Depression is a mental illness that affects how a person feels, thinks and handles daily activities. Antidepressants are prescribed to alleviate the symptoms of depression and help the brain process and use certain chemicals that regulate mood or stress. Unfortunately, existing medications usually require two to four weeks of use before patients respond. In a recent Paper of the Week in the Journal of Biological Chemistry, Mark M. Rasenick and his team at the University of Illinois at Chicago describe why antidepressants have a delayed impact.
One consistent finding in brain and some peripheral cells of patients who suffer depression is depletion of cyclic adenosine monophosphate, or cAMP. cAMP is a second messenger. Regular antidepressant treatment activates signaling pathways to cause an increase in accumulation of cAMP and transcription of cAMP-regulated genes, which include genes for neurotransmitters and growth factors, to alleviate the symptoms of depression. Antidepressants work to increase the brain's concentrations of various neurotransmitters, such as norepinephrine, dopamine, noradrenaline, adrenaline and serotonin. Researchers suggest that the antidepressants' effects may be mediated through induction of the system that generates cAMP. But they need to understand why there is a delay in clinical efficacy of antidepressant action.
Rasenick and his team used glioma cells that lacked the monoamine transport proteins, including serotonin reuptake transport proteins, which are one of the binding sites for many antidepressants. They demonstrated that in the absence of SERT, antidepressants accumulate gradually in the plasma membrane microdomains of glioma cells. Next, Rasenick and colleagues showed that a sustained treatment with an antidepressant drug called escitalopram, better known by brand names of Lexapro and Cipralex, translocated the G-protein Gαs from lipid rafts. Lipid rafts are specialized regions of the plasma membrane that have been shown to inhibit the cAMP-generating cascade. Gαs went from lipid rafts to nonraft regions of the plasma membrane in the glioma cells, which enhanced its signaling ability.
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