The Flinders Sensitive Line of rats, a rat model of depression, has elevated brain glucose utilization when compared to normal rats and the Flinders Resistant Line of rats
Introduction
It is generally accepted that human depression is a very complex disorder which involves both the brain and extra cranial systems (Fava and Kendler, 2000, Hyman and Nestler, 1996, Vaidya and Duman, 2001, Maes et al., 2008a, Maes et al., 2008b). The involvement of many different systems in the body certainly creates complex interactions which are probably, in part, responsible for the heterogeneity of the patient sample itself, as well as the heterogeneity of the responses to treatment. Common pathways of the brain neuronal activities are likely reflected in cerebral glucose utilization. Because of this, measurements of regional glucose utilization could be very useful in assessing the overall changes in neuronal activities associated with brain biochemical activities, both at a normal state level and in some disease states.
Animal models of depression should have three different distinct values: (1) face validity (how closely the model resembles the psychiatric condition); (2) construct validity (consistency of the model with the theoretical rationale); and (3) predictive validity (how closely the action of the drugs in the model resemble the actions of these drugs in the human disease) (Willner and Mitchell, 2002, Yadid et al., 2000). The FSL rat model of human depression possesses all of these three values (Yadid et al., 2000), with a relatively large number of similarities to the human disease. A very important aspect of an animal model of depression is the alleviation of behavioral depressive symptoms following chronic, but not acute, treatment with antidepressants, and this aspect is also present in the FSL model (Overstreet, 2002, Yadid et al., 2000). In this study, we report measurements of glucose utilization in both the FSL and FRL rats and compare the rCGlu in these strains with those in the SPD rats and normal, control rats. The measurements were performed using the 2-DG autoradiographic method (Sokoloff et al., 1977).
It is probably the best approach to use well defined animal models, at least for certain parameters overlapping between the human disorder and the animal model of depression. One good animal model of depression is the Flinders Sensitive Line (FSL) of rats, which has many similarities to withdrawn human depression (Overstreet et al., 2005, Yadid et al., 2000). The FSL rat model of depression meets all three requirements for a good animal model (see above). It was derived from Sprague–Dawley rats by selective breeding and has been defined as a phenotype with a behavioral supersensitivity to diisopropyl fluorophosphate (Overstreet et al., 1979, Russell et al., 1982). A second line derived in the same breeding has a sub-sensitivity to the same agent and has been termed the Flinders Resistant Line (FRL). There have been many behavioral, endocrine, receptor, and 5-HT synthesis studies performed (Overstreet et al., 2005, Yadid et al., 2000, Hasegawa et al., 2006, Nishi et al., 2009a, Nishi et al., 2009b, Kanemaru et al., 2008, Kanemaru et al., 2009) in FSL rats, but there has not been a systematic evaluation of glucose utilization in this animal model of depression. Glucose is the major source of energy for brain biochemical processes. Because of the discrepancies reported in human studies measurements (e.g. Videbech, 2000, Drevets et al., 1998) in a good animal model of depression, like FSL rats, became essential. This knowledge could assist us in better understanding the many neurochemical and behavioral differences (abnormalities) present in this rat model of depression, and possibly allow us to extrapolate to human depression.
Through the years, many studies, using positron emission tomography (PET), of regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGlu) in depressed patients have been conducted. Unfortunately, the results are very heterogeneous. There have been reports in which rCGlu was found to be increased in depressed patients relative to the normal controls, and other reports in which rCGlu was found to be decreased in depressed patients relative to the controls (Videbech, 2000, Drevets et al., 1998). Because of these contradictory results, which in part could be related to the heterogeneity of the clinical samples, studies of regional glucose utilization in good animal models (homogeneity of sample is insured) of depression could be very informative and helpful in understanding the biochemical differences between depressed patients and normal subjects. Similar findings, as those mentioned above, for rCGlu, have been reported when comparing the rCBF between normal subjects and people diagnosed with depression (e.g., Uytdenhoef et al., 1983).
Studies have also been done in which rCBF and rCGlu were measured prior to, and following, treatment with antidepressants (e.g., Mayberg et al., 1999, Mayberg et al., 2000, Smith et al., 2002a, Smith et al., 2002b) using PET. One of the repeated findings has been the reduction of glucose utilization in the frontal brain regions, including the anterior cingulate and the prefrontal cortex in depressed patients and the normalization of glucose utilization in patients following successful treatments with antidepressants (Mayberg et al., 1997, Mayberg et al., 1999, Smith et al., 2002a, Smith et al., 2002b). These studies suggested that measurements of the rCGlu may be informative in our understanding of depression and treatment with antidepressants, despite the fact that glucose utilization does not describe a well defined brain biochemical process. At the same time, these studies also pointed to the fact that depression is a rather heterogeneous disorder and, as such, the studies are very often contradictory and not particularly easy to understand or to accept as conclusive of general concepts. The PET measurements were performed using 18F-labelled 2-fluoro-2-deoxy-glucose (FDG), based on the deoxyglucose model developed in rats using 14C-labelled 2-deoxy glucose (2-DG) (Sokoloff et al., 1977). The 2-DG autoradiographic method is based on a 3-rate constant and 3-compartment (plasma, precursor and metabolic) biological model. This autoradiographic method permits the quantitative determination of glucose utilization in a relatively large number of brain regions and with a reasonably sound special resolution; approximately 0.1 mm (Goochee et al., 1980), permitting a qualitative visualization of structures as small as 0.025 mm (Sokoloff, 2008).
On the basis of monoaminergic (both dopaminergic and serotonergic; Zangen et al., 1997, Zangen et al., 1999, Dremencov et al., 2004, Hasegawa et al., 2006), behavioral (Yadid et al., 2000, Overstreet et al., 2005), receptor densities (Nishi et al., 2009b) and other neurochemical differences (Yadid et al., 2000, Overstreet et al., 2005) between FSL and SPD rats, it was hypothesized that glucose utilization (as a reflection of the sum of both excitatory and inhibitory inputs; both require energy) will be elevated in the FSL rats relative to the normal SPD rats. This elevation will be particularly pronounced in the brain limbic regions (e.g., amygdala, accumbens, hippocampus), and the dopaminergic and serotonergic cell body structures (e.g., dorsal raphe (DR) and median raphe (MR), ventral tegmental area (VTA).
Section snippets
Materials and methods
The studies were performed on SPD (N = 6), FSL (N = 8), and FRL (N = 6) male rats weighing between 207 and 270 g. There were no significant differences between the mean weights or ages of rats in different groups [mean ± SD; 242 ± 5 g (SPD); 249 ± 22 g (FSL); 241 ± 24 g (FRL)]. Similarly, there was no significant difference in the ages (around 60 days old) of FSL and FRL rats, while the exact age of the SPD rats was not available. The SPD rats were obtained from Charles River, Quebec, Canada (St. Constant,
Results
There was no significant difference in the physiological parameters (, , pH, body weight, and hematocrit) between the different groups of rats, and all of the values were within normal range, as reported in previous experiments (Hasegawa et al., 2006, Kanemaru et al., 2008). However, there was a significant difference (F(2,17) = 20.6; p < 0.001) in the blood glucose measurements (mean ± SD) between the FSL (blood glucose = 163 ± 15 [mg/100 ml]) and other two strains (SPD glucose = 129 ± 12 [mg/dl]; FRL
Discussion
The most important findings of this study are elevated glucose utilization in the naïve FSL rats relative to the normal SPD rats in many limbic brain regions (Table 1; Fig. 2) shown in previous studies in humans to be relevant to depressive states (Drevets et al., 1998, Videbech, 2000). In addition, in humans, antidepressant treatments influenced rCGlu in many of these limbic structures. Also, there is a higher glucose utilization in the FSL “depressed” rats relative to the “non-depressed” FRL
Acknowledgements
This work was supported by the Croatian Ministry of Science, Education and Sport (219-1081970-2032) and the Canadian Institute for Health Research (MOP-42438). The authors wish to thank Ms. Valerie Ann Cherneski for her editorial help, and Dr. D.H. Overstreet for generously providing the breeding pairs of FSL and FRL rats.
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Permanent address: Department of Neurosurgery, University of Yamanashi, 1110 Shimokato Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan.