Brain Advance Access originally published online on June 17, 2008
Brain 2008 131(8):2071-2083; doi:10.1093/brain/awn117
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Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine
1Department of Pediatrics, 2Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 3Research, West Los Angeles Veterans Administration Medical Center and 4Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Correspondence to: Andrey Mazarati, MD, PhD, David Geffen School of Medicine at UCLA, Room 22-474 MDCC (175217), Los Angeles, CA 90095-1752, USA E-mail: mazarati{at}ucla.edu
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
Key Words: comorbidity; depression; epilepsy; hippocampus; serotonin
Abbreviations: 5-HT, serotonin; 5-HIAA, 5-hydroxyindolacetic acid; ADT, afterdischarge threshold; ADD, afterdischarge duration; FCV, fast cyclic voltammetry; FLX, fluoxetine; FST, forced swim test; HPLC, high performance liquid chromatography; PCA, parachloroamphetamine; SE, status epilepticus; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitors; TLE, temporal lobe epilepsy.
Received January 24, 2008. Revised March 26, 2008. Accepted May 12, 2008.