RESUMO
BACKGROUND: Converging findings support a role for extra-hypothalamic CRF in the mediation of the stress response. The influence of CRF in the amygdala is well established, while less is known of its role in other areas of the forebrain where CRF and CRF(1) receptors are also expressed. In the present study CRF was genetically induced to allow forebrain-restricted expression in a temporally-defined manner at any time during the mouse lifespan. This mouse model may offer the possibility to establish a model of the pathogenesis of recurrent episodes of depression. METHODS: Mice were engineered to carry both the rtTA transcription factor driven by the CamKII alpha promoter and the doxycycline-regulated operator (tetO) upstream of the CRF coding sequence. Molecular, biochemical and behavioural characterisation of this mouse is described. RESULTS: Following a three-week period of transcriptional induction, double transgenic mice showed approximately 2-fold increased expression of CRF mRNA in the hippocampus and cortex, but not hypothalamus. These changes were associated with 2-fold increase in morning corticosterone levels, although responses to the dexamethasone suppression test or acute stress were unaffected. In contrast, induced mice displayed modestly altered behaviour in the Light and Dark test and Forced Swim test. CONCLUSIONS: Transient induction of CRF expression in mouse forebrain was associated with endocrine and mild anxiety-like behavioural changes consistent with enhanced central CRF neurotransmission. This mouse allows the implementation of regimens with longer or repeated periods of induction which may model the initial stages of the pathology underlying recurrent depressive disorders.
Assuntos
Comportamento Animal/fisiologia , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/fisiologia , Prosencéfalo/fisiologia , Animais , Ansiedade/etiologia , Ansiedade/genética , Ansiedade/fisiopatologia , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Primers do DNA/genética , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos do Humor/etiologia , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologiaRESUMO
Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.
