RESUMO
Recent data show that corticolimbic expression of the effector immediate early gene Arc is up-regulated by standard antidepressant drugs. Here, we tested the effect upon Arc expression of a novel antidepressant and selective 5-hydroxytryptamine/noradrenaline reuptake inhibitor (SNRI), (-)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005). Arc mRNA abundance in frontal, cingulate, orbital and parietal cortices, hippocampus (CA1 pyramidal layer) and striatum was elevated in rats treated daily for 14 but not 7 days with 10 mg/kg i.p. S33005 compared to saline. Fourteen but not 7 days treatment with 10 mg/kg i.p. venlafaxine, the prototypical SNRI, also elevated Arc mRNA, but its effects were not as pronounced and detected in fewer regions, compared to S33005. Neither S33005 nor venlafaxine altered Arc mRNA after acute injection nor altered brain derived neurotrophic factor mRNA after repeated administration. These data demonstrate that sustained treatment with SNRIs increases Arc expression in corticolimbic regions, and underpin previous neurochemical and behavioural evidence that S33005 is efficacious in models predictive of antidepressant action.
Assuntos
Antidepressivos/farmacocinética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Cicloexanóis/farmacocinética , Proteínas Imediatamente Precoces/genética , Proteínas do Tecido Nervoso/genética , Inibidores da Captação de Neurotransmissores/farmacocinética , Animais , Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Córtex Cerebral/ultraestrutura , Cicloexanóis/administração & dosagem , Proteínas do Citoesqueleto , Esquema de Medicação , Expressão Gênica/genética , Injeções Intraperitoneais , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Cloridrato de VenlafaxinaRESUMO
RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces an acute hyperthermic response and induces localised neuronal activation, which can be visualised via expression of immediate-early genes. The pharmacological and anatomical basis of these effects are unclear. At high doses, MDMA also causes selective neurotoxicity at serotonergic nerve terminals. OBJECTIVE: We investigated the effect of 5-hydroxytryptamine (5-HT) depletion on the acute hyperthermic response to MDMA and the pattern of neuronal excitation indicated by Arc (activity-regulated cytoskeleton associated gene) in naive rats and following administration of MDMA at a neurotoxic dose. METHODS: Expression of Arc mRNA was investigated by in situ hybridisation histochemistry using 35S-labelled oligonucleotide probe. RESULTS: MDMA induced a significant hyperthermia together with increased Arc mRNA expression in cortical regions, caudate-putamen and CA1 hippocampus but not hypothalamus. At 21 days after a neurotoxic dose of MDMA, brain 5-HT and 5-HIAA levels were significantly reduced by 21-32%. In these animals, both the hyperthermic response and the pattern and extent of Arc mRNA expression induced by a subsequent dose of MDMA were unaltered. However, basal Arc expression was significantly increased in cortical regions and CA1 hippocampus. CONCLUSION: We conclude that the acute hyperthermic response induced by MDMA is not attenuated by moderate depletion of 5-HT, further questioning mediation via a serotonergic mechanism. Arc mRNA induction by MDMA exhibits highly localised expression, which is not altered following 5-HT depletion. However, following a neurotoxic dose of MDMA, basal expression of Arc is increased, particularly in cortex and CA1, suggesting that mechanisms underlying synaptic plasticity might also be modified.
Assuntos
Encéfalo/metabolismo , Febre/metabolismo , Proteínas Imediatamente Precoces/biossíntese , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/biossíntese , Antagonistas da Serotonina/toxicidade , Serotonina/metabolismo , Animais , Proteínas do Citoesqueleto , Febre/induzido quimicamente , Proteínas Imediatamente Precoces/genética , Hibridização In Situ , Masculino , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Proteínas do Tecido Nervoso/genética , Ratos , Antagonistas da Serotonina/administração & dosagemRESUMO
Recent data show that corticolimbic expression of the effector immediate early gene Arc is up-regulated by standard antidepressant drugs. Here, we tested the effect upon Arc expression of a novel antidepressant and selective 5-hydroxytryptamine/noradrenaline reuptake inhibitor (SNRI), (-)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005). Arc mRNA abundance in frontal, cingulate, orbital and parietal cortices, hippocampus (CA1 pyramidal layer) and striatum was elevated in rats treated daily for 14 but not 7 days with 10 mg/kg i.p. S33005 compared to saline. Fourteen but not 7 days treatment with 10 mg/kg i.p. venlafaxine, the prototypical SNRI, also elevated Arc mRNA, but its effects were not as pronounced and detected in fewer regions, compared to S33005. Neither S33005 nor venlafaxine altered Arc mRNA after acute injection nor altered brain derived neurotrophic factor mRNA after repeated administration. These data demonstrate that sustained treatment with SNRIs increases Arc expression in corticolimbic regions, and underpin previous neurochemical and behavioural evidence that S33005 is efficacious in models predictive of antidepressant action.
Assuntos
Antidepressivos/farmacocinética , Córtex Cerebral/efeitos dos fármacos , Cicloexanóis/farmacocinética , Proteínas Imediatamente Precoces/genética , Proteínas do Tecido Nervoso/genética , Inibidores da Captação de Neurotransmissores/farmacocinética , Animais , Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Córtex Cerebral/fisiologia , Córtex Cerebral/ultraestrutura , Cicloexanóis/administração & dosagem , Proteínas do Citoesqueleto , Esquema de Medicação , Expressão Gênica/genética , Injeções Intraperitoneais , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Cloridrato de VenlafaxinaRESUMO
The in vivo binding of the 5-HT(2A) receptor-selective positron emission tomography (PET) ligand [(11)C]MDL 100907 and its sensitivity to endogenous 5-HT were quantified in rat brain using quad-HIDAC, a novel high-resolution PET camera for small animals. Specific binding of [(11)C]MDL 100907, estimated using volume of interest (VOI) to cerebellum ratios, corresponded well with both the known distribution of 5-HT(2A) receptors and tissue:cerebellum ratios obtained using ex vivo dissection. Specific binding was blocked by predosing with either nonradioactive MDL 100907 (0.2 or 0.4 mg/kg i.v.) or the 5-HT(2A/2C) receptor antagonist ketanserin (2 mg/kg i.v.), but was unaffected in rats pretreated with the 5-HT releasing agent, fenfluramine (10 mg/kg i.p.). In parallel studies, the same dose of fenfluramine was shown to be sufficient to cause an increase in the expression of the immediate early genes (IEG) c-fos and Arc mRNA in cortical regions with high 5-HT(2A) receptor density. This increase was blocked by MDL 100907 (0.2 mg/kg i.v.), confirming a 5-HT(2A) receptor-mediated effect. The results demonstrate that PET with [(11)C]MDL 100907 is insensitive to an increased concentration of synaptic 5-HT, implying that the ligand can be used clinically to monitor 5-HT(2A) receptor function or dysfunction in disease or during therapy, without the need to consider concomitant changes in neurotransmitter concentration.
