Flinders Resistant Line Rats Research Articles

Brain 5-HT synthesis in the Flinders Sensitive Line rat model of depression: An autoradiographic study

Alterations of serotonin (5-HT) levels and serotonergic transmission have been associated with depression. 5-HT synthesis is an important factor of serotonergic neurotransmission that may also be altered in depression. Many studies of the relationships between brain serotonergic functions and affective disorders have been performed in different animal models. In this study, brain regional 5-HT synthesis was examined using the α-[ 14C]methyl- l-tryptophan (α-MTrp) autoradiographic method in a genetic rat model of depression, Flinders Sensitive Line (FSL) rats, and was compared to both the Flinders Resistant Line (FRL) rats and the control Sprague–Dawley (SD) rats. The plasma concentration of free tryptophan in the FSL rats was not significantly different ( p > 0.05; ANOVA and post-hoc Bonferroni correction) when compared to that of the FRL and SD rats. The FSL rats had significantly lower 5-HT synthesis (one sample two-tailed t-test on the ratio) than both the FRL and SD rats (the mean ratios were 0.78 ± 0.12 and 0.73 ± 0.15, respectively). Overall, the 5-HT synthesis in the FRL rats was not significantly different ( p > 0.05) from that in the SD rats (one sample two-tailed t-test on the ratio and the mean ratio was 0.93 ± 0.13). Studies of individual brain structures, such as the raphe nuclei and their many terminal areas, including the nucleus accumbens, cingulate and frontal cortex, hippocampus, amygdala, and thalamus revealed significant reductions (typically 25–50%) in 5-HT synthesis in the FSL rats compared to the non-depressive FRL and SD rats. These results suggest that significantly reduced 5-HT synthesis in the raphe nuclei and limbic areas in FSL rats may contribute to their depressive features.

Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression

In order to study the gene–environment interaction as well as investigate prophylactic/ameliorative effects of early intervention on development of adult life psychopathology, we superimposed maternal separation on an animal model of depression the Flinders Sensitive Line (FSL) rats and their controls the Flinders Resistant Line (FRL) rats and studied behavior following treatment with escitalopram. Animals were maternally separated for 180 min/day from postnatal day 2 (PND 2) to 14. The control groups were left undisturbed. Treatment with escitalopram or vehicle admixed to food pellets was commenced on PND 43 and continued until PND 73. The Porsolt swim test was carried out on PND 65. Baseline FRL/FSL differences in body weight and swim duration, considered to be an inverse index of depression, were found ( p's < 0.001). In the FSL, maternal separation further decreased swim duration ( p < 0.001) while the FRL strain was unaffected. Escitalopram had no effect in FRL, but increased swim duration in both maternally non-separated and separated FSL ( p < 0.05 and p = 0.001; respectively). These results confirm the strain differences between the FSL and FRL and demonstrate that the long-term effects of early life adverse experience will to a significant degree depend on the genetic make-up of an individual. Finally, antidepressant treatment reversed behavioral abnormalities caused by genetic and environmental factors. This study highlights the importance of genetic factors in susceptibility to early life adverse events, and demonstrates the efficiency of early antidepressant treatment in reversing behavioral abnormalities, both those caused by genetic factors and by environmental factors.

S.04.04 Abnormalities in behaviour and reduction in expression of specific hippocampal genes genes by prenatal stress in female offspring are reversed by neonatal handling

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 α-[14C]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.

Antidepressant-like effects of the vasopressin V1b receptor antagonist SSR149415 in the Flinders Sensitive Line rat

There is an increased interest in the potential of vasopressin receptor antagonists as antidepressants because of the involvement of vasopressin in stress-related behavioral changes. The present study sought to provide confirmatory evidence for the antidepressant-like effects of the selective vasopressin V1b receptor antagonist SSR149415, which had been previously demonstrated in a variety of animal models. The Flinders Sensitive Line (FSL) rat, a selectively bred animal model of depression, was chronically treated for 14 days with SSR149415 (1, 10, and 30 mg/kg), vehicle, or desipramine (5 mg/kg) as a positive control. Approximately 22–24 h after the last treatment, the rats were exposed to a single 5-min session in a cylinder containing 25 °C water and immobility was recorded. A control group of Flinders Resistant Line (FRL) rats was included as a reference group as well as one treated with 10 mg/kg SSR149415. Vehicle-treated FSL rats exhibited much more immobility than the FRL rats, and desipramine-treated FSL rats had much lower scores, as expected. Treatment with SSR149415 reduced immobility in the FSL rats at all doses, but only the higher doses reduced it such that they were no longer different from the FRL rats. In contrast, SSR149415 did not alter the lower immobility of the FRL rats. The social interaction test of anxiety was also examined in the FSL rats, at 20–22 h after the last of the 14 injections. Results showed that the 10 and 30 mg/kg doses of SSR149415 increased the time spent in social interaction in the FSL rats, suggesting anxiolytic effects. These findings confirm the antidepressant-like potential of SSR149415 and suggest that it may also have anxiolytic effects. It is likely that the strategy of testing selective vasopressin V1b receptor antagonists will be fruitful.

Running has Differential Effects on NPY, Opiates, and Cell Proliferation in an Animal Model of Depression and Controls

Physical activity has documented beneficial effect in treatment of depression. Recently, we found an antidepressant-like effect of running in an animal model of depression, the Flinders Sensitive Line (FSL) and demonstrated that it was associated with increased hippocampal cell proliferation. In this study, we analyzed levels of mRNAs encoding the neuropeptide Y (NPY) and the opioid peptides dynorphin and enkephalin in hippocampus and correlated these to cell proliferation in the FSL and in the 'nondepressed' Flinders Resistant Line (FRL) strain, with/without access to running wheels. Running increased NPY mRNA in dentate gyrus and the CA4 region in FSL, but not in FRL rats. NPY mRNA increase was correlated to increased cell proliferation in the subgranular zone of dentate gyrus. Baseline dynorphin and enkephalin mRNA levels in the dentate gyrus were lower in the FSL compared to the FRL strain. Running had no effect on dynorphin and enkephalin mRNAs in the FSL strain but it decreased dynorphin mRNA, and there was a trend to increased enkephalin mRNA in the FRL rats. Thus, it would appear that the CNS effects of running are different in 'depressed' and control animals; modification of NPY, a peptide associated with depression and anxiety, in depressed animals, vs effects on opioids, associated with the reward systems, in healthy controls. Our data support the hypothesis that NPY neurotransmission in hippocampus is malfunctioning in depression and that antidepressive treatment, in this case wheel running, will normalize it. In addition, we also show that the increased NPY after running is correlated to increased cell proliferation, which is associated with an antidepressive-like effect.

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat

In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24-h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.

The antidepressant effect of running is associated with increased hippocampal cell proliferation

A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.

Blunted response to cocaine in the Flinders hypercholinergic animal model of depression

The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. Considering the strong comorbidity between depression and cocaine dependence we investigated the well-documented behavioral and molecular effects of cocaine in the FSL and their control Flinders resistant line (FRL) rats. First, we found no difference between the two lines to establish cocaine self-administration; both lines reached stable responding within 10 days of training at a fixed ratio-1 schedule of reinforcement (1.5 mg/kg/injection). However, the FSL rats exhibited reduced cocaine intake at a dose of 0.09 mg/kg/injection in a within-session dose-response curve (0.02, 0.09, 0.38, 1.5 mg/kg/injection). Second, we examined the effects of repeated cocaine administration on locomotor activity, dopamine overflow and striatal prodynorphin mRNA expression. We found the FSL rats to be low responders to novelty and to exhibit less locomotor activation after repeated cocaine administration (30 mg/kg, i.p., daily injections for 10 days) than their controls. Microdialysis sampling from the nucleus accumbens shell revealed no significant difference in the dopamine overflow between the rat lines, neither during baseline nor after cocaine stimulation. Postmortem analyses of striatal prodynorphin mRNA expression (using in situ hybridization histochemistry) revealed a differentiated response to the cocaine exposure. In contrast to control FRL rats, the FSL rats showed no typical cocaine-evoked elevation of prodynorphin mRNA levels in rostral subregions of the striatum whereas both strains expressed increased prodynorphin mRNA levels in the caudal striatum after cocaine administration. In conclusion, the FSL animal model of depression demonstrates marked blunting of the locomotor and dynorphin neuroadaptative responses to cocaine in accordance with its enhanced cholinergic sensitivity.

Pseudo‐affective visceromotor responses and HPA axis activation following colorectal distension in rats with increased cholinergic sensitivity

We analysed visceromotor (VMR) and corticosterone responses to colorectal stimuli under control conditions and following acoustic stress in rats selectively bred for increased sensitivity to cholinergic agonists, the Flinders Sensitive Line (FSL) rats, compared with Flinders Resistant Line (FRL) rats. FSL rats demonstrated a significant VMR response at the smallest distension pressure, whereas no response was evident in FRL controls. FSL rats also demonstrated enhanced VMR responses at both larger distension levels compared with FRL rats. Colorectal distension (CRD) produced significant increases in serum corticosterone levels, which were comparable in FRL and FSL. Noise stress induced divergent corticosterone responses in FRL and FSL, but did not affect VMR to CRD in either group. These data suggest that FSL rats show altered VMR responses to CRD and disturbed hypothalamic-pituitary-adrenal axis responses to acute stress.

Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression

Due to the interest in the antidepressant potential of nonpeptide corticotropin-releasing factor (CRF)1 receptor antagonists, the present investigation examined the antidepressant-like effects of the CRF1 receptor antagonist CP-154,526 on the exaggerated swim test immobility in the Flinders Sensitive Line (FSL) rat, a genetic animal model of depression. Chronic treatment with CP-154,526 (10 mg/kg; 2× day) for 14 days increased swimming in the Flinders Sensitive Line rats. Citalopram (5 and 10 mg/kg; 2× day) and desipramine (5 mg/kg; 1× day) also significantly increased swimming in the Flinders Sensitive Line rats, as expected. However, neither CP-154,526 nor citalopram (10 mg/kg) altered swimming times in the control Flinders Resistant Line (FRL) rats. Citalopram (10 mg/kg) and CP-154,526 also increased the abnormally low level of social interaction behavior in the Flinders Sensitive Line rats. These findings indicate that citalopram and CP154,526, a CRF1 receptor antagonist, have both antidepressant and anxiolytic effects that can be detected in an experimental model of depression only and not in “normal” control animals.

Phenotypic differences in cholinergic responses of distal colonic epithelium.

The Flinders sensitive line (FSL) rats exhibit an increased cholinergic responsiveness in vivo when compared to their counterparts, the Flinders resistant line (FRL) rats. The functional consequences of this phenotypic difference on colonic mucosal function are not known. We sought to determine whether isolated distal colonic mucosa from the two strains exhibit differential responses to cholinergic agonists. The responses of the distal colonic mucosa from two lines of rats to carbachol were compared by recording changes in short-circuit current. The ion movements associated with these changes were assessed by flux analysis of the radiotracers, 22Na and 36Cl. The anticipated hyper-responsiveness to cholinergic stimulation in FSL rats was not seen. Carbachol responses were significantly enhanced by indomethacin pretreatment only in FRL rats. Tetrodotoxin (TTX) pretreatment significantly reduced responses to carbachol in FSL rats at all concentrations tested, though this was only seen with lower concentrations in FRL rats. Flux analysis indicated that both lines absorbed Na+ and Cl- under basal conditions and that a significant residual flux was present. Stimulation with carbachol led to significant reductions in net Na+ and Cl- fluxes in both lines. The changes in net Na+ and Cl- flux in both lines stem largely from a decrease in mucosal to serosal fluxes of both ions with an increase in serosal to mucosal flux of Cl-. The striking difference is the significant reduction in residual flux seen only in FRL rats. Indomethacin pretreatment abolished the changes in residual flux seen in FRL rats. Thus the responses to carbachol in these rats had at least three components: (a) a direct effect on the transporting colonocyte, (b) an indirect effect mediated by an arachidonic acid metabolite, and (c) another indirect effect involving a neurotransmitter. The relative contributions of each of these components were different in the two lines.

Flinders sensitive line (FSL) rats have increased gastric accommodation capacity compared to flinders resistant line (FRL) and sprague dawley (SD) rats

Flinders sensitive line (FSL) rats have increased gastric accommodation capacity compared to flinders resistant line (FRL) and sprague dawley (SD) rats

Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of a rat model of depression

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Moreover, it has been hypothesized that these molecules play a role in the pathophysiology as well as treatment of depression. Using an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL), we investigated the effects of electroconvulsive stimuli (ECS) on brain NGF and BDNF. ECS or SHAM ECS were administered eight times, with a 48-h interval between each treatment. NGF and BDNF were measured with enzyme-linked immunosorbent assay (ELISA). In the hippocampus ECS increased NGF concentration in FSL but not FRL rats. ECS decreased NGF concentration in the frontal cortex of FSL rats. In both FSL and FRL rats ECS increased NGF levels in the striatum. In contrast, ECS did not change BDNF concentration in hippocampus, frontal cortex and striatum of FSL and FRL rats. Our data support the notion that neurotrophin concentrations may be altered by ECS.

Reduced primary antibody responses in a genetic animal model of depression.

Clinical depression is associated with multiple abnormalities of immune function, including reduced virus-specific responses. This study tested the hypothesis that the Flinders Sensitive Line (FSL) rat, a promising genetic animal model of depression, would exhibit reductions in antigen-specific primary antibody responses to immunization. FSL (N = 13) and control Flinders Resistant Line (FRL; N = 14) rats were immunized with the protein antigen keyhole limpet hemocyanin (KLH; 300 microg/kg), and KLH-specific immunoglobulin (Ig)M, IgG, IgG1, and IgG2a responses were measured before and 3, 5, 7, 11, and 14 days after immunization. In separate experiments, production of interferon-gamma (IFN-gamma) by cells from naive and KLH-immunized animals was measured in vitro to determine whether strain differences in antibody production might be associated with differential production of this regulatory cytokine. KLH-specific production of IgM (p <.01) and IgG2a (p <.05) was significantly reduced in the FSL rats compared with the FRL controls. There were no strain differences in IgG or IgG1 production. Although IFN-gamma production between the two strains was similar in naive animals, cells from KLH-immunized FSL rats produced significantly less IFN-gamma when stimulated with KLH in vitro than cells from KLH-immunized FRL controls (p =.01). This study extends previous reports of altered immune function in the FSL rats to include reduced in vivo antigen-specific antibody responses. Moreover, diminished production of IFN-gamma by KLH-primed lymphocytes may contribute to lower antibody production in these animals. Collectively, these data suggest deficiencies in type 1 T-helper cell-mediated immunity in the FSL rats.

Increased density of galanin binding sites in the dorsal raphe in a genetic rat model of depression

The Flinders Sensitive Line rats showed an increased immobility response by 104% (P<0.01) in the forced swim test with respect to the Flinders Resistant Line rats (control). The Flinders Sensitive Line rats also had an increase of [125I]galanin (porcine) binding in the dorsal raphe (55±3.3 fmol/mg protein) with respect to the Flinders Resistant Line rats (38±3.6 fmol/mg protein) (42%, P<0.05) without changes in galanin receptor affinity and with a significant reduction (32.3%, P<0.05) of galanin-like immunoreactivity in the dorsal raphe. The results indicate that enhancement of galanin receptor function in the dorsal raphe rich in 5-HT neurons could be a mechanism involved in the production of depressive-like activity in this animal model of depression.

A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma.

The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in chemical intolerance in humans.

Changed Concentrations of Tachykinins and Neuropeptide Y in Brain of a Rat Model of Depression: Lithium Treatment Normalizes Tachykinins

Lithium's therapeutic mechanism of action is unknown. In lithium-treated normal rats, increased striatal concentrations of neurokinin A (NKA)-like immunoreactivity (LI), substance P (SP-LI) and neuropeptide Y (NPY-LI) have been reported. To investigate whether these effects might be of therapeutic relevance, Flinders Sensitive Line rats (FSL), an animal model of depression, and control Flinders Resistant Line (FRL) rats were during a 6-week period fed chow to which either lithium or vehicle was admixed. Following sacrifice, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. NKA-LI and SP-LI were markedly decreased in striatum and increased in frontal cortex in FSL compared to control FRL animals. Lithium treatment abolished these differences. Basal concentrations of NPY-LI were decreased in hippocampus of FSL rats, but unaffected by lithium. The present study suggests that changed tachykinins and NPY may underlie the characterized depressive-like phenotype of the FSL rats. It is hypothesized that altering tachykinin peptidergic neurotransmission in striatum and frontal cortex constitutes a mechanism of action of lithium and that such a mechanism might be of therapeutic relevance.

Neuropeptide Y in male and female brains of flinders sensitive line, a rat model of depression. Effects of electroconvulsive stimuli

Human and animal studies suggest that neuropeptide Y (NPY), a peptide co-localized and co-released with classical neurotransmitters, is involved in the pathogenesis of affective disorders. In addition, lithium, electroconvulsive treatments (ECT in humans and ECS in rodents) and antidepressants affect NPY in a specific temporal- and brain-region fashion. These results have been obtained on healthy male rats; females and/or “depressed” animals have essentially not been studied. Consequently, we studied brain NPY-like immunoreactivity (-LI) under basal conditions and following a series of ECS in both male and female Flinders Sensitive Line (FSL), an animal model of depression, and their controls, the Flinders Resistant Line (FRL) rats. Furthermore, we examined whether the oestrus cycle affects NPY-LI in these strains. Following sacrifice by focused microwave irradiation, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. Hippocampal NPY-LI in both sexes was significantly lower in the “depressed” FSL compared to the control FRL. ECS increased NPY-LI in both male and female rats in both FSL and FRL strains in hippocampus, frontal cortex and occipital cortex. In the hypothalamus, the increase was found only in the FSL rats. In both FSL and control rats, the basal NPY-LI was lower in the hippocampus of female compared to male rats. NPY-LI did not vary during the different phases of the oestrus cycle. These results suggest that the gender differences are not due to NPY-LI variations during the oestrus. The results are consistent with our hypothesis that NPY plays a role in the pathophysiology of depressive disorders and provide further evidence that one of the modes of ECS action is to elevate NPY in the limbic system. Assumption that gender differences in NPY could explain increased rates of depression in women is speculative, but is in line with the findings in the present study.

Neuropeptide Y in brains of the Flinders Sensitive Line rat, a model of depression. Effects of electroconvulsive stimuli and d-amphetamine on peptide concentrations and locomotion

Neuropeptide Y (NPY), has been implicated in the pathophysiology of depression and the mechanisms of action of electroconvulsive treatment (ECT). In this series of experiments, we explored whether there are differences between Flinders Sensitive Line (FSL) rats, an animal model of depression, and controls, Flinders Resistant Line (FRL) in (1) baseline brain NPY-LI concentrations, (2) effects of ECS on locomotion and brain neuropeptides, (3) amphetamine effects on behavior, and (4) effects of ECS pretreatment on subsequent effects of amphetamine on behavior. Both strains were divided into two groups, receiving eight ECS or ShamECS. Twenty-four hours after the last session, animals were habituated in activity boxes for 45 min before given d-amphetamine (1.5 mg · kg −1, subcutaneously) or vehicle. Locomotor activity was then recorded for an additional 45 min. Twenty-four hours later, rats were sacrificed by microwave irradiation, the brains dissected into frontal cortex, occipital cortex, hippocampus, hypothalamus and striatum, and the neuropeptides extracted and measured by radioimmunoassay. No differences between FSL and FRL rats in baseline locomotor activity were found. FSL compared to FRL animals showed a significantly larger locomotion increase following saline and a significantly smaller increase following amphetamine. ECS pretreatment significantly decreased the saline effects on locomotion in the FSL and the amphetamine effects in the FRL rats. ‘Baseline’ NPY-like immunoreactivity (LI) concentrations were lower in the hippocampus of the ‘depressed’ rats. ECS increased NPY-LI in frontal cortex, occipital cortex and hippocampus of both strains. The hippocampal NPY-LI increase was significantly larger in the FSL compared to FRL animals.

Depressive Characteristics of FSL Rats: Involvement of Central Nicotinic Receptors

Antidepressant effects of acute or chronic nicotine treatments in swim test immobility of Flinders sensitive line (FSL) rats, an animal model of depression, were recently demonstrated (Tizabi et al. Psychopharmacology 142:193, 1999). In the present study we sought to determine whether the antidepressant effects of nicotine could be blocked by the nicotinic antagonist, mecamylamine (MEC). Moreover, the effects of chronic nicotine treatment on [ 3H]cytisine binding in discrete brain regions of FSL and their control Flinders resistant line (FRL) rats were also evaluated. Adult male FSL rats were treated with MEC (0.5 mg/kg) 20 min prior to an acute or chronic nicotine administration. MEC by itself did not affect the immobility in swim test. However, it completely blocked the acute or chronic nicotine effects. Daily nicotine injection (0.4 mg/kg/day for 14 days) resulted in an increase in [ 3H]cytisine binding primarily in the FRL rats. An increase in nicotinic receptor binding following chronic nicotine administration is believed to reflect desensitization of these receptors. These findings, coupled with previous observation of higher basal nicotinic receptors in FSL rats, further support the involvement of central nicotinic receptors in depressive characteristics of these rats. Moreover, the data suggest therapeutic potential for selective nicotinic receptor agonists in depressive disorders.