Review
The Flinders Sensitive Line rat: A selectively bred putative animal model of depression

https://doi.org/10.1016/j.neubiorev.2005.03.015Get rights and content

Abstract

The Flinders Sensitive Line (FSL) rats were originally selectively bred for increased responses to an anticholinesterase agent. The FSL rat partially resembles depressed individuals because it exhibits reduced appetite and psychomotor function but exhibits normal hedonic responses and cognitive function. The FSL rat also exhibits sleep and immune abnormalities that are observed in depressed individuals. Neurochemical and/or pharmacological evidence suggests that the FSL rat exhibits changes consistent with the cholinergic, serotonergic, dopaminergic, NPY, and circadian rhythm models but not the noradrenergic, HPA axis or GABAergic models of depression. However, evidence for the genetic basis of these changes is lacking and it remains to be determined which, if any, of the neurochemical changes are primary to the behavioral alterations. The FSL rat model has been very useful as a screen for antidepressants because known antidepressants reduced swim test immobility when given chronically and psychomotor stimulants did not. Furthermore, rolipram and a melatonin agonist were shown to have anti-immobility effects in the FSL rats and later to have antidepressant effects in humans. Thus, the FSL rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed individuals and has been very effective in detecting antidepressants.

Section snippets

Initial development of lines

The original rationale behind the development of the Flinders Line rats was to create a strain/line of rats that was genetically resistant to the effects of the organophosphate anticholinesterase agent, diisopropyl fluorophosphate (DFP), so that the mechanisms involved could be compared with those involved in the development of tolerance to DFP (Russell and Overstreet, 1987). However, the selective breeding program led to the development of a strain/line of rats that was genetically more

Behavioral characteristics

In this section we discuss how closely the FSL rat resembles depressed individuals with regard to key behavioral symptoms, sleep parameters and associated variables, such as immune function, asthma, and inflammatory bowel disease (IBS).

Theoretical models

Hypotheses of the neurochemical basis of depressive disorders abound, so the present section will consider a limited number of theories, primarily those for which there are some data in the FSL rat that might permit a tentative conclusion.

Selective breeding strategy

The FSL and FRL rats were selectively bred using an outbreeding strategy that avoided matings between close relatives. Three responses to the anticholinesterase agent, diisopropyl fluorophosphate (DFP), were used: hypothermia, reduced water intake and reduced body weight (Overstreet et al., 1979). Six to ten mating pairs were used per generation and selection was applied for 30 generations. More recently, for at least 10 years, the FSL and FRL rat colonies have been maintained as closed

Therapeutic drugs

The FSL rat has been used to test for the antidepressant-like effects of classical antidepressants and selective serotonin reuptake inhibitors (SSRIs) as well as a variety of novel agents that presumably have different actions from the well-characterized antidepressants. This work has recently been summarized (Overstreet, 2002), so only a brief commentary on the previously published studies will be given. The remainder of this section will focus on the results that have been collected over the

Conclusions and future directions

Although the FSL rat exhibits several behaviors that are parallel to symptoms of depression in humans, there are also mismatches. The most notable examples are the anhedonia and cognitive disturbances in depressed individuals and normal reward-related behavior and food-motivated learning in FSL rats (Table 1). Whether these behaviors would be preferentially altered in FSL rats after exposure to stressors such as the CMS procedure, as was anhedonia (Pucilowski et al., 1993), remains to be

Acknowledgements

The generous financial support of the governments of Israel, Sweden, and the United States is acknowledged. We express our thanks to the many colleagues, graduate students and technicians who have assisted on the experiments described in this review paper.

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