Rats bred for susceptibility to depression-like phenotypes have higher kainic acid-induced seizure mortality than their depression-resistant counterparts

Abstract

Epidemiological evidence suggests that epilepsy and depression are comorbid diseases. In fact, depression is the most common neuropsychiatric disorder associated with epilepsy, particularly temporal lobe epilepsy, and individuals with a history of depression are at a higher risk for developing epilepsy than the general population. Despite the epidemiological evidence for this link, there has been little experimental evidence to support the connection or elucidate possible underlying mechanisms. In an effort to address this problem and develop an animal model of epilepsy and depression comorbidity, we assessed seizure susceptibility and severity parameters in rats selectively bred for either susceptibility (the SwLo, SUS, and HYPER lines) or resistance (the SwHi, RES, and MON RES lines) to depression-like phenotypes. We found that rats bred for susceptibility to depression-like phenotypes experienced higher mortality following kainic acid-induced seizures than their resistant counterparts. In contrast, most line differences were not recapitulated when flurothyl was used to elicit seizures. Stress reduced kainic acid-induced mortality rates in all lines except the HYPER rats, supporting previously established indications that the stress response of HYPER rats is abnormal. These combined results support a neurobiological link between epilepsy and depression, advancing us towards an animal model of their comorbidity.

The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing

“…Importantly, when SwLo rats were given an antidepressant, chronic but not acute administration increased their swim test activity (West and Weiss, 1998a). Information on neurotransmitter involvement was limited, but studies suggest involvement of both glutamatergic (Tabb et al, 2007) and dopaminergic (West et al, 1999a;West et al, 1999b) mechanisms as well as alterations of the stress axis (Gutman et al, 2008). Since dysfunctions (hyper-or hypoactivity) of the hypothalamic-pituitary-adrenal axis may play a prominent role in the development of major depressive disorders (Bale, 2006;De Kloet et al, 1998;Holsboer, 2000), researchers have attempted to generate animal models that mimic these neuroendocrine core symptoms with the goal of unraveling the parameters underlying increased or decreased stress reactivity (Touma et al, 2008).…”

Seizure Susceptibility and Epileptogenesis in a Rat Model of Epilepsy and Depression Co-Morbidity

“…Although the focus of this study was on the SwLo rats as a model for susceptibility to epilepsy and depression, the SwHi rats are also of interest. Because the depression-and epilepsy-like phenotypes of 'wild-type', non-selected rats tend to fall somewhere in between those of SwLo and SwHi rats (Tabb et al, 2007;Weiss et al, 1998;Weiss et al, 2008;unpublished data), the SwHi rats may be a model for co-morbidity resilience.…”

“…In that paper, we reported that SwLo rats have increased mortality following kainic acid-induced limbic seizures, but no differences in flurothyl-induced generalized seizure susceptibility, suggesting that the SwLo rats are specifically sensitive to limbic seizures (Tabb et al, 2007). This was of particular interest because the rate of depression is higher for patients with temporal lobe epilepsy, who suffer from recurrent limbic seizures, than other forms of epilepsy (Kondziella et al, 2007;Piazzini et al, 2001).…”

“…Although several studies have assessed depression-like symptoms in epilepsy-prone animals (Jobe, 2003;Jones et al, 2008;McIntyre and Gilby, 2007;Pineda et al, 2011), there is only one study in which seizure susceptibility was assessed in an animal model of depression, the Swim LoActive (SwLo) rats (Tabb et al, 2007), which were selectively bred for low activity in a swim test and also exhibit other depression-like and anhedonic behaviors such as decreased response to dopaminergic drugs and increased intracranial self-stimulation threshold (Weiss et al, , 2008West et al, 1999a, b;C. West, personal communication).…”

Neuronal plasticity and epilepsy: modern concepts and mechanisms of epilepsy and depression comorbidity

“…В большом исследовании, проведенном на крысах, выведенных на чувствительность (линии SwLo, SUS, HYPER) или резистентность (линии SwHi, RES, MON RES) к депрессивноподобным фенотипам, показано, что первая группа линий демонстрирует более высокую смертность после судорожной активности, вызванной ка-иновой кислотой, в сравнении со второй, резистентной [33]. Крысы линии SwLo, селективно отобранные на де-прессивноподобное поведение, характеризуются повы-шенной чувствительностью к лимбическим судорогам, при этом усиленная физическая активность снижает как проявления депрессии, так и конвульсивную активность в ответ на введение пилокарпина [34].…”