Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors

Abstract

1. The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in KD for specific [3H]paroxetine binding, and the in vivo SERT-binding potency was in the order of paroxetine>>fluoxetine, sertraline>fluvoxamine. 2. The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long-lasting binding activity of brain SERT after the fluoxetine administration. 3. Oral administration of each SSRI suppressed significantly the marble-burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble-burying behaviour correlated significantly with their brain SERT binding activities. 4. In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT-binding characteristics is closely associated with the pharmacokinetics and inhibition of marble-burying behaviour.

Figure 1

Relationship between oral doses of SSRIs and brain SERT-binding activity (percent increase in K_D values for specific [³H]paroxetine binding). Mice received fluvoxamine (6.91–69.1 μmol kg⁻¹), fluoxetine (2.89–28.9 μmol kg⁻¹), paroxetine (0.27–2.67 μmol kg⁻¹) and sertraline (2.92–29.2 μmol kg⁻¹) orally, and the mean values at the times when plasma drug concentration and SERT-binding activity became maximal (0.5 or 1 h for fluvoxamine, 4 h for fluoxetine, paroxetine and sertraline) were utilised for linear-regression analysis. Each point represents mean±s.e.m. of four to five mice.

Figure 2

Time courses of brain SERT-binding activity (percent increase in K_D values for specific [³H]paroxetine binding) (a) and plasma concentration (b) at 0.25 to 48 h after oral administration of fluvoxamine (69.1 μmol kg⁻¹), fluoxetine (28.9 μmol kg⁻¹), paroxetine (2.67 μmol kg⁻¹) and sertraline (29.2 μmol kg⁻¹). The plasma concentration of norfluoxetine was also plotted. Each point represents mean±s.e.m. of three to five mice.

Figure 3

Effects of oral administration of fluvoxamine (a, 69.1 μmol kg⁻¹), fluoxetine (b, 28.9 μmol kg⁻¹), paroxetine (c, 2.67 μmol kg⁻¹) and sertraline (d, 29.2 μmol kg⁻¹) on the marble-burying behaviour in mice. At 0.25–48 h after the oral administration of these drugs, mice were placed into the cubic plastic box in which 20 glass marbles were evenly spaced on sawdust, and the number of marbles buried at least two-thirds was counted for 30 min. Each column represents mean±s.e.m. of five to eight (vehicle-treated group) and six to nine (SSRI-treated group) mice. Asterisks show a significant difference from the vehicle control values, ^*P<0.05, ^**P<0.01, ^***P<0.001.

Figure 4

Effects of oral administration of fluvoxamine (69.1 μmol kg⁻¹), fluoxetine (28.9 μmol kg⁻¹), paroxetine (2.67 μmol kg⁻¹) and sertraline (29.2 μmol kg⁻¹) on the locomotor activity in mice. At 1–48 h after the oral administration of SSRIs, the total locomotor activity of mice for 30 min was measured by an activity sensor. Each column represents mean±s.e.m. of eight (vehicle-treated group) and five to eight (SSRI-treated group) mice.

Figure 5

Relationship between binding activity of brain SERT (percent increase in K_D values for specific [³H]paroxetine binding) and inhibitory effect of marble-burying behaviour (percent decrease in the number of marbles buried by mice) after oral administration of fluvoxamine (69.1 μmol kg⁻¹), fluoxetine (28.9 μmol kg⁻¹), paroxetine (2.67 μmol kg⁻¹) and sertraline (29.2 μmol kg⁻¹). The data for brain SERT-binding activity and suppression of marble-burying behaviour were derived from Figure 2 and Figure 3, respectively. The mean values at each time point were utilised for correlation analysis, where y, x and r represent inhibitory effect of marble-burying behaviour, brain SERT-binding activity and correlation coefficient, respectively.