Aberrant accumulation of serotonin in dopaminergic neurons.
Gene targeting approaches greatly facilitate insight into the functioning of monoamine transporters, the targets of potent antidepressants. The serotonin transporter ( 5-HTT) is the molecular target of a large number of antidepressants. To assess the clearance of serotonin (5-HT) in the absence of the 5-HTT, we have generated double knockout mice lacking both the 5-HTT and the catabolizing enzyme monoamine oxidase A ( MAOA). We found aberrant 5-HT accumulation in the striatum of these MAOA/ 5-HTT double knockout mice. By additional ablation of the dopamine transporter ( DAT), this aberrant 5-HT accumulation was abolished in MAOA/ 5-HTT/ DAT triple knockout mice. Thus, aberrant uptake of 5-HT occurs in dopaminergic terminals under conditions of elevated 5-HT levels, and this aberrant uptake is mediated by the DAT. These findings have important consequences for antidepressant therapy, since during treatment of depression with selective serotonin reuptake inhibitors, clearance of 5-HT by dopaminergic neurons may reduce the desired therapeutic elevation of extracellular 5-HT levels. This provides a molecular rationale for improving antidepressant efficacy by additional pharmacological inhibition of the DAT.[1]References
- Aberrant accumulation of serotonin in dopaminergic neurons. Mössner, R., Simantov, R., Marx, A., Lesch, K.P., Seif, I. Neurosci. Lett. (2006) [Pubmed]
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