RESUMO
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by poor attention, impulse control and hyperactivity. A significant proportion of ADHD patients are also co-morbid for other psychiatric problems including mood disorders and these patients may be managed with a combination of psychostimulants and anti-depressants. While it is generally accepted that enhanced catecholamine signalling via the action of psychostimulants is likely responsible for the cognitive improvement in ADHD, other neurotransmitters including acetylcholine and histamine may be involved. In the present study, we have examined the effect of lisdexamfetamine dimesylate (LDX), an amphetamine pro-drug that is approved for the treatment of ADHD on acetylcholine and histamine efflux in pre-frontal cortex and hippocampus alone and in combination with the anti-depressant s-citalopram. LDX increased cortical acetylcholine efflux, an effect that was not significantly altered by co-administration of s-citalopram. Cortical and hippocampal histamine were markedly increased by LDX, an effect that was attenuated in the hippocampus but not in pre-frontal cortex when co-administered with s-citalopram. Taken together, these results suggest that efflux of acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially influenced by the co-administration of s-citalopram. Attention deficit hyperactivity disorder (ADHD) is characterized by poor attention, impulse control and hyperactivity. Some ADHD patients are also co-morbid for mood disorders and may be managed with psychostimulants (e.g. lisdexamfetamine, LDX) and anti-depressants (e.g. s-citalopram). LDX increased the efflux of acetylcholine and histamine, neurotransmitters involved in cognitive function, which were differentially influenced when co-administered with s-citalopram. Acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially affected by the co-administration of s-citalopram.
Assuntos
Acetilcolina/metabolismo , Citalopram/administração & dosagem , Dextroanfetamina/administração & dosagem , Hipocampo/metabolismo , Liberação de Histamina/fisiologia , Córtex Pré-Frontal/metabolismo , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Liberação de Histamina/efeitos dos fármacos , Dimesilato de Lisdexanfetamina , Masculino , Microdiálise/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.
Assuntos
D-Aminoácido Oxidase/farmacologia , Pirróis/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Serina/farmacologia , Tiofenos/farmacologia , Idoso , Animais , Maleato de Dizocilpina/farmacologia , Habituação Psicofisiológica , Humanos , Masculino , Modelos Moleculares , Ratos , Ratos Wistar , Esquizofrenia/sangue , Esquizofrenia/líquido cefalorraquidiano , Serina/sangue , Serina/líquido cefalorraquidiano , Tiofenos/químicaRESUMO
A dysregulated hypothalamic-pituitary-adrenal axis (HPA) has been implicated in major depressive disorder and most commonly used animal models of depression have been shown to elevate circulating levels of plasma corticosterone. We have compared the effects of chronic and acute corticosterone administration on hippocampal cell proliferation (as measured by BrdU immunohistochemistry), hippocampal volume and the appearance of anxiety (light dark box) and depression (forced swim test) like behaviours in CD1 mice. We have also examined the effects of chronic administration of fluoxetine and imipramine on these parameters. Chronic (14 days) but not acute treatment with corticosterone resulted in reduced hippocampal cell proliferation and granule cell layer volume, these changes were prevented by co-administration of imipramine and fluoxetine. In contrast, acute and 7 day but not 14 or 21 day treatment with corticosterone gave rise to a "depressed" phenotype in the forced swim test. Mice treated for 14 days with corticosterone also developed an anxious phenotype in the light dark box but only upon repeated testing. The results presented here demonstrate that moderately elevated corticosterone for a prolonged period is sufficient to induce cellular changes in the hippocampus that are prevented by chronic administration of antidepressants.
Assuntos
Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Corticosterona/farmacologia , Depressão/psicologia , Hipocampo/citologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Antimetabólitos , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Corticosterona/sangue , Fluoxetina/farmacologia , Hipocampo/anatomia & histologia , Hipocampo/efeitos dos fármacos , Imipramina/farmacologia , Imuno-Histoquímica , Iluminação , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Natação/psicologiaRESUMO
Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED.
Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Animais , Transtorno da Compulsão Alimentar/diagnóstico por imagem , Transtorno da Compulsão Alimentar/psicologia , Encéfalo/diagnóstico por imagem , Modelos Animais de Doenças , HumanosRESUMO
RATIONALE: Insomnia is a common and disabling complaint for which there is a need for improved treatments. Successful drug discovery relies on the use of appropriate animal models to assess likely outcome in the clinic. OBJECTIVES: The purpose of this study was to develop a translational, caffeine-induced model of insomnia in rats and healthy volunteers. We used sleep onset latency (SOL) as a comparable sleep measure between the two species. The model was validated by two effective sleep-promoting agents with different pharmacology, zolpidem and trazodone, which have GABA-ergic and serotonergic mechanisms, respectively. MATERIALS AND METHODS: In rats, radiotelemetry transmitters with electroencephalogram and electromyogram electrodes were implanted for sleep recording. Animals were administered with caffeine alone (10 mg/kg) or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg), or vehicle, in crossover experiments. Home polysomnography was performed in 12 healthy male volunteers in a randomised, placebo-controlled, 4-week crossover study. Subjects received placebo, caffeine (150 mg) or caffeine in combination with zolpidem (10 mg) or trazodone (100 mg). Subjective sleep effects in volunteers were assessed using the Leeds Sleep Evaluation Questionnaire. RESULTS: Caffeine caused a significant prolongation in objective SOL in rats and humans. This effect was sensitive to zolpidem and trazodone, both of which attenuated the caffeine-induced increase in SOL. Furthermore, both hypnotics restored the disruption in subjective measures of sleep onset caused by caffeine in volunteers. CONCLUSIONS: This model therefore provides a promising paradigm in which we can study novel treatments for sleep disorders and an opportunity for direct comparison of results between rodents and humans.
Assuntos
Cafeína , Estimulantes do Sistema Nervoso Central , Modelos Animais de Doenças , Agonistas GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Sono/efeitos dos fármacos , Adulto , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletroencefalografia , Eletromiografia , Agonistas GABAérgicos/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Polissonografia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/prevenção & controle , Telemetria , Trazodona/farmacologia , ZolpidemRESUMO
Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.
Assuntos
Ansiedade/tratamento farmacológico , Temperatura Corporal/efeitos dos fármacos , Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Febre , Fluoxetina/administração & dosagem , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Ratos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Especificidade da Espécie , Estresse Psicológico , TelemetriaRESUMO
Expression of the anti-apoptotic protein Bcl-2 has been shown to increase in the hippocampus and cortex following chronic administration of mood stabilizers such as lithium and valproate, but the effects of long-term antidepressant administration have not been demonstrated. CD1 mice were dosed either acutely or chronically with either antidepressants or 5-HT receptor subtype selective antagonists. Cortex, hippocampus and hypothalamus from these mice were analysed by Western blot for changes in expression of Bcl-2 and Bax protein. Fourteen day but not acute treatment with citalopram (20 mg/kg), imipramine (10 mg/kg) and amitriptyline (10 mg/kg) in mice significantly elevated hippocampal Bcl-2 protein expression as compared to vehicle treated animals (59, 48 and 42% respectively). Similarly, fourteen day but not acute treatment with the 5-HT(1A) and 5-HT(2C/2B) receptor antagonists WAY100635 (0.3 mg/kg) and SB221284 (1 mg/kg) also markedly and significantly increased hippocampal Bcl-2 expression (95 and 52% respectively). Bcl-2 expression was unaffected in cortex by any treatment. There was a smaller increase of hippocampal Bax protein levels following treatment with imipramine after 1 or 14 days, and following citalopram and amitriptyline after 14 but not 1 day. These data present the first substantive evidence that clinically used antidepressants increase the expression of hippocampal Bcl-2 as did chronic blockade of 5-HT(1A) and 5-HT(2C/2B) receptors, which may be involved in the mechanism of action of antidepressants. The induction of hippocampal Bcl-2 expression by long-term antidepressant treatment may contribute to the clinical efficacy of such compounds via its well described neurotrophic and/or anti-apoptotic effects on neuronal function.
Assuntos
Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Antagonistas da Serotonina/farmacologia , Amitriptilina/farmacologia , Análise de Variância , Animais , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Citalopram/farmacologia , Fluorbenzenos/farmacologia , Hipocampo/metabolismo , Imipramina/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Piperazinas/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/metabolismoRESUMO
We have previously shown, using radioligand binding studies, that N-methyl-d-aspartate (NMDA) NR1 and NR2A receptor subunits density was decreased in the forebrain of morphine-dependent rats. We have now determined if morphine-dependent rats display regional differences in NMDA receptor expression and whether such changes are functionally relevant. In morphine-dependent rats, the expression of NR1 and NR2A subunits protein, as determined by Western blotting with NMDA receptor subunit antibodies, were decreased in frontal cortex and hippocampus but significantly increased in the nucleus accumbens. The expression of the NR2B subunit was unchanged in all regions examined. In separate groups of morphine-dependent rats, MK-801-induced hyperactivity (thought to be mediated via modulation of nucleus accumbens dopamine release) was significantly enhanced in morphine-dependent animals. Similarly, the MK-801-induced increase of dopamine metabolism was significantly increased in the nucleus accumbens of morphine-dependent animals as compared to sham controls. Results provide both biochemical and behavioural evidence to suggest that NMDA receptor function in the nucleus accumbens, at least with respect to an interaction with the limbic dopamine system, is markedly enhanced in morphine-dependent rats. This increase in function may be associated with an enhanced expression of NMDA receptors, particularly those in the nucleus accumbens containing the NR2A subunit. Taken together, these data support several studies in the literature indicating that NMDA receptors in the nucleus accumbens are involved in the process of opiate dependence.
Assuntos
Expressão Gênica/efeitos dos fármacos , Dependência de Morfina/fisiopatologia , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Maleato de Dizocilpina , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipercinese/induzido quimicamente , Sistema Límbico/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Freely-fed, female, rats were trained in a two-lever, delay-discounting task: one lever delivered a single chocolate-flavoured pellet immediately and the other a three-pellet reward after increasing delay (0, 4, 8, 16, 32 s). Rats were divided into two groups (i.e. binge-eating rats given irregular, limited access to chocolate in addition to normal chow and controls maintained on normal chow). Both groups exhibited increased preference for the immediate reward as the delay interval was lengthened. The discounting rate was significantly greater in binge-eating rats than non-binge-eating controls, especially as the behaviour became more established indicating that increased impulsivity and intolerance of delayed reward are part of the psychopathology of binge-eating. Lisdexamfetamine (0.8 mg/kg, orally ( d-amphetamine base)) reversed the reduced preference of binge-eating rats for larger rewards at delay intervals of 4 s, 8 s and 32 s and across all sessions. Lisdexamfetamine-treated binge-eating rats consumed the same number of pellets as vehicle-treated, binge-eating rats and non-binge-eating controls eliminating the possibility lisdexamfetamine's actions on appetite or satiety mediated its effects on operant responding for food pellets in delay-discounting. In summary, binge-eating rats showed increased impulsive choice compared with non-binge-eating controls that was reversed by lisdexamfetamine, complementing results showing lisdexamfetamine reduced impulsiveness scores in patients with binge-eating disorder.
Assuntos
Bulimia/tratamento farmacológico , Dextroanfetamina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Pró-Fármacos/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Feminino , Alimentos , Masculino , Ratos , Ratos Wistar , RecompensaRESUMO
The current study examined the long-term effect of brief exposure to 3,4-methylenedioxymethamphetamine (MDMA) on local cerebral glucose utilization (LCGU) in specific brain regions immediately following administration of the 5-HT2A/2C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Wistar rats (post-natal day (PND) 28, n = 24) were administered MDMA (5 mg/kg, i.p.) or saline (1 ml/kg, i.p.) four times daily for 2 consecutive days and core body temperature was recorded. Fifty-five days later and 10 min following injection of DOI (1 mg/kg, i.p.) or saline, LCGU was measured using the [14C]2-deoxyglucose (2-DG) technique. In the 4 hours following the initial injection (PND 28), MDMA-treated rats exhibited significant hyperthermia compared with saline-treated controls (p < 0.05-0.01). Eight weeks later, immediately following DOI challenge, LCGU was significantly elevated (an increase of 47%, p < 0.05) in the nucleus accumbens of MDMA/DOI pretreated rats, compared with that in MDMA/saline pre-treated controls. A similar trend was observed in other areas such as the lateral habenula, somatosensory cortex and hippocampal regions (percentage changes of 27-41%), but these did not reach significance. Blood glucose levels were significantly elevated in both groups of DOI-treated rats (p < 0.05-0.01). Thus, brief exposure of young rats to an MDMA regimen previously shown to cause anxiety-like behaviour and modest serotonergic neurotoxicity (Bull et al., 2004) increased DOI-induced energy metabolism in the nucleus accumbens and tended to increase metabolism in other brain regions, including the hippocampus, consistent with the induction of long-term brain region specific changes in synaptic plasticity.
Assuntos
Glicemia/metabolismo , Encéfalo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Alucinógenos/toxicidade , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Serotoninérgicos/toxicidade , Animais , Autorradiografia , Desoxiglucose/metabolismo , Injeções Intraperitoneais , Masculino , Núcleo Accumbens/efeitos dos fármacos , Pré-Medicação , Ratos , Ratos WistarRESUMO
Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms.
Assuntos
Transtorno da Compulsão Alimentar/fisiopatologia , Transtorno da Compulsão Alimentar/psicologia , Encéfalo/fisiopatologia , Cognição/fisiologia , Recompensa , Animais , Atenção , Transtorno da Compulsão Alimentar/genética , Tomada de Decisões/fisiologia , Dopamina/metabolismo , Dopamina/fisiologia , Feminino , Humanos , Comportamento Impulsivo/fisiologia , Masculino , Motivação , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologiaRESUMO
Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box. Entry into the compartment with the jar triggered the conditioning stimulus after a variable interval, and foot-shock 10 seconds later if the rat did not leave. Residence in the 'safe' compartment with no jar did not initiate trials or foot-shocks. By frequently entering the chocolate-paired compartment, binge-eating rats completed their 10 trials more quickly than non-binge controls. Binge-eating rats spent a greater percentage of the session in the chocolate-paired compartment, received foot-shocks more frequently, and tolerated foot-shocks for longer periods; all consistent with compulsive and perseverative behaviour. The d-amphetamine prodrug, lisdexamfetamine, has recently received US approval for the treatment of moderate to severe binge-eating disorder in adults. Lisdexamfetamine (0.8 mg/kg po [d-amphetamine base]) decreased chocolate consumption by binge-eating rats by 55% and markedly reduced compulsive and perseverative responding in the model. These findings complement clinical results showing lisdexamfetamine reduced compulsiveness scores in subjects with binge-eating disorder.
Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Bulimia/tratamento farmacológico , Comportamento Compulsivo/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Ratos , Ratos Wistar , RecompensaRESUMO
RATIONALE: Effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue, are an important aspect of depression and other disorders. Motivational symptoms are resistant to some treatments, including serotonin transport (SERT) inhibitors. OBJECTIVES: Tests of effort-based choice using operant behavior tasks (e.g., concurrent lever pressing/ chow feeding tasks) can be used as animal models of motivational symptoms. Tests of effort-related choice allow animals to choose between high-effort actions that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued rewards (i.e., less preferred or lower magnitude). Rats treated with the vesicular monoamine transport inhibitor tetrabenazine, or the cytokine interleukin-1ß (IL-1ß), which are associated with depressive symptoms in humans, can alter effort-related choice, reducing selection of the high effort alternative (lever pressing) while increasing intake of freely available chow. METHODS: The present studies focused upon the ability of lisdexamfetamine (LDX) to increase exertion of effort in rats responding on effort-based choice tasks under several different conditions. RESULTS: LDX attenuated the shift from fixed ratio 5 lever pressing to chow intake induced by tetrabenazine and IL-1ß. In contrast, the SERT inhibitor s-citalopram failed to reverse the effects of tetrabenazine. When given in combination with tetrabenazine+s-citalopram, LDX significantly increased lever pressing output compared to tetrabenaine+citalopram alone. LDX also increased work output in rats responding on a progressive ratio/chow feeding choice task. CONCLUSIONS: LDX can increase work output in rats responding on effort-based choice tasks, which may have implications for understanding the neurochemistry of motivational symptoms in humans.
Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Citalopram/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Recompensa , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Interações Medicamentosas , Comportamento Alimentar/efeitos dos fármacos , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.
Assuntos
Anfetamina/farmacologia , Benzodiazepinas/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Sistema Límbico/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Receptores de Dopamina D2/metabolismo , Análise de Variância , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Sinais (Psicologia) , Antagonistas de Dopamina/farmacologia , Generalização do Estímulo , Masculino , Olanzapina , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.
Assuntos
Anestésicos/farmacologia , Etomidato/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptores de GABA-A/metabolismo , Animais , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Separação Celular , Estado de Consciência/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Marcação de Genes , Técnicas In Vitro , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora/efeitos dos fármacos , Técnicas de Patch-Clamp , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Células de Purkinje/citologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/fisiologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/genética , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/genética , Triazóis/farmacologiaRESUMO
Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.
Assuntos
Ansiedade/induzido quimicamente , Agonistas GABAérgicos/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Ansiedade/psicologia , Química Encefálica/efeitos dos fármacos , Carbolinas/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Fibroblastos/metabolismo , Agonistas GABAérgicos/metabolismo , Humanos , Masculino , Camundongos , Técnicas de Patch-Clamp , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
Compared to other rat strains, the Wistar-Kyoto rats show increased amount of REM sleep, one of the characteristic sleep changes observed in depressed patients. The aims of this study were firstly to validate a simple sleep stage discriminator and then compare the effect of antidepressants on suppression of rapid eye movement (REM) sleep in Wistar-Kyoto rats and an outbred rat strain (Sprague-Dawley). Rats were implanted with telemetry transmitters with electroencephalogram/electromyogram electrodes. Following recovery, the animals were orally dosed at light onset with either desipramine (20 mg/kg), fluoxetine (10 mg/kg), citalopram (10 or 40 mg/kg) or vehicle in a cross-over design. Every 12-s epoch was automatically scored as WAKE, NREM or REM sleep. Results confirm that Wistar-Kyoto rats show increased amount of REM sleep and decreased REM latency compared with Sprague-Dawley rats. All antidepressants significantly suppressed REM sleep in Sprague-Dawley rats, but only the high dose of citalopram suppressed REM sleep in Wistar-Kyoto rats. These findings suggest that the enhanced REM activity in Wistar-Kyoto rats is less sensitive to the effect of antidepressants and therefore does not provide any additional predictive validity for assessing antidepressant efficacy.
Assuntos
Antidepressivos/farmacologia , Sono REM/efeitos dos fármacos , Administração Oral , Animais , Temperatura Corporal/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Citalopram/farmacologia , Estudos Cross-Over , Desipramina/farmacologia , Eletroencefalografia , Eletromiografia , Fluoxetina/farmacologia , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Sono REM/fisiologia , Especificidade da EspécieRESUMO
Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Bulimia/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Animais , Baclofeno/farmacologia , Benzazepinas/farmacologia , Benzodiazepinas/farmacologia , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Olanzapina , Prazosina/farmacologia , Pró-Fármacos/farmacologia , Racloprida/farmacologia , Ratos , Ratos Wistar , Rolipram/farmacologiaRESUMO
This study examined the involvement of the 5-HT(2A) receptor in the long-term anxiogenic effect of a brief exposure of young rats to 3,4-methylenedioxymethamphetamine (MDMA) using the social interaction and elevated plus-maze paradigms. Wistar rats (post-natal day (PND) 28) received either MDMA (5 mg/kg i.p.) or saline (1 ml/kg i.p.) hourly for 4 h on 2 consecutive days. Locomotor activity was measured for 60 min after the first injection and core body temperature was recorded at regular intervals over 4 h. On PND 84, without further drug administration, social interaction was assessed between treatment-matched rat pairs derived from separate litters. On PND 86, rats received either the 5-HT(2A/2C) receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg i.p.) or saline and locomotor activity, wet-dog shakes and back muscle contractions were monitored. The change in elevated plus-maze behaviour was assessed following the same injection on PND 87. Acutely, MDMA produced a significant hyperlocomotion and hyperthermia (p<0.01). Following 55 days of abstinence, social interaction was reduced by 27% in MDMA pre-treated rats compared with that in controls (p<0.01). On the elevated plus-maze, pre-treatment with MDMA prevented the anxiogenic effect of DOI. On PND 92, hippocampal, frontal cortical and striatal 5-hydroxytryptamine (5-HT) was significantly reduced in MDMA pre-treated rats by between 16% and 22%, without any accompanying change in [(3)H]paroxetine binding in cortical homogenates. In conclusion, exposure of young rats to repeated MDMA caused serotonin depletion and induced 'anxiety-like' behaviour in the social interaction test accompanied by a long-lasting reduction in specific 5-HT(2A) receptor mediated behaviour.
Assuntos
Atividade Motora/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Comportamento Social , Anfetaminas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Atividade Motora/fisiologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT2 de SerotoninaRESUMO
In the retina, activation of dopamine receptors, particularly the D2-like family (D2, D3, D4 receptor subtypes), with quinpirole suppresses the light sensitive cAMP pool and inhibits melatonin synthesis in photoreceptor cells. We have characterised rat retinal D4 receptors using the D4 selective radioligand [(125)I] L-750667 which bound specifically and saturably to rat retinal membranes with high affinity (K(d) 0.06+/-0.02 nM) and exhibited a D4 receptor pharmacology. Comparison of the binding kinetics of [(125)I] L-750667 and [(3)H] spiperone revealed B(max) values of 134+/-27 fmol/mg and 219+/-47 fmol/mg respectively, indicating that the dopamine D4 receptor is a major component of D2-like dopamine receptors in the rat retina. Modulation of retinal cAMP levels by quinpirole was used to evaluate the functional relevance of rat retinal dopamine D4 receptors. Quinpirole (0.03-3 micro ) produced a dose-related decrease of the light sensitive cAMP pool which was reversed by haloperidol, clozapine and the D4 selective antagonist, L-745870 with a rank order of potency suggesting that the quinpirole effect is due to activation of the dopamine D4 receptors. The D2 selective ligand L-741626 had no effect on the quinpirole response confirming that the D4 receptor is the major receptor subtype mediating dopamine induced suppression of adenylate cyclase in the retina.