Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac)

Abstract

Fluoxetine (Prozac) is the most widely prescribed medication for the treatment of depression. Nevertheless, little is known about the molecular basis of its clinical efficacy, apart from the fact that fluoxetine increases the synaptic availability of serotonin. Here we show that, in vivo, fluoxetine, given either acutely or chronically, regulates the phosphorylation state of dopamine-and cAMPregulated phosphoprotein of M r 32,000 (DARPP-32) at multiple sites in prefrontal cortex, hippocampus, and striatum. Acute administration of fluoxetine increases phosphorylation of DARPP-32 at the protein kinase A site, Thr-34, and at the casein kinase-1 site, Ser-137, and decreases phosphorylation at the cyclin-dependent kinase 5 site, Thr-75. Each of these changes contributes, through distinct signaling pathways, to increased inhibition of protein phosphatase-1, a major serine͞threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetinemediated increase in AMPA receptor phosphorylation at Ser-845-GluR1 and the beneficial responsiveness to fluoxetine in an animal test of antidepressant efficacy were strongly reduced in DARPP-32 knockout mice, indicating a critical role for this phosphoprotein in the antidepressant actions of fluoxetine. Mice chronically treated with fluoxetine had increased levels of DARPP-32 mRNA and protein and a decreased ability to increase phospho-Ser-137-DARPP-32 and phospho-Ser-831-GluR1. These chronic changes may be relevant to the delayed onset of therapeutic efficacy of fluoxetine.A gents that enhance serotonergic neurotransmission, such as serotonin reuptake inhibitors (e.g., fluoxetine), and monoamine oxidase inhibitors (e.g., moclobemide), are effective as antidepressants. Although these agents immediately increase the synaptic availability of serotonin, there is a temporal delay in the onset of their beneficial actions. Recent studies in experimental animals have focused on understanding the effects of various antidepressant agents on signal transduction pathways in neurons located in brain regions thought to be implicated in depression (1, 2). In particular, it has been shown that treatment with various antidepressants, including fluoxetine, enhances the efficacy of the cAMP-dependent protein kinase A (PKA) pathway at several different levels in the frontal cortex and hippocampus (1). The possibility that the cAMP͞PKA system is involved in the action(s) of antidepressants is strongly supported by evidence from basic and clinical studies showing that cAMP phosphodiesterase inhibitors, such as rolipram, have antidepressant efficacy (3, 4).One major target protein for the cAMP͞PKA pathway is dopamine-and cAMP-regulated phosphoprotein of M r 32,000 ref. 5). DARPP-32 is enriched in striatum and the olfactory tubercle (6). Moderate to high levels of DARPP-32 also are found in several extrastriatal regions, such as cerebral cortex, hippocampu...

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