Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies.

Strain differences in maternal neuroendocrine and behavioral responses to stress and the relation to offspring cocaine responsiveness.

Early life stress exposure, including prenatal stress (PNS), influences subsequent risk for many disorders, including substance abuse, and these effects interact with genetic factors to determine risk for disease. We previously demonstrated gene X environmental interactions across the BXD recombinant inbred mouse strain panel and their progenitor strains in PNS modulation of cocaine-induced reward and locomotion. Critical to dissecting genetic interactions with PNS is consideration of the modes of stress transmission to the offspring. Both maternal neuroendocrine responses during stress and subsequent maternal-offspring interactions following stress may serve as transmission modes for PNS-induced changes in cocaine responsiveness. Therefore, we characterized the maternal stress response by measuring restraint stress-induced plasma corticosterone (CORT) during gestation as well as effects of restraint stress on dam-pup contact in the first 10 postnatal days in BXD and progenitor mouse strains. Restraint stress interacted with strain to affect plasma CORT levels and dam-pup contact, indicating heritable variation of the maternal stress response. Furthermore, strain-level variance in maternal stress response correlated to the impact on cocaine response exhibited by adult offspring. These findings implicate multiple modes of maternal stress response in alterations of offspring drug responsiveness and indicate that assessment of maternal endocrine and behavioral responses during early life can be utilized to dissect the complex intersection of maternal factors, the response of the offspring and genetics.

Estradiol increases choice of cocaine over food in male rats.

Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5µg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females.