AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats

Abstract

The neurotransmitter, serotonin, is involved in several brain functions, including both normal, physiological functions, and pathophysiological functions. Alterations in any of the normal parameters of serotonergic neurotransmission can produce several different psychiatric disorders, including major depression. In many instances, brain neurochemical variables are not able to be studied properly in humans, thus making the use of good animal models extremely valuable. One of these animal models is the Flinders Sensitive Line (FSL) of rats, which has face, predictive and constructive validities in relation to human depression. The objective of this study was to quantify the effect of the tryptophan hydroxylase (TPH) activation inhibitor, AGN-2979, on the FSL rats (rats with depression-like behaviour), and compare it to the effect on the Flinders Resistant Line (FRL) of rats used as the control rats. The effect was evaluated by measuring changes in regional serotonin synthesis in the vehicle treated rats (FSL-VEH and FRL-VEH) relative to those measured in the AGN-2979 treated rats (FSL-AGN and FRL-AGN). Regional serotonin synthesis was measured autoradiographically in more than 30 brain regions. The measurements were performed using alpha-[(14)C]methyl-l-tryptophan as the tracer. The results indicate that AGN-2979 did not produce a significant reduction of TPH activity in the AGN-2979 group relative to the vehicle group (a reduction would have been observed if there had been an activation of TPH by the experimental setup) in the FSL rats. On the other hand, there was a highly significant reduction of synthesis in the FRL rats treated by AGN-2979, relative to the vehicle group. Together, the results demonstrate that in the FSL rats, AGN-2979 does not affect serotonin synthesis. This suggests that there was no activation of TPH in the FSL rats during the experimental procedure, but such activation did occur in the FRL rats. Because of this finding, it could be hypothesized that TPH in the FSL rats cannot be easily activated. This may contribute to the development of depressive-like symptoms in the FSL rats ("depressed" rats), as they cannot easily modulate their need for elevated amounts of this neurotransmitter, and possibly other neurotransmitters. Further, because these rats represent a very good model of human depression, one can hypothesize that humans who do not have readily activated TPH may be more prone to develop depression.

Figure 1

A set of autoradiograms exemplifying regional differences between 5-HT synthesis in the FSL and FRL rats. The control rats were treated with a vehicle (FSL-VEH and FRL-VEH) while the treatment group was treated with 10 mg/kg of AGN-2979. The meanings of the abbreviations are provided in the list of abbreviations.

Figure 2

The changes in regional synthesis were calculated relative to the synthesis in the control treated rats for the brain regions in which significant effects were observed in the FRL rats. The error bars are SEM. The bar graph clearly depicts the variability of the effect of the AGN-2979 treatment in the FRL rats and a lack of significant effect in the FSL rats. In addition, it shows the similarity of the effects in the FRL and normal SPD rats. The values of the x-axis correspond to brain regions as follows: 1=CxCin; 2=CxEnt; 3=CxF; 4=CxP; 5=CL; 6=AMY; 7=AN; 8=AONu; 9=DS; 10=HiD; 11=DR; 12=MR; 13=Rpo; 14=CPL; 15=GP; 16=SNc; 17=SNr; 18=ThD; 20=ThV; 21=LG; 22=MBF. The meanings of these abbreviations are provided in the list of abbreviations. The symbol indicates the regions in which AGN-2979 produced a significant effect in FRL rats following FDR correction. The effects in all of the brain regions of SPD rats, used as comparisons, were significant (Hasegawa et al. 2005).