The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The present proposal tests the hypothesis that epilepsy-associated depression may stem from specific dysfunction of central noradrenergic transmission. The study focuses on the ascending noradrenergic pathway and on the plasticity of ?2A adrenoreceptors that regulate norepinephrine (NE) release in this pathway. The study employs an animal model whereby chronic epilepsy and concurrent depression-like impairments develop in Wistar rats following pilocarpine-induced status epilepticus. The first part of the study describes perturbations in central noradrenergic transmission in relation to the severity of depressive behavioral impairments, the latter being measured and classified using the forced swim test. The strength and the integrity of noradrenergic transmission in the locus coeruleus-forebrain (i.e. the hippocampus and the neocortex) noradrenergic projections will be measured by means of the in vivo fast cyclic voltammetry, as well as the tyrosine hydroxylase immunofluorescence. The number and the function of ?2A adrenoreceptors that regulate NE release (i.e. somatodendritic autoreceptors in locus coeruleus and axonal autoreceptors in the forebrain), as well those that regulate serotonin release in the forebrain (i.e. heteroreceptors) will be characterized using autoradiography and electron microscopy. The second part of the study examines whether restoring noradrenergic transmission in the ascending pathway exerts therapeutic effects in animals with epilepsy-associated depression. A selective norepinephrine reuptake inhibitor reboxetine will be delivered over two weeks. A selective ?2A adrenoreceptor blocker RX-821002 will be administered locally into the locus coeruleus, the hippocampus, the neocortex, and in raphe nucleus, in order to target specific population of ?2A adrenoreceptors. The effects of treatments on depressive behavior, norepinephrine and serotonin release in the forebrain, tyrosine hydroxylase expression, as well as the number, function and subcellular localization of ?2A adrenoreceptors will be examined using respective techniques listed above. In the third part of the study possible upstream mechanisms leading to central noradrenergic dysfunction will be examined. The dysregulation of the hypothalamo-pituitary-adrenocortical axis will be studied using radioimmunoassay and correlated with the extent of noradrenergic impairments;further the effects of a glucocorticoid receptor blocker mifepristone delivered locally into the locus coeruleus, on central noradrenergic deficits and depressive behavior will be examined. The proposed studies will contribute to our understanding of mechanisms of the comorbidity between epilepsy and depression, to the development of evidence-based therapies of this condition, and to improving of the quality of life in those epilepsy patients who suffer from concurrent depression.

Public Health Relevance

Depression is frequently observed in, and contributes to the poor quality of life in patients with epilepsy;at the same time, mechanisms that underlie epilepsy-associated depression remain poorly understood, and effective therapies of this condition are lacking. The proposed project uses an experimental model of epilepsy to examine a possible mechanism that leads to the development of depression in epilepsy patients. Advancement of knowledge in this area will contribute to the development of effective therapies and to improving the quality of life in those epilepsy patients who suffer from concurrent depression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Pineda, Eduardo; Jentsch, J David; Shin, Don et al. (2014) Behavioral impairments in rats with chronic epilepsy suggest comorbidity between epilepsy and attention deficit/hyperactivity disorder. Epilepsy Behav 31:267-75
Kwon, Young Se; Pineda, Eduardo; Auvin, Stephane et al. (2013) Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. J Neuroinflammation 10:30
Pineda, Eduardo; Shin, Don; You, Su Jeong et al. (2013) Maternal immune activation promotes hippocampal kindling epileptogenesis in mice. Ann Neurol 74:11-9
Vezzani, Annamaria; Aronica, Eleonora; Mazarati, Andrey et al. (2013) Epilepsy and brain inflammation. Exp Neurol 244:11-21
Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman et al. (2012) Interleukin-1? causes fluoxetine resistance in an animal model of epilepsy-associated depression. Neurotherapeutics 9:477-85
Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman et al. (2011) Plasticity of presynaptic and postsynaptic serotonin 1A receptors in an animal model of epilepsy-associated depression. Neuropsychopharmacology 36:1305-16
Mazarati, Andrey; Maroso, Mattia; Iori, Valentina et al. (2011) High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products. Exp Neurol 232:143-8
Pineda, Eduardo; Shin, Don; Sankar, Raman et al. (2010) Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms. Epilepsia 51 Suppl 3:110-4
Mazarati, Andrey M; Pineda, Eduardo; Shin, Don et al. (2010) Comorbidity between epilepsy and depression: role of hippocampal interleukin-1beta. Neurobiol Dis 37:461-7
Auvin, Stephane; Mazarati, Andrey; Shin, Don et al. (2010) Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 40:303-10