Research report
Rats with congenital learned helplessness respond less to sucrose but show no deficits in activity or learning

https://doi.org/10.1016/S0166-4328(03)00259-6Get rights and content

Abstract

Inbred rat strains for congenital learned helplessness (cLH) and for congenital resistance to learned helplessness (cNLH) were investigated as a model to study genetic predisposition to major depression. Congenitally helpless rats respond less to sucrose under a progressive ratio schedule. This is not confounded by locomotor hypoactivity: in contrast, cLH rats show a slight hyperactivity during the first 5 min of an open field test. cLH rats acquire operant responding to sucrose as readily as cNLH rats and exhibit normal memory acquisition and retrieval in the Morris water maze, thus ruling out general learning deficits as the cause of the decreased response to sucrose. Reduced total responses and reduced breaking points for sucrose in the cLH strain argue for anhedonia, which is an analogue to loss of pleasure essential for the diagnosis of major depressive episodes, and thus confirm the validity of congenitally learned helpless rats as a model of major depression.

Introduction

Animal models are needed to investigate the neurobiology underlying major depression [28], [29]. Learned helplessness is a well established stress model of major depression with good construct validity [42], [43]: uncontrollable and unpredictable stress induces learned helplessness in the rat [33], [34]. The model shows good face validity with vegetative changes such as weight loss, loss of libido, and increased REM sleep [1], [7], [8]. Endocrine changes with decreased dexamethason suppression during learned helplessness and pharmacological specificity for antidepressant drug treatment also argue for an animal model of major depression [15], [36]. Moreover, reduced behavioral plasticity of learned helplessness goes along with alterations in monoaminergic systems [9], [10], [11], [12], [25]. Learned helplessness lasts for more than 1 week which is comparable to the duration of human depressive episodes if the rats’ much shorter life span is considered [17], [41]. In our paradigm moderate stress induces learned helplessness only in a portion of susceptible animals, thus modeling the human susceptibility to depression [40]. By selectively breeding learned helpless animals and non-learned helpless, respectively, two lines have been developed: one shows congenital learned helplessness (cLH) the other one exhibits resistance to learned helplessness (cNLH) [18].

A loss of pleasure (anhedonia) and interest in nearly all activities is an essential feature of major depressive episodes. Anhedonia is commonly tested in rats as a decreased consumption of sweet palatable solutions [44]. More specific than total intake of sucrose, operant responding for sucrose under a progressive ratio (PR) schedule can be used to assess the motivational state of the responding animals [23]. The breaking point where an animal stops responding determines how much effort an animal is willing to exert to gain access to an reinforcing substance [24]. The breaking point therefore can be used to assess the effectiveness of the reinforcement which is determined by the reinforcer and the hedonic capacity of the individual, but also to compare the persistence of the animals to exert sustained effort over time [32]. We thus used the PR schedule to measure differences in anhedonia in cLH and cNLH rats.

Section snippets

Animals

By selecting for susceptibility for learned helplessness, two lines of rats were generated: cLH (congenitally learned helpless) and cNLH (congenitally non-helpless). Breeding of the helplessness colonies has been described [21], [22], [37], [38], [39]. Briefly, Sprague–Dawley rats were tested in the learned helplessness paradigm [40]. Twenty-four hours after a total of 20 min uncontrollable and unpredictable 0.8 mA footshocks, the rats were tested in an escape paradigm where foot shock could be

Results

Animals from both strains learned to press the lever for sucrose during a 24-h session on a FR1 and did not differ in FR1 responses for sucrose during the training sessions for 24 or 1 h, no matter if tested after water deprivation or without water deprivation. After 24 h water deprivation, cLH rats had 214±40 lever presses during a 1-h session, whereas cNLH rats responded 210±36 times. Without water deprivation, lever presses were reduced to 116±39 h−1 in cLH and 133±36 h−1 in cNLH. However,

Discussion

Essential features of major depressive episodes are either depressed mood or a marked loss of interest and pleasure in nearly all activities. Communication of changes in mood and thoughts during depressive episodes relies on language and is not testable in animal models. Therefore, anhedonia or the reduced capacity to experience pleasure is an important analogue of major depression in animal models [42], [43]. The consumption of sweet palatable solutions or pellets as a measure of hedonia is

Acknowledgements

The authors thank Dr. B. Krumm for help with statistical analysis, Dr. C. Sanchis Segura for helpful comments on the manuscript, and C. Zacher and H. Schamber for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft to B.V. (VO 621 3-1) and P.G. (GA 427 4-1).

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