Regular ArticleSucrose consumption test reveals pharmacoresistant depression-associated behavior in two mouse models of temporal lobe epilepsy
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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2020, Life SciencesCitation Excerpt :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.