A PET imaging study of 5-HT1A receptors in cat brain after acute and chronic fluoxetine treatment
Introduction
Serotonin 1A receptors (5-HT1AR) play a key role in the antidepressant effects of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs). In brain 5-HT nuclei, such as the nucleus raphe dorsalis (NRD), these receptors are located on the plasma membrane of 5-HT cell bodies and dendrites (Sotelo et al., 1990, Kia et al., 1996, Riad et al., 2000) and act as autoreceptors that negatively regulate the firing and hence release of 5-HT by these neurons (Sprouse and Aghajanian, 1987, Hjorth and Magnusson, 1988, Hutson et al., 1989, Sharp et al., 1989). Electrophysiological and microdialysis studies in rodents have indicated that, at the onset of SSRI treatment, the resulting increase in extracellular 5-HT (Bel and Artigas, 1992, Rutter and Auerbach, 1993, Kreiss and Lucki, 1995, Hervás and Artigas, 1998) activates 5-HT1A autoreceptors and therefore reduces 5-HT neuron firing and release (Adell and Artigas, 1991, Hjorth and Auerback, 1994, Rutter et al., 1995). However, 5-HT1A autoreceptors are subject to a desensitization (Kennett et al., 1987, Beer et al., 1990, Seth et al., 1997), which is transient after acute treatment with an agonist or SSRI (Casanovas et al., 1997, Le Poul et al., 2000), but allows for a return to initial firing rate and release of 5-HT from neurons, without negative feedback, after 2 or 3 weeks of SSRI treatment (Blier et al., 1984, Hamon et al., 1988, Jolas et al., 1994, Le Poul et al., 1995, Le Poul et al., 2000, Czachura and Rasmussen, 2000). Because this desensitization of 5-HT1A autoreceptors must take place for 5-HT neurotransmission to increase under SSRI treatment, it may be viewed as a prerequisite to the therapeutic efficacy of these drugs as antidepressants (for reviews, see Blier and de Montigny, 1994, Piñeyro and Blier, 1999).
Using quantitative electron microscopic immunocytochemistry with a highly specific antibody against 5-HT1AR (El Mestikawy et al., 1990), we have previously shown in rat that acute treatment with the selective 5-HT1AR agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), or with the SSRI fluoxetine (Prozac®), induces an internalization of more than 35% of plasma membrane 5-HT1A autoreceptors in the NRD (Riad et al., 2001, Riad et al., 2004). This internalization may account for the early desensitization of 5-HT1A autoreceptors after acute treatment, and it is not observed in pyramidal and granule cells of the hippocampus, the 5-HT1AR of which (heteroreceptors) do not desensitize (Piñeyro et al., 1994, Haddjeri et al., 1998). In parallel experiments with β-sensitive microprobes implanted next to the NRD and into hippocampus, we have also demonstrated that acute treatment with 8-OH-DPAT or with fluoxetine entails equivalent decreases of the specific in vivo binding of the 5-HT1AR PET radioligand [18F]MPPF in the NRD, without any concomitant change in hippocampus (Riad et al., 2004, Zimmer et al., 2004). These decreases could be imputed to the internalization of 5-HT1A autoreceptors since the local availability of [18F]MPPF in vivo, as measured by microdialysis (Zimmer et al., 2004), as well as its in vitro binding in NRD and hippocampus, as measured by autoradiography in tissue sections, did not differ between control and fluoxetine-treated rats (Riad et al., 2004).
Because the decreased [18F]MPPF binding in NRD, associated with the internalization of 5-HT1A autoreceptors, might provide an index of desensitization of these receptors at the onset of antidepressant treatment, we undertook the present brain imaging study to examine the possibility of detecting and measuring this event with PET, following acute and chronic treatment with the SSRI fluoxetine. Knowing that the distribution and binding properties of 5-HT1A autoreceptors were comparable in feline and rodent NRD (Charnay et al., 1997, Ginovart et al., 2000, Aznavour et al., 2006), the experiments were carried out in cat in order to avoid limitations in imaging resolution that might compromise the acquisition of microPET data on rat NRD. It turned out, however, that reliable interpretation of the results after chronic treatment required information from a concomitant immunocytochemical electron microscopic study, which had to be carried out in rat due to the limited cross-species reactivity of available 5-HT1A receptor antibodies. Part of the latter findings was therefore included as preliminary data in the present report.
Section snippets
Acute and chronic fluoxetine treatment (cat)
These studies were performed in accordance with French (87-848, Ministère de l’Agriculture et de la Forêt) and European Economic Community (86-60, EEC) guidelines for care of laboratory animals and were approved by the regional ethical animal use committee. Three adult male cats, weighing 3–4 kg, were obtained from Charles River Laboratories (L’Arbresle, France). Each animal was subjected to five [18F]MPPF scanning sessions, two for determining baseline values, two after acute fluoxetine
PET imaging and measurement of [18F]MPPF binding
In keeping with earlier demonstrations (Ginovart et al., 2000, Aznavour et al., 2006), there was a strong accumulation of radioactivity in several regions of cat brain after the intravenous injection of [18F]MPPF (Fig. 1, Fig. 2). Above background labeling was visualized in infralimbic cortex (Figs. 1A–C), cingulate cortex (Figs. 1D–L), lateral septum (Figs. 1D–F), hippocampus (Fig. 1, Fig. 2) and NRD (Fig. 1, Fig. 2). Co-registration of PET and MRI images confirmed the anatomical localization
Methodological considerations
The present PET study demonstrated a significant decrease in [18F]MPPF BP in cat NRD following acute but not chronic fluoxetine treatment. The realignment of PET and MRI images in each cat was crucial in obtaining these data and ensuring the reliability of the measurements. Indeed, a shift in the spatial orientation of the cat’s head could have altered the results, in such a small brain region. In view of the small size of the cat NRD and the resolution of the PET camera, the BP values of this
Acknowledgments
N. Aznavour is a recipient of a postdoctoral fellowship from the Swiss National Science Foundation. The authors are grateful to V. Gualda and M. Malleval for their technical support in the PET experiments and D. Sappey-Marinier for his help with MRI. This research was supported by the French program CNRS-CEA “Imagerie du Petit Animal” to L.Z. and grant NRF 3544 from the Canadian Institutes for Health Research to L.D.
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