and de novo lipogenesis (DNL) were estimated. As for indicators of the inflammatory tissue state, we measured myeloperoxidase (MPO) activity and gene expression of F4/80, tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, and IL-10. The HCD led to a lower deposition of SFA, MUFA, n-3 PUFA, and n-6 PUFA compared to HFD. However, the HCD increased arachidonic acid levels, SFA/n-3 PUFA ratio, DNL, SCD-1, D6D, and MPO activities, and expression of IL-6, contrasting with the general idea that increased lipid deposition is associated with more intense inflammation. The HCD was more potent to induce skeletal muscle inflammation than the HFD, regardless of the lower lipid accumulation.
Assuntos
Animais , Masculino , Coelhos , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Músculo Esquelético/metabolismo , Inflamação/metabolismo , Peso Corporal , Ingestão de Energia , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/metabolismo , Expressão GênicaRESUMO
The present study compared cocaine-induced hyperlocomotion and cocaine i.v. self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after i.p. cocaine injection (0-60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine i.v. self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical i.v. insertion of an in-dwelling catheter, and required to respond for i.v. cocaine (0.25-4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following i.p. injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior.
Assuntos
Encéfalo/metabolismo , Cocaína/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Cocaína/metabolismo , Condicionamento Operante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , AutoadministraçãoRESUMO
Tissue plasminogen activator, tPA, is induced in the brain by electrical activity leading to synaptic remodeling. It is also induced in the prefrontal cortex (PFC) by acute cocaine. We investigated cocaine-induced locomotor activity, the development of sensitisation to cocaine and cocaine self-administration in mice lacking the gene encoding tPA. Mice lacking tPA (tPA knockout mice, tPA-/-) showed normal spontaneous activity, exhibited cocaine-induced locomotor activity at lower doses than wild-type (WT) control mice and showed a greater degree of cocaine-induced locomotor activity following repeated administration. tPA-/- and WT mice did not differ significantly in the time to acquire self-administration of cocaine (20 microg/i.v. infusion) under an FR2 schedule. Following acquisition of this behavior, these groups also did not differ significantly in the rate of cocaine self-administration across the next three sessions. However, WT mice decreased responses on the active lever during signaled periods when reinforcer was not available; in contrast, tPA-/- mice did not. The emission of non-reinforced responses was most marked at the beginning of each 90 min daily session. This pattern of responding was not seen in tPA-/- mice pressing for food under an FR2 schedule of reinforcement. These results suggest that tPA may play a specific role either in retention of information between sessions or in behavioural inhibition in cocaine self-administration.
Assuntos
Química Encefálica/genética , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Ativador de Plasminogênio Tecidual/genética , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Injeções Intravenosas , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/química , Córtex Pré-Frontal/efeitos dos fármacos , Recompensa , AutoadministraçãoRESUMO
In order to examine whether tolerance develops to the discriminative stimulus and reinforcing effects of ketamine, rats were trained either to discriminate ketamine (10mg/kg) from saline or to self-administer ketamine (1.1mg/kg/injection), and then treated with chronic ketamine (32mg/kg), administered i.p. every 8 hours for 7 days. No shift in the dose-response curve for either paradigm was obtained following this chronic regimen. However, following a 2-week rest period in which animals had no exposure to ketamine, the dose-response curve was shifted two-fold to the left, indicating increased sensitivity to the drug. Reinstatement of training shifted the dose-response curve back to the right in both paradigms. These results suggest that tolerance to the discriminative stimulus and reinforcing effects of ketamine develops during training. Examination of the self-administration training data support this assumption, since inter-reinforcer time decreases, reflecting an increase in ketamine intake over training sessions.
RESUMO
These experiments tested the hypothesis that cross-tolerance between ethanol (EtOH) and diazepam would occur in a drug discrimination paradigm. One group of rats (n = 28) was trained to discriminate EtOH (1.0g/kg, i.p.) from vehicle; another group of rats (n = 10) was trained to discriminate diazepam (5.6mg/kg, i.p.) from vehicle. Subjects were trained using a two-lever choice procedure where food was delivered under a fixed-ratio 10 schedule of reinforcement. In rats trained to detect EtOH, both EtOH (0.1-1.78g/kg) and diazepam (0.32-10mg/kg) dose dependently substituted for EtOH. Chronic administration of EtOH (6.8g/kg/12h for 7 days) resulted in 3-fold tolerance to EtOH and 6-fold cross-tolerance to the ability of diazepam to substitute for EtOH; chronic administration of diazepam (20mg/kg/8h for 7 days) failed to confer cross-tolerance to EtOH nor did it produce tolerance to the ability of diazepam to substitute for EtOH. In rats trained to detect diazepam, diazepam (0.56-10mg/kg) but not EtOH (0.1-1.78g/kg) substituted for diazepam. Chronic administration of diazepam (20mg/kg/8h for 7 days) produced 3-fold tolerance to diazepam; in contrast, chronic administration of EtOH (6.8g/kg/12h for 7 days) failed to confer cross-tolerance to diazepam. The dissociation of the cross-substitution and cross-tolerance patterns between EtOH and diazepam suggests that the population of benzodiazepine receptors that mediates substitution of diazepam for EtOH differs from the population of benzodiazepine receptors that mediates substitution of diazepam for diazepam.
RESUMO
The present experiment tested the hypothesis that 5-HT1B receptors are involved in the reinforcing effects of cocaine. Transgenic mice lacking 5-HT1B receptors were used as subjects and compared with wild-type mice for the acquisition and maintenance of intravenous (IV) cocaine self-administration. Male 129/Sv-ter and 5-HT1B-minus 129/Sv-ter inbred mice (Columbia University, New York) were initially trained to press a lever under a fixed-ratio schedule 2, first for sweetened condensed milk as reinforcer and subsequently for cocaine (2.0 mg/kg/infusion). When a stable baseline of responding was obtained, each subject was tested under different doses of cocaine (1.0, 2.0, and 4.0 mg/kg), with the number of reinforcers per hour used as the dependent variable. Both strains successfully acquired food-shaping and cocaine self-administration, but the mutant mice presented a significantly shorter latency to meet IV cocaine self-administration acquisition criteria (p < 0.05). However, both wild-type and mutant mice had similar dose-response to cocaine. These results suggest that the 5-HT1B receptors may be implicated in the propensity to self-administer cocaine, but other mechanisms might be involved in the maintenance of cocaine self-administration.
Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Autoadministração , Animais , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Reforço PsicológicoRESUMO
The LYS49-PLA2s myotoxins have attracted attention as models for the induction of myonecrosis by a catalytically independent mechanism of action. Structural studies and biological activities have demonstrated that the myotoxic activity of LYS49-PLA2 is independent of the catalytic activity site. The myotoxic effect is conventionally thought to be to due to the C-terminal region 111-121, which plays an effective role in membrane damage. In the present study, Bn IV LYS49-PLA2 was isolated from Bothrops neuwiedi snake venom in complex with myristic acid (CH3(CH2)12COOH) and its overall structure was refined at 2.2 Å resolution. The Bn IV crystals belong to monoclinic space group P21 and contain a dimer in the asymmetric unit. The unit cell parameters are a = 38.8, b = 70.4, c = 44.0 Å. The biological assembly is a "conventional dimer" and the results confirm that dimer formation is not relevant to the myotoxic activity. Electron density map analysis of the Bn IV structure shows clearly the presence of myristic acid in catalytic site. The relevant structural features for myotoxic activity are located in the C-terminal region and the Bn IV C-terminal residues NKKYRY are a probable heparin binding domain. These findings indicate that the mechanism of interaction between Bn IV and muscle cell membranes is through some kind of cell signal transduction mediated by heparin complexes.
Assuntos
Bothrops , Lisina , Ácido Mirístico/metabolismo , Fosfolipases A2/química , Fosfolipases A2/metabolismo , Venenos de Víboras/enzimologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Heparina/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Multimerização Proteica , Estrutura Quaternária de Proteína , Análise de Sequência de DNAAssuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Alimentos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Esquema de Reforço , Reforço Psicológico , Autoadministração , Estimulação QuímicaRESUMO
Knockout mice lacking serotonin(1B) (5-hydroxytryptamine(1B); 5-HT(1B)) receptors (1BKO) exhibit increased sensitivity to the stimulant and reinforcing effects of indirect dopamine (DA) agonists and are more reactive to mild stressors such as handling and the injection procedures that commonly occur when using the intraperitoneal (i.p.) route of drug administration. Since the intravenous (i.v.) route of administration allows minimal handling and injection-induced stress, the present study was designed to evaluate the effect of the administration route on amphetamine-induced locomotor activation and behavioural sensitization in 1BKO mice. For this purpose, 1BKO and wild-type (WT) control mice were administered i.p. or i.v. amphetamine in a within-session design, which allows evaluation of a complete dose-response curve within a single session. The locomotor stimulant effects of i.p. (0.5-4.0 mg/kg) and i.v. (0.6-1.2 mg/kg) amphetamine were investigated both acutely and following repeated treatments (four treatments at 48 h intervals). The results showed that acute i.p. amphetamine injection induced a significant higher horizontal activity peak effect in 1BKO mice, while this difference was less profound after acute i.v. injection. However, repeated i.p. or i.v. administration of amphetamine induced significantly higher locomotion in 1BKO mice. We conclude that the stimulant effects of amphetamine can be influenced by the route of administration in a genotype-dependent manner, and that route of drug administration (and associated variables) should be considered an important factor in studies of psychostimulant action in knockout mice.
Assuntos
Anfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Serotonina/genética , Animais , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/genética , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Receptor 5-HT1B de SerotoninaRESUMO
A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.
Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Motivação , Quinoxalinas/farmacologia , Receptores de AMPA/efeitos dos fármacos , Animais , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Infusões Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Autoadministração/psicologiaRESUMO
Psychopathological disorders, and depression in particular, are strongly linked to eating attitude in obese patients. The identification of cannabinoid CB1 receptors (CB1Rs) in areas of the central nervous system (CNS) that have been implicated in regulation of mood and food intake suggests that these receptors may mediate such a behavioral link. The goal of this study was to evaluate CB1R modulation of antidepressant-like effects and food intake. For this purpose, 129/SVE and C57BL/6 male mice were acutely dosed intraperitoneally (i.p.) with the CB1R inverse agonist AM251 (3-30 mg/kg) and tested, respectively, in the tail-suspension test (TST) and in the forced-swim test (FST), which have been used widely as tests sensitive to antidepressant compounds. Like the antidepressant desipramine (DMI, 16 mg/kg), AM251 significantly reduced immobility at 10 mg/kg in the TST and at 1 and 10 mg/kg in the FST. Such a decrease of immobility was not accompanied by an increase in motor activity in the open field, suggesting that occupancy of CB1R by AM251 induced antidepressant-like effects. This was supported by two additional experiments. First, the co-administration of the CB1R agonist CP55940, at a dose that did not induce motor impairment or profound hypothermia (0.01 mg/kg), reversed effects of AM251 in the TST. Secondly, effects of AM251 in the FST were absent in CB1R knockout (KO) mice. In addition to an antidepressant-like effect, AM251 reduced fasting-induced hyperphagia over a comparable dose range. Taken together, these data suggest that regulation of mood and food intake might be obtained through inverse agonism of CB1R.
Assuntos
Afeto/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Animais , Antidepressivos/farmacologia , Infusões Parenterais , Masculino , Camundongos , Camundongos Knockout , Atividade Motora , Receptor CB1 de Canabinoide/genéticaRESUMO
When ethanol is used as a training stimulus in drug discrimination experiments, benzodiazepines (such as diazepam) as well as non-competitive N-methyl-D-aspartate (NMDA) antagonists (such as ketamine) substitute for ethanol; in contrast, when a benzodiazepine or an NMDA antagonist is used as a training drug, ethanol does not substitute reliably. In the present experiments, we trained rats to discriminate a mixture of diazepam and ketamine, to test the hypothesis that ethanol would substitute for this drug combination. Using a two-lever choice procedure with food as a reinforcer, 22 rats were trained to discriminate a mixture of diazepam (5.6 mg/kg) and ketamine (10 mg/kg) from vehicle. When administered as a mixture, diazepam and ketamine substituted for the training mixture in a dose-dependent manner. When administered separately, diazepam or ketamine substituted for the mixture with full substitution occurring at 5.6 and 17.8 mg/kg, respectively. Ethanol almost completely substituted for the mixture at 1 g/kg. There was no cross-substitution between diazepam and ketamine in rats trained to discriminate diazepam (5.6 mg/kg, n = 10) or ketamine (10 mg/kg, n = 12) from vehicle. In addition, ethanol did not substitute for the training drug in either of these discriminations. These results suggest that the simultaneous action of GABAA agonist and NMDA antagonist mechanisms produce a greater ethanol-specific discriminative stimulus than activation of either component individually.