Chronic fluoxetine treatment has a larger effect on the density of a serotonin transporter in the Flinders Sensitive Line (FSL) rat model of depression than in normal rats

Abstract

The 5-hydroxytryptamine system is thought to play a crucial role in the pathophysiology of depression and represents the target for selective 5-HT reuptake inhibitors (SSRIs). Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were bred from Sprague-Dawley (SPD) rats to produce strains with increased (FSL) or decreased (FRL) sensitivity to the cholinesterase inhibitor. The FSL rats have been identified as a good model of depression. Many studies in normal rats showed that chronic treatments with SSRIs reduce the densities of SERT. The objective of the present investigation was to assess the influence of chronic fluoxetine treatment on SERT density (Bmax; fmol/mg) in the FSL rat model of depression, relative to that in the FRL rats and SPD rats. FSL, FRL and SPD rats were randomly assigned into groups receiving the vehicle or 10 mg/kg of fluoxetine i.p. for 14 days. Binding was assessed by incubating the brain sections in a buffer containing 20 pM of [(125)I]-RTI-55 [[(125)I](-)-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane and 200 nM of GBR12935 [1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine]. The fluoxetine treatment reduced B(max) in all three rat strains when the saline and respective fluoxetine groups were compared (e.g., the FSL-SAL relative to FSL-FLX groups). Chronic fluoxetine treatment reduces the densities of SERT in the FSL rats to a larger extent than in the normal SPD control rats.

Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: A [123I]β-CIT SPECT study

“…Chronic SSRI treatment has been reported to reduce SERT B max in a quantitative autoradiographic study of rat brain, i.e. (Kovacevic et al, 2010), but the possibility of carryover of medication was not addressed in that study. At least in HEK293 cells, incubation with an SSRI evoked internalization of SERT, which would predict lower binding in vivo (Lau et al, 2008).…”

Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good

“…Consequently, extracellular levels in the forebrain return to equilibrium levels with prolonged treatment (Popa et al, 2010). There are other changes that take place with chronic antidepressant use to maintain homeostasis, including alterations in the density and functioning of serotonin receptors, transporters, and enzymes (Holt and Baker, 1996; Hyman and Nestler, 1996; Adell et al, 2005; Kovacevic et al, 2010). …”

Monitoring serotonin signaling on a subsecond time scale

“…Across brain regions, brain slice and in vivo voltammetric measurements report similar values of t 1/2 ranging from approximately 1 to 3 seconds (O'Connor and Kruk, 1994; Iravani et al, 1999; Davidson and Stamford, 2000; Hashemi et al, 2012). Rates of neurotransmitter clearance may positively correlate with the density of transporter sites in a given brain region: Bunin et al (1998) report clearance rates of 1300 ± 20 nM/s in the DRN and 570 ± 70 nM/s in the SNr, and quantitative autoradiographic studies report 2–4-fold greater SERT binding levels in the DRN (Kovachich et al, 1988; Kovacevic et al, 2010). However, some comparisons of SERT density across brain regions do not support this conclusion, particularly in species other than rat, so more thorough investigation of the relationship between transporter expression and SERT density is needed.…”