Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes. Rx drugs

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Br J Pharmacol. 2002 Mar;135(5):1115-22.
Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography.

Pejchal T, Foley MA, Kosofsky BE, Waeber C.

Massachusetts General Hospital, Harvard Medical School, Neuroscience Center, Room 6403, Charlestown, MA 02129, USA.

1. Selective Serotonin Reuptake Inhibitors (SSRIs) are thought to have a delay in therapeutic efficacy because of the need to overcome the inhibitory influence of raphe 5-HT(1A) autoreceptors. Prolonged SSRI administration has been reported to desensitize these autoreceptors. We have used [(35)S]-GTP gamma S autoradiography to determine whether this desensitization occurs at the level of receptor/G protein coupling. 2. Male mice were injected intraperitoneally once a day with saline or 20 mg kg(-1) fluoxetine for either 2 days or 14 days. 5-HT(1A) receptor binding and coupling to G proteins were assessed using [(3)H]-8-OH-DPAT and [(35)S]-GTP gamma S autoradiography, respectively. 3. The 5-HT receptor agonist 5-carboxamidotryptamine (5-CT) stimulated [(35)S]-GTP gamma S binding in the substantia nigra, as well as in hippocampus and dorsal raphe nucleus. The 5-HT(1A) receptor antagonist p-MPPF (4-fluoro-N-(2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl)-N-(2-pyridinyl)benzamide) blocked this effect in the latter regions, whereas the 5-HT(1B/D) antagonist GR-127,935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-l-yl)-phenyl]-amide) only decreased labelling in substantia nigra. 4. Fourteen-day fluoxetine treatment decreased 5-CT-stimulated [(35)S]-GTP gamma S binding in dorsal raphe (saline: 112 +/- 12% stimulation; fluoxetine: 66 +/- 13%), but not in substantia nigra (99 +/- 14% vs 103 +/- 7%) or hippocampus (157 +/- 3% vs 148 +/- 18%). Two-day fluoxetine treatment did not alter 5-CT-stimulated [(35)S]-GTP gamma S binding in any of the brain areas investigated. 5. Decreased [(35)S]-GTP gamma S binding was not due to receptor down-regulation, since the density of raphe [(3)H]-8-OH-DPAT binding sites was unaffected by fluoxetine treatment. 6. These results suggest that the desensitization of presynaptic 5-HT(1A) receptor function occurs at the level of receptor-G protein interaction on dorsal raphe neurons, and may underlie the therapeutic efficacy of long-term SSRI treatment.

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Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3182-7.
Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac).

Svenningsson P, Tzavara ET, Witkin JM, Fienberg AA, Nomikos GG, Greengard P.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.

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 cAMP-regulated 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 serine/threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetine-mediated 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.

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Exp Brain Res. 2002 Mar;143(2):191-7. Epub 2002 Jan 24.
Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.

Bianchi M, Moser C, Lazzarini C, Vecchiato E, Crespi F.

Department of Biology, GlaxoSmithKline Group, GlaxoWellcome, SpA Medicine Research Centre, Via Fleming 4, 37100 Verona, Italy.

Low levels of central serotonin (5-HT) have been related to the state of depression, and 5-HT is the major target of the newer antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs). Neurons and platelets display structural and functional similarities, so that the latter have been proposed as a peripheral model of central functions. In particular, in blood more than 99% of 5-HT is contained in platelets, so that one could consider changes in 5-HT levels in platelets as a mirror of changes in central 5-HT. Here, this hypothesis has been studied via the analysis of the influence of: (1) the forced swimming test (FST, which has been proved to be of utility to predict the clinical efficacy of antidepressants in rodents) and (2) treatment with the SSRI fluoxetine upon 5-HT levels monitored in brain regions and in peripheral platelets by means of electrochemical in vivo and ex vivo measurements. The results obtained confirm that the FST increases immobility; furthermore they show a parallel and significant decrease in cerebral (brain homogenate) and peripheral (in platelet-rich plasma, PRP) voltammetric 5-HT levels following the FST in naive rats. In addition, subchronic treatment with fluoxetine was followed by a significant increase in 5-HT levels in PRP, while the same SSRI treatment performed within the FST resulted in a decrease in the 5-HT levels in PRP. However, this decrease was inferior to that observed without SSRI treatment. These data suggest that there is an inverse relationship between immobility and the levels of 5-HT in PRP and that these peripheral 5-HT levels are sensitive to: (1) the FST, (2) the treatment with fluoxetine and (3) the combination of both treatments, i.e. SSRI + FST. It has been reported that SSRI treatment at first inhibits the 5-HT transporter in brain, resulting in increased extracellular 5-HT, while following sustained SSRI treatments decreased intracellular levels of central 5-HT were observed. Accordingly, the present data show that the initial block of 5-HT reuptake is revealed by the selective increase in 5-HT levels (extracellular content) measured in PRP (not in insulated platelets, IPs) the 1st day of fluoxetine treatment. The initial action of this SSRI upon the 5-HT transporter in brain has also been confirmed by in vivo voltammetric data showing selective increase in the serotonergic signal following local injection of fluoxetine into the brain region studied. Successively, the major effect monitored is a decrease in 5-HT levels, which is more evident in IPs than in PRP. However, it is known that following 2 weeks treatment with an SSRI, 5-HT autoreceptors are desensitized and the serotonin synthesis is restored, together with the intracellular 5-HT levels. The present data showing that the levels of 5-HT in IPs tend to return to control values 12 days after the beginning of chronic fluoxetine treatment suggest that 5-HT levels in IPs (intracellular environment) mirror the influence of SSRI treatment upon the central 5-HT system. On the other hand, at day 12 of the chronic fluoxetine treatment, 5-HT content remains low in PRP. Similarly, low levels of 5-HT have been monitored in brain homogenate of rats chronically treated with fluoxetine. This would support the similarity between PRP preparation and brain homogenate as in both cases cells are disrupted by sample preparation. In conclusion this work supports the literature in proposing platelets as a peripheral model of central functions. In particular, the present data support the idea that peripheral 5-HT platelet levels can reflect the state of the central 5-HT system in conditions of depression. Furthermore, the main outcome of this study is that PRP may mirror central extracellular 5-HT levels, whilst IPs mirror neuronal 5-HT changes.

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