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. 2016 May 23;6:26633.
doi: 10.1038/srep26633.

Selective Serotonin 5-HT1A Receptor Biased Agonists Elicitdistinct Brain Activation Patterns: A pharmacoMRI Study

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Free PMC article

Selective Serotonin 5-HT1A Receptor Biased Agonists Elicitdistinct Brain Activation Patterns: A pharmacoMRI Study

G Becker et al. Sci Rep. .
Free PMC article

Abstract

Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology.

Conflict of interest statement

A.N.-T. is employee and stock-holder of Neurolixis.

Figures

Figure 1
Figure 1. Mean ± SEM change (%) in overall BOLD signal intensity compared to the baseline level.
The time courses obtained from each rat, i.e. the average of all pixels from dorsal striatum ROI in individual datasets, were normalized by subtracting the average baseline (zero on average, by definition). Pharmacological challenges (mean + SEM) were carried out 72 hours after the control test, i.e. saline solution (mean–SEM). Upon each time course is drawn the chemical structure of the corresponding compound. (a) 8-OH-DPAT (n = 8). (b) MPPF (n = 6). (c) F13714 (n = 9). (d) F15599 (n = 6).
Figure 2
Figure 2. Areas of significant activation following i.p. injection of 8-OH-DPAT.
Data are processed in successive 3-min blocks from onset of injection (T1) to the end of acquisition (T5). Statistically significant areas for each time bin, for 8 rats, using an ANOVA for 8-OH-DPAT minus saline injection (p < 0.001 uncorrected). Z score in colour scale, bregma coordinates on the left scale, time scale start at T1 (15 minutes after the beginning of the MRI session).
Figure 3
Figure 3. Areas of significant activation following i.p. injection of MPPF.
Data are processed in successive 3-min blocks from onset of injection (T1) to the end of acquisition (T5). Statistically significant areas for each time bin, for 6 rats, using an ANOVA for MPPF minus saline injection (p < 0.001 uncorrected). Z score in color scale, bregma coordinates on the left scale, time scale start at T1 (15 minutes after the beginning of the MRI session).
Figure 4
Figure 4. Areas of significant activation following i.p. injection of F13714.
Data are processed in successive 3-min blocks from onset of injection (T1) to the end of acquisition (T5). Statistically significant areas for each time bin, for 9 rats, using an ANOVA for F13714 minus saline injection (p < 0.001 uncorrected). Z score in color scale, bregma coordinates on the left scale, time scale start at T1 (15 minutes after the beginning of the MRI session).
Figure 5
Figure 5. Areas of significant activation following i.p. injection of F15599.
Data are processed in successive 3-min blocks from onset of injection (T1) to the end of acquisition (T5). Statistically significant areas for each time bin, for 6 rats, using an ANOVA for F15599 minus saline injection (p < 0.001 uncorrected). Z score in color scale, bregma coordinates on the left scale, time scale start at T1 (15 minutes after the beginning of the MRI session).
Figure 6
Figure 6. Topography of the main activated regions after injection of 5-HT1A ligands.
(a) 8-OH-DPAT as a prototypical 5-HT1A agonist. (b) MPPF as a 5-HT1A “silent antagonist” (without any activation). (c) F13714 as a 5-HT1A biased agonist. (d) F15599 as a 5-HT1A biased agonist. Colours indicate the chronology of activation (yellow, T1; orange, T2; red, T3; purple, T4; blue, T5).
Figure 7
Figure 7. phMRI protocol time line.
The 30-min scan was divided into two 15-min sections (pre-injection and post-injection). T0 was the pre-injection scan and included all 300 volumes in the 15-min time bin. The injection scans were divided into five lots of 60 scans time bins (30 min each, T1 to T5).

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