Behavioral Characteristics of Pharmacologically Selected Lines of Rats: Relevance to Depression

Darin J. Knapp, Lynette C. Daws, David H. Overstreet

Bowles Center for Alcohol Studies and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.
Departments of Physiology and Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, USA.

DOI: 10.4236/wjns.2014.43026                

Abstract

This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to the anticholinesterase, diisopropylfluorophosphate (DFP). FSL rats are more sensitive to the hypothermic effects of cholinergic, serotonergic, and dopaminergic agonists but less sensitive to the locomotor or stereotypic effects of dopamine agonists. FSL rats exhibit greater immobility in the forced swim test and reduced social interaction compared with FRL rats, but do not differ in saccharin intake, behavior in the elevated plus maze, or responses for rewarding brain self-stimulation. The exaggerated immobility and reduced social interaction are counteracted by chronic treatment with antidepressants. Because FSL rats were more sensitive to 5-HT1A receptor agonists, high (HDS) and low (LDS) 8-OH-DPATsensitive lines were selectively bred for differential hypothermic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). HDS rats were also more sensitive to the hypothermic effects of oxotremorine, a cholinergic agonist, but selection for this response did not diverge with later selection. HDS rats exhibited greater immobility in the forced swim test than LDS rats and this correlated response could be seen early in selection (generation 3). HDS rats also showed reduced social interaction compared to LDS rats, but did not differ in behavior in the elevated plus maze. These findings confirm that selection for hypothermic responses to pharmacological agents do have behavioral consequences, notably the production of depressive-like phenotypes, which can be counteracted by chronic antidepressant treatment. Because increased 5-HT1A receptor sensitivity was common to both selected lines (FSL and HDS), neurobiological processes dependent on this receptor could contribute to the abnormal behaviors that manifest in these rat lines and thus suggesting a mechanism underlying depressive behaviors in humans. However, available human data are inconsistent with this hypothesis and suggest that other mechanisms underlie these behavioral abnormalities in HDS and FSL rats. These mechanisms as well as additional behavioral testing in these rat lines will be discussed.

 

Keywords

Diisopropylfluorophosphate (DFP), 8-Hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), Flinders Sensitive Line (FSL), Flinders Resistant Line (FRL) Rats, High and Low 8-OH-DPAT Sensitive (HDS & LDS) Rats, Muscarinic Receptors, 5-HT1A Receptors, Forced Swim Test, Social Interaction Test, Elevated Plus Maze, Depression, Anxiety

1. Introduction

The current brief review discusses the development of two pharmacologically selected lines of rats and some of the behavioral consequences of the selected breeding. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to an anticholinesterase agent, diisopropylfluorophosphate (DFP), in order to determine whether similar mechanisms might be involved in the tolerance, sensitivity, and resistance to such agents [1] . Serendipitously, over the ensuing years, it became clear that FSL rats are a putative rodent model of depression, with strong face, constructive and predictive validity [2] -[4] . Because FSL rats have increased sensitivity to the hypothermic response to 8-hydroxy-2-(diN-propylamino)tetralin (8-OH-DPAT) [5] [6] , interest in the potential involvement of the 5-HT1A receptor in their depressive phenotype was sparked. Subsequently, high (HDS) and low (LDS) DPAT-sensitive lines were selectively bred on the basis of their hypothermic responses to the serotonin-1A (5-HT1A) receptor agonist, 8-OH-DPAT [7] . Both FSL and HDS rats share some striking similarities, including greater sensitivity to cholinergic and 5-HT1A agonists, and both exhibit exaggerated immobility in the forced swim test relative to FRL and LDS rats. As discussed in this review, other behavioral characteristics relevant to a depressive-like phenotype also manifest. Consequently, both FSL and HDS rats may be considered putative animal models of depression and useful in the assessment of potential antidepressants.

3. HDS and LDS Lines

3.1. Initial Selection

As discussed, the FSL rat was found to be more sensitive to 5-HT agonists than the FRL rat [5] [23] . Moreover, exaggerated immobility in the forced swim test was correlated with 5-HT sensitivity but not cholinergic sensitivity [6] . Consequently, a selective breeding study was conducted using 8-OH-DPAT, a selective 5-HT1A receptor agonist. A genetically heterogeneous rat strain, established by the interbreeding of 8 inbred strains, was obtained from the National Institutes of Health Heterogeneous Stock colony [2] . Once established, rats were challenged with 8-OH-DPAT at puberty (30 days) and core body temperature was recorded 30 min later with a rectal probe. The ten males and females showing the greatest decrease in temperature were used to establish the high “DPAT” sensitive line (HDS), while the ten males and females showing the least decrease in temperature were used to establish the low “DPAT” sensitive line (LDS). The remaining rats were inter-mated to establish the randomly selected line (RDS). Mating strategy avoided brother-sister breeding and took place at about 70 days of age, after the rats were subjected to the forced swim test. At about 35 days of age, the hypothermic response of rats to either 8-OH-DPAT or the cholinergic agonist, oxotremorine, was recorded (30 min after drug administration). There was a bidirectional rapid selection for the differential hypothermic effects of 8-OH-DPAT, with the HDS rats exhibiting a 0.5˚C greater drop than the RDS rats and the LDS being (0.5˚C lower by the 3^rd generation). There was also a smaller but significant difference in the response of LDS and HDS rats to cholinergic agonists, which became larger with increasing generations [5] . A follow-up study revealed that the HDS rats became even more sensitive to 8-OH-DPAT over generations, with a decrease in core body temperature up to 4˚C compared to 1.3˚C - 1.9˚C for RDS rats, and 0.5˚C for LDS rats [91] .

3.2. Serotonergic Effects

The hypothermic response to 8-OH-DPAT was blocked by a 5-HT1A receptor antagonist but not a 5-HT7 antagonist, a finding that confirmed that the hypothermic effects of 8-OH-DPAT were mediated by its action at 5-HT1A receptors rather than 5-HT7 receptors [91] . Receptor binding studies revealed that HDS rats exhibited higher 5-HT1A receptor binding in cortical and limbic regions compared to RDS and LDS rats, but there were no differences in raphe or hypothalamic nuclei [91] [92] . Later studies using behavioral tests reflective of selective 5-HT receptor action showed that behaviors initiated by stimulation of 5-HT2 or 5-HT3 receptors did not differ between HDS and LDS rats, whereas a behavior reflective of 5-HT1A receptor stimulation did [93] . Furthermore, differences in 5-HT1A binding sites between HDS and LDS rats were confirmed and determined not to be related to changes in G proteins [93] . Thus, selective breeding for the hypothermic effect of 8-OH-DPAT has been quite selective for 5-HT1A receptors and is associated with elevated 5-HT1A receptors, but not in regions normally associated with regulation of body temperature (e.g., hypothalamus). Further evidence for the selectivity of 5-HT1A receptor sensitivity comes from in vivo microdialysis studies. There were no differences in baseline extracellular 5-HT but HDS rats showed a greater increase in extracellular 5-HT after fenfluramine, a 5-HT releasing agent [94] .

3.3. Other Neurotransmitter Systems

The cholinergic system has been the only system explored in HDS and LDS lines to date. HDS rats have increased sensitivity to the hypothermic effects of oxotremorine, which appeared early in development of the lines [5] but did not show further separation with continued selection for 8-OHDPAT [91] . The fact that rats selected for cholinergic sensitivity are more sensitive to the hypothermic effects of 5-HT1A receptor agonists, while those selected for 5-HT1A receptor sensitivity are more sensitive to the hypothermic effects of muscarinic agonists suggests that some common factor beyond the receptors might be involved. Possible factors will be considered in the discussion (see [4] )

3.4. Behavioral Characteristics

Initial studies focused on the FST because immobility in this test was correlated with hypothermic effects of a 5-HT1A receptor agonist in the FSL and FRL F2 progeny [6] . Likewise, differences in immobility occurred early on in the selection for 5-HT1A-induced hypothermic effects, with HDS rats being more immobile, as predicted [5] . Later studies confirmed the exaggerated immobility in HDS rats, indicative of a depressive-like phenotype. Surprisingly, HDS rats drank more saccharin in the sucrose preference test suggesting that these rats do not display anhedonia, a prominent feature of depression [91] . Sucrose intake by HDS rats was reduced to a greater extent by 8-OHDPAT treatment compared to LDS rats [91] . These findings, along with those from other behavioral tests, are shown in Table2

Social interaction and behavior in the elevated plus maze are two tests of anxiety-related behavior. HDS rats exhibited reduced social interaction without a change in activity. HDS and LDS rats did not differ in either total entries or entries into the open arms of the elevated plus maze [95] [96] . Thus, the HDS rat, like the FSL rat, showed anxiety-like behavior on the social interaction task but not the elevated plus maze. To further characterize these rats the effects of intrahippocampal 8-OH-DPAT were studied. LDS but not HDS rats exhibited an anxiogenic effect in the social interaction test, while no effects of intrahippocampal 8-OH-DPAT were observed in the elevated plus maze [95] . Acute fluoxetine treatment had similar anxiogenic effects in the social interaction test, without effects in the elevated plus maze [96] . On the other hand, chronic fluoxetine treatment did not affect behavior in the social interaction test, but had an anxiogenic effect in HDS rats in the elevated plus maze [96] . Furthermore, the intrahippocampal effects of 8-OH-DPAT were not altered after chronic fluoxetine treatment, suggesting that sensitivity of the 5-HT1A receptor was not changed [96] . These findings are hard to reconcile with the increased sensitivity to 5-HT1A-receptor agonist-induced hypothermia [2] [91] and elevated 5- HT1A receptors [92] [93] in HDS rats.

Another study employed the acoustic startle response, with baseline results being similar to those for FSL and FRL rats [14] . Like FRL rats, LDS rats exhibited an increased response to the tone [97] . However, the conditioned startle response was unaffected. Both 8-OHDPAT and buspirone increased startle in LDS rats but not HDS rats [97] . This increased effect in LDS rats does not seem to be consistent with the increased hypothermic sensitivity to 8-OH-DAT and suggests that the increased sensitivity of HDS rats may be specific for hypothermic effects.

Another study provided evidence for a similar conclusion. To investigate possible anxiety-like behavior in HDS rats, a conflict task was employed. After water restriction, rats obtained water in a drinking tube that was electrified for some time periods. These periods were paired with a tone and resulted in a 10-fold suppression of drinking [98] . HDS rats received fewer shocks and drank less water under baseline conditions than LDS rats, a finding that suggested anxiety-like behavior [98] . Low doses of 8-OH-DPAT produced small increases in shocks received (anxiolytic effect), while higher doses produced a reduction in water intake; these effects were comparable in HDS and LDS rats [98] . Thus, while anxiety-like behavioral differences were seen in HDS and LDS rats, there was no differential anxiolytic effect of 8-OH-DPAT. The final study employed a differential reinforcement of low (DRL) rates of responding task because of earlier evidence showing this task to be sensitive to antidepressant treatments [99] . If the rat responds too often, its rate of reinforcement is reduced. The HDS rats responded at a high rate and thus had a lower reinforcement rate than LDS rats [99] . Both the HDS and LDS rats responded to 8-OH-DPAT with a decrease in response rate and an increase in reinforcement rate [99] . In contrast, desipramine, a well-known antidepressant, selectively increased reinforcement rate in both lines [99] . Since antidepressants increase reinforcement rates, it was thought that the “depressed” HDS rats might exhibit a reduced reinforcement rate, but this was not the case. It is likely that the DRL task is reflective of different aspects of behavior than the forced swim test, because the latter involves a larger degree of stress.

Behavioral characterization of HDS and LDS lines is not yet complete. It will be useful to have information about these lines on tasks that differentiated the FSL and FRL rats, such as REM sleep and circadian rhythms (see Table 1) or their response to chronic treatment with other antidepressants (e.g., [71] -[77] ). Nevertheless, the HDS rats are quite similar to the FSL rats for virtually all of the behaviors that have been studied in both groups (compare Table 1 with Table 2).

Acknowledgements

This work was supported by funding to Darin Knapp (City of Hope Foundation) and Lynette Daws (NIH grants R01 MH64489 and R01 MH093320)

Conflicts of Interest

The authors declare no conflicts of interest.

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