Elsevier

Experimental Neurology

Volume 263, January 2015, Pages 263-271
Experimental Neurology

Regular Article
Sucrose consumption test reveals pharmacoresistant depression-associated behavior in two mouse models of temporal lobe epilepsy

https://doi.org/10.1016/j.expneurol.2014.09.004Get rights and content

Highlights

  • Sucrose consumption test detects anhedonia in two mouse epilepsy models.

  • Anhedonia is present during early epilepsy and persists in the chronic disease phase.

  • Anhedonia is resistant to chronic antidepressive drug treatment in both models.

  • P-glycoprotein knock-out does not improve treatment efficacy.

Abstract

Among the comorbidities observed in epilepsy patients depression is the most frequent one. Likewise, depression by itself is accompanied by an increased risk to develop epilepsy. Both epilepsy and depression are characterized by a high incidence of pharmacoresistance, which might be based on overactivity of multidrug transporters like P-glycoprotein at the blood–brain barrier. Using genetically modified mice in preclinical epilepsy research is pivotal for investigating this bidirectional relationship. In the present study, we used the sucrose consumption test (SCT) in the pilocarpine and the intrahippocampal kainate mouse post-status epilepticus model to reveal anhedonic behavior, i.e. hyposensitivity to pleasure, as a key symptom of depression. Mice were repetitively investigated by SCT during early epilepsy and the chronic phase of the disease, during which response to antidepressant drug treatment was assessed. SCT revealed long-lasting anhedonia in both models. Anhedonia appeared to be pharmacoresistant, as neither chronic treatment with imipramine in the pilocarpine model nor chronic treatment with fluoxetine in the kainate model could annihilate the differences in sucrose consumption between control and epileptic mice. Moreover, knock-out of P-glycoprotein did not improve the treatment effect of fluoxetine. In conclusion, our findings show for the first time that the SCT is suited for detection of depression-like behavior in mouse models of temporal-lobe epilepsy. Both models might serve as tools to further investigate the neurobiology and pharmacology of epilepsy-associated pharmacoresistant depression.

Introduction

Depression is the most frequent psychiatric comorbidity in epilepsy (VALENTE and BUSATTO FILHO, 2013, KANNER, 2003b). Up to 50% of pharmacoresistant epilepsy patients, especially those with temporal-lobe epilepsy (TLE), are affected by depression (Kanner, 2003a). Moreover, suicide risk in epilepsy patients is increased ten times compared to the general population (Kanner, 2003b). Otherwise, epidemiologic data underline that people with depression have an up to 7-fold increased risk of developing epilepsy (Garcia, 2012). The bidirectional relationship between epilepsy and depression is still poorly understood. A common feature of both diseases is the high percentage of pharmacoresistant patients. In general, seizures in one third of epilepsy patients do not respond to antiepileptic drug intake (Kwan and Brodie, 2000). Similar to epilepsy, pharmacoresistance to antidepressants is defined as non-response to adequate treatment with two or more antidepressants of different mechanism of action (El Hage et al., 2013). Prevalence of non-response to the first trial antidepressant is around 50% (Nemeroff, 2007, Wiborg, 2013). One widely studied mechanism of pharmacoresistance in epilepsy is increased antiepileptic drug efflux mediated by overexpression of multidrug transporters at the blood–brain barrier in the epileptic focus region (Löscher and Potschka, 2005). As several antidepressants are substrates of such multidrug transporters this mechanism could also be of relevance in depressive patients (LÖSCHER and POTSCHKA, 2005, O'BRIEN et al., 2012b).

Characterizing animal models of TLE with respect to occurrence of depression as comorbidity is pivotal for understanding pathomechanisms underlying the association of epilepsy and depression and for development of new treatments. Mouse models, in which epilepsy develops after an initial status epilepticus (SE), provide a high potential to identify mechanisms of epileptogenesis and pharmacoresistance, particularly because of the availability of genetically modified mice. We recently investigated depression-like symptoms in two mouse models of TLE (pilocarpine, intrahippocampal kainate) in which epileptogenesis is promoted by induction of a self-sustaining SE (GRÖTICKE et al., 2007, GRÖTICKE et al., 2008, MÜLLER et al., 2009a, MÜLLER et al., 2009b). For this purpose, we applied two widely used tests to identify depression-like behavior in rodents, the forced swimming test and the tail suspension test. Both tests assess the rodents' response to an inescapable situation (threat of drowning and being suspended by the tail), measured as time spent swimming or struggling and time spent immobile. Increased immobility is interpreted as the behavioral equivalent of “hopelessness” or “depressed mood” as a major symptom of depressive disorders (Crawley, 2007). Surprisingly, we found that in both tests, epileptic mice did not show the behavior which is usually characterized as depression-like, but presented opposite paradoxic behavior (GRÖTICKE et al., 2007, GRÖTICKE et al., 2008, MÜLLER et al., 2009b, MÜLLER et al., 2009a). We suggested that in both tests, the epileptic mice do not understand the context of the experimental situation, i.e. they do not realize that they are in a hopeless situation, this might be explained by simultaneous presence of impaired learning and memory and anxiety-associated behavior which both have also been found in these mice. Thus, there is still a need for suitable behavioral tests to elucidate depression-like behavior in epileptic mice. The sucrose or saccharin consumption test (SCT) is not based on despair induction but builds on the innate preference of rodents towards sweet food. The test evaluates anhedonia, i.e. hyposensitivity to pleasure, which is a cardinal symptom of depression in human patients (Kanner et al., 2012). In rodents, anhedonic behavior can be measured by simultaneously offering them access to both tap water and sweetened fluid. A healthy subject will prefer the latter, while an anhedonic animal will consume less sweet solution but equal amounts of water compared to controls. Advantageously, the SCT can be performed in the rodents' home cage, hereby minimizing a potential stress- or anxiety-induced bias of results. The SCT has already been studied following rapid kindling in immature rats (Mazarati et al., 2007), in rat models of genetic epilepsy (JONES et al., 2008, RUSSO et al., 2013b, SARKISOVA et al., 2003), in PTZ-kindled mice (Russo et al., 2013a), and in the pilocarpine model of TLE in rats (MAZARATI et al., 2008, MAZARATI et al., 2010), but no studies are available in mouse models of chronic limbic epilepsy.

Here, we investigated whether SCT is an appropriate experimental set up for revealing depressive-like behavior during early and late epilepsy in the pilocarpine and intrahippocampal kainate mouse models. Furthermore, we tried to overcome anhedonic behavior in both TLE models by chronic antidepressive treatment, and finally evaluated whether P-glycoprotein (Pgp) deficiency improves effectiveness of antidepressive treatment with fluoxetine.

Section snippets

Animals

Mice were randomly allocated to the eight experimental groups included in the present study (Table 1). For experiments in the pilocarpine model, female FVB/N wild-type mice were purchased from Charles River (Sulzfeld, Germany) at the age of 6 weeks. For experiments in the intrahippocampal kainate model, female FVB/N wild-type mice and Pgp knock-out (mdr1a/b(−/−)) mice (generated on a FVB/N background) were obtained from Taconic (Ejby, Denmark) at the age of 5 to 6 weeks. After arriving at our

Spontaneous recurrent seizures after pilocarpine- and kainate–induced status epilepticus

In mice following pilocarpine-induced SE, first SRS were detected during the video-monitoring period 6 weeks following SE. All mice of the “sucrose group” exhibited at least one SRS in this time period. In the “saccharin group,” SRS could be detected in 4 of 6 mice. All seizures were secondary generalized (≥ stage 4). Assessment of seizure frequency during drug treatment by video monitoring was not possible as SCT required presence of the mice in their home cages.

In mice following kainate-induced

Discussion

To our knowledge, this is the first study investigating anhedonia as a comorbidity of epilepsy in post-SE models of TLE in mice. The main findings are as follows: SCT reveals anhedonia as a symptom of depressive-like behavior during early epilepsy and the chronic phase of the disease in mice. Anhedonia is present in two different models of TLE in mice, the pilocarpine and the focal kainate model. Chronic treatment with two different antidepressive drugs does not eliminate anhedonia. Lack of the

Conclusions

Our findings indicate that post-SE mouse models of TLE are suitable tools for investigating the neurobiology and pharmacology of epilepsy–depression–comorbidity, and for development of future disease-preventing treatment strategies. In future studies SCT can serve as a useful tool for revealing depression-associated behavior in preclinical epilepsy research.

Acknowledgments

We thank Edith Kaczmarek, Heike Breuer, Steffen Langemeyer, Daniela Deus, Ina Leiter and Kerstin Römermann for their assistance during performance of experiments. Sabine Klein was supported by scholarships of Society for Epilepsy Research e. V. and of FAZIT foundation. Sanofi–Aventis Deutschland GmbH is kindly acknowledged for providing us with fluoxetine. The study was supported by a grant of the German Research Foundation (DFG, grant number Lo 274/10-2).

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      Further, our results corroborate Huang et al. [28] who showed in their model of epilepsy, that animals with epilepsy had decreased sucrose consumption when compared to saline animals. Klein et al. [29] in their two-mouse model of epilepsy observed reduced sucrose consumption in rats with epilepsy which is a sign of pharmacoresistant depression [29]. In the forced swim test, we found that epilepsy increased the immobility time when compared to the treatment groups suggesting despair-like behavior [30].

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    Present address: Department of Nuclear Medicine, Preclinical Molecular Imaging, Hannover, Medical School, Hannover, Germany.

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