A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats

Abstract

Deficiencies in brain serotonergic neurotransmission, which is in part associated with the alteration of brain serotonin (5-HT) receptors, have been proposed as part of a neurochemical imbalance in affective disorders, including depression. The drugs used for the treatment of these disorders generally act through and/or on the serotonergic system. Different animal models of depression have provided researchers with tools to obtain a better understanding of drug actions and possibilities to obtain insight into the neurochemical bases of these disorders. The measurements of the 5-HT 1A and 5-HT 1B receptor densities in a rat model of depression, Flinders Sensitive Line (FSL) rats, and comparisons with Sprague-Dawley (SPD) and Flinders Resistant Line (FRL) rats, are reported here. The receptor sites were quantified by autoradiography in more than twenty-five distinct brain regions known to have relatively large densities of respective sites. Some brain regions (e.g., dental gyrus, septal nucleus) were divided into several parts, according to previously known subdivisions, because of a substantial heterogeneity of these receptors. The densities in the FSL rats ("depressed" rats) were compared statistically to those in the SPD rats. In addition, comparisons were made to the densities in the FRL rats (rats not showing depressive symptoms). Comparisons were performed with the SPD and FRL rats because both of these strains have been used as control animals in studies of FSL rats. The results show that the densities of 5-HT 1A receptors are not significantly different between the FSL and SPD rats, but they are significantly different from the FRL rats. 5-HT 1A receptor density is significantly higher in the FRL rats than the SPD rats. The 5-HT 1B receptors were significantly greater in the FSL rats than in either the SPD or FRL rats. In addition, the FRL rats have 5-HT 1B receptor densities significantly lower in many brain regions than the SPD rats. The data presented here, in addition to previously reported differences in regional synthesis between these strains and the effect of acute citalopram on synthesis, suggest that SPD rats are likely a more appropriate control than FRL rats, when studies of FSL rats are performed with drugs acting directly or indirectly on, or through, the brain serotonergic system. However, comparisons, particularly of neurochemical and/ or biological parameters in FRL rats, may reveal new insight into the alterations of 5-HT neurotransmission in this animal model of depression and possibly human depression, as well as the elevation of symptoms with treatments. The data also suggest that there could be a different fraction 3Correspondence to:

The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing

“…Diksic and colleagues also reported the following serotonergic changes in the FSL rats: 1) increased 5-HT1B receptors (Nishi et al, 2009a); 2) decreased 5-HT1A receptors (Sato et al, 2011); 3) greater ability of fluoxetine to reduce serotonin transporter expression (Kova cevi c et al, 2010); 4) increased brain glucose utilization , although it remains unclear how this observation relates to reports on serotonergic abnormalities; and 5) decreased levels of metabotropic glutamate receptor 5 compared with those observed in SD and FRL rats (Kova cevi c et al, 2012).…”

Neurochemical and Behavioural Changes in Rat Models of Depression

“…In the FRL rats, chronic buspirone treatment induced decreased 5-HT synthesis in half of the regions tested (including most of the cortical regions, nucleus accumbens, medial and lateral geniculate and dorsal raphe), but there was otherwise no change in the other half. 141 These discrepant effects of the drugs acting on the 5-HT system in the FSL and FRL rats suggest a different regulation of 5-HT synthesis in those strains, which may be due to the different densities of the key receptors regulating 5-HT synthesis, such as the lower densities of 5-HT 1A and higher densities of 5-HT 1B in the FSL rats, 29 the receptor sites serving as autoreceptors in the cell bodies and terminal regions, respectively.…”

Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

“…The cholinergic hypersensitivity gives rise to changes in other neurotransmitter systems, because the FSL rat has lower density of 5-HT 1A receptors but a higher density of 5-HT 1B receptors in several brain regions compared with those of the FRL rat (Nishi et al, 2009). In the rat forced swim test, FSL rats display depressive-like behavior that is reversed by antidepressants (Wegener et al, 2011).…”