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The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression, was cross-bred with its normal control, the Flinders Resistant Line (FRL) rat, in order to investigate the relationship between cholinergic sensitivity, the selected variable, and two apparent genetically correlated variables, serotonergic sensitivity and swim test immobility. Cross-breeding established F1, F2 and back-cross progeny, with at least 20 rats of each sex for each group. Cholinergic sensitivity was assessed as the hypothermic response to oxotremorine (0.2 mg/kg) in 30 day old rats. Serotonergic sensitivity was assessed as the hypothermic response to 8-OH-DPAT, a serotonin (5-HT)-1A agonist, in 35–40 day old rats. Immobility was assessed as the time spent immobile in a 5 min swim test in 60–70 day old rats. For each variable, there were highly significant group differences, with the parental FSL and FRL groups being at the extremes. The segregating populations tended to be intermediate between the parental lines and were generally significantly different from both FSL and FRL groups. However, the crosses more closely resembled the FRL parent for only the cholinergic responses, the distributions for 8-OH-DPAT and immobility suggesting predominantly additive genetics. Statistical analyses with chi square to compare response distributions and regression to quantify the association between variables in the segregating populations confirmed that cholinergic sensitivity was different from serotonergic sensitivity and immobility, which were significantly correlated with each other. These findings suggest that the exaggerated immobility in the FSL rats, which can be counteracted by antidepressants and serotonin reuptake inhibitors, is more closely associated with their 5-HT1Asupersensitivity than their cholinergic supersensitivity.

National Institutes of Health (NIH) heterogeneous stock (HS) rats were obtained and genetically selected for either larger (HI line) or smaller (LO line) hypothermic responses to the selective serotonin-1A (5-HT1A) agonist 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). A randomly bred (RA) control line was also bred in parallel. There was a rapid response to selection, with HI and LO SI progeny already showing significantly different hypothermic responses to DPAT. The data for the S3 progeny indicated that selection was proceeding in both directions, with the hypothermic response of the LO line being about 0.5°C less than that of the RA line (p< 0.01) and the hypothermic response of the HI line being about 0.7°C greater (p< 0.01). The selected lines also differed in their hypothermic responses to the cholinergic agonist oxotremorine, but these differences did not change with further selection. These findings indicate that selection for 5-HT1Asensitivity may occur quite rapidly and that changes in muscarinic sensitivity do not parallel those changes in serotonergic sensitivity.

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these “therapeutic” effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond “therapeutically” to antidepressants and not psychomotor stimulants.