The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression.

Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT(1B) agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[(14)C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT(1B) agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT(1B) receptors.

Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: an autoradiographic study.

Depression is a brain disorder and there is still only a partial understanding of its underlying pathophysiology. Antidepressant medications with a fast onset have not yet been developed. In addition to the monoaminergic systems, the brain glutaminergic system has been implicated in the etiology of depression. Animal studies of depression have gained importance because they permit a more invasive manipulation of the subjects than human studies. In the present study, we measured the densities of the brain regional metabotropic glutaminergic receptor 5 (mGluR5) in the Flinders Sensitive Line (FSL) rat model of depression and two groups of control rats, the Flinders Resistant Line (FRL) and Sprague Dawley (SPD), the parent strain for both the FSL and FRL rats. The FSL rats showed lower densities of mGluR5 in many brain regions compared to either the SPD and/or FRL rats. In addition, the densities in the FRL rats were larger than in the SPD rats, suggesting possible problems in using FRL rats as controls. The presented data suggest that mGluR5 is lower in animal models of depression which could be related to the cognitive and emotional dysfunctions in the FSL rat model of depression and could be relevant to a better understanding of depression in humans.

Upregulated arachidonic acid signalling in the olfactory bulbectomized rat model of depression.

The olfactory bulbectomized rat is an animal model of depression with a number of neurochemical, neuroendocrinological and behavioural features resembling human depression. Arachidonic acid (AA) is a second messenger released from the neuronal membrane phospholipids following the stimulation of the receptors coupled with G-proteins to the cytosolic phospholipase A (cPLA(2)) signalling pathway. The signalling of several neurotransmitter systems which are deregulated in OBX rats (serotonergic, dopaminergic, cholinergic, and glutamatergic) converges on the cPLA(2) signalling pathway. The aim of the present study was to assess the incorporation coefficient k* [ml/g/s] of AA in a large number of brain regions in the OBX rat, as a parameter reflecting AA turnover. Male Sprague-Dawley rats (160-200 g) were randomly assigned into an intact Sprague-Dawley (SPD) group, a Sham-operated (SHAM) group or an olfactory bulbectomized (OBX) group (n=5 per group). Two weeks following the surgeries (SHAM and OBX rats) or without any prior intervention (SPD rats), the k* was measured using [1-(14)C] AA autoradiography. Two-way ANOVA followed by the Newman-Keuls test revealed the following: (1) significantly increased AA turnover in the OBX rats, relative to the SHAM rats, in 17 out of 27 assessed brain regions; and (2) no significant differences in AA turnover between the SHAM and the SPD rats. The results suggest the upregulation of one or more neurotransmitter systems or receptors acting through the PLA(2) signalling pathway, or the components of the cPLA(2) signalling system itself. Taken together with the previous measurements, one can conclude that this elevation is likely related to upregulation in the brain serotonergic system because of the elevated 5-HT synthesis of the OBX rats.

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.

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.

Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study.

RATIONALE: Chronic treatment with the selective serotonin reuptake inhibitor, citalopram, normalizes several behavioral and neurochemical abnormalities in the olfactory bulbectomized (OBX) rat model of depression. OBJECTIVE: To assess the changes in regional cerebral glucose utilization (rCGU) following chronic treatment with citalopram in OBX and sham-operated rats. METHODS: Male Sprague Dawley rats (160-190 g) were used. Two weeks following the surgeries, the rats were implanted with osmotic minipumps which delivered 10 mg/kg/day of citalopram (the sham-CTP and OBX-CTP groups) or saline (to the sham-SAL and OBX-SAL groups) for 2 weeks. Following the treatment, the rates of rCGU were determined in 43 brain regions using 2-[(14)C]deoxyglucose (2-[(14)C]DG) autoradiography. RESULTS: The general linear model statistical analysis revealed significantly lower rCGU in the OBX-SAL group compared to the sham-SAL group in the medial prefrontal cortex and the median forebrain bundle. The sham-CTP group had significantly lower rCGU relative to the sham-SAL group in the medial prefrontal cortex. The OBX-CTP group had significantly lower rCGU than the OBX-SAL group in the anterior olfactory nucleus, orbitofrontal cortex, frontal cortex, anterior cingulate cortex, visual cortex, and substantia nigra--pars reticulata. The rCGU in the OBX-CTP group was significantly lower than that in the sham-CTP group in the anterior olfactory nucleus, orbitofrontal cortex, visual cortex, and substantia nigra--pars reticulata. CONCLUSION: The results imply that chronic citalopram treatment, shown previously to result in behavioral normalization in OBX rats, establishes a new pattern of rCGU, rather than normalizing it to the pattern of the sham-CTP rats.

[Prevalence of acute cerebrovascular disease in Bizovac, Osijek-Baranya county: a door-to-door survey in eastern Croatia]. / Prevalencija akutne cerebrovaskularne bolesti na podrucju opcine Bizovac u Osjecko-Baranjskoj zupaniji: rezultati populacijske studije vrata-do-vrata.

BACKGROUND AND PURPOSE: A door-to-door survey was carried out in Bizovac area, Osijek-Baranya County in east Croatia. A cluster sample of 1899 inhabitants were screened to determine the prevalence of acute cerebrovascular disease (CVD): transient ischemic attacks (TIA) and stroke in this population. METHODS: We used a modified version of the World Health Organization screening instrument. A door-to-door survey of stroke was conducted in five Osijek suburbs, east Croatia. The data obtained were compared with data in personal records of the study subjects. RESULTS: On March 31, 2005, the prevalence of acute CVD was 3370/100.000 (stroke 1948/100,000 and TIA 1422/100,000), of CVD in males 3047/100,000 (stroke 1959/100,000 and TIA 1088/100,000); of CVD in females 3673/100,000 (stroke 1939/100,000 and TIA 1735/100,000); and the prevalence of acute CVD progressively increased with age: in 45-54 age group 1290/00,000 (stroke 942/100,000, TIA 348/100,000); in 55-64 age group 7895/100,000 (stroke 5623/100,000, TIA 2272/100,000); in 65-74 age group 11386/100,000 (stroke 7393/100,000, TIA 3993/100,000); and in 75-84 age group 14035/100,000 (stroke 10001/100,000, TIA 4034/100,000) as the highest figure. CONCLUSION: The study revealed a very high prevalence of acute CVD in the study area and confirmed CVD as one of the leading medical and public health issues in Bizovac area, Osijek-Baranya County, east Croatia.