Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury.

Progesterone (PROG) has been shown to protect the brain from traumatic injury and is now in Phase III clinical trials. Our work shows that PROG's beneficial effects can be reduced in vitamin D hormone (VDH)-deficient subjects. VDH can modulate neuronal apoptosis, trophic factors, inflammation, oxidative stress, excitotoxicity, and myelin and axon repair. We investigated whether VDH combined with PROG could improve behavioral outcomes more than PROG alone in VDH-sufficient rats given bilateral contusions of the medial frontal cortex. PROG and different doses of VDH (1 µg/kg, VDH1; 2.5 µg/kg, VDH2; 5 µg/kg, VDH3) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were given subcutaneously over 8 days with tapering over the last 2 days. Neurobehavioral tests, necrotic cavity, neuronal death and activation of astrocytes were evaluated 21 days post-injury. We found that PROG and PROG + VDH preserve spatial memory processing. VDH1 + PROG improved performance in acquisition more effectively than PROG alone, indicating that the low VDH dose is optimal for combination therapy. There were no significant differences in necrotic cavity size among the groups. The density of positive staining for reactive astrocytes (glial fibrillary acidic protein (GFAP)) increased and the cell bodies and processes of GFAP-positive cells were enlarged in the PROG + VDH1 group. Our data indicate that the combination of PROG and VDH is more effective than PROG alone in preserving spatial and reference memory, and that PROG plus low-dose VDH can activateGFAP reactions up to 21 days after injury. This effect may be one of the mechanisms underlying PROG's neuroprotective effects in combination with VDH.

Incentive salience of cocaine across the postpartum period of the female rat.

UNLABELLED: RATIONALE-OBJECTIVES: Our prior conditioned place preference (CPP) work demonstrates that late (day16) postpartum female rats consistently prefer cocaine- over pup-associated chambers, whereas far fewer early postpartum (day8) females prefer the cocaine-associated chamber. The present study examines early and late postpartum females' preference for a cocaine-associated chamber when contrasted with a chamber associated with saline (rather than pups). MATERIALS AND METHODS: Postpartum females were tested for conditioned preference for chambers associated with cocaine (10 mg/kg subcutaneous (SC) or 0.5, 5, 10, or 20 mg/kg intraperitoneal (IP) injections) versus saline; preferences of virgin female and male rats for select cocaine stimuli (10mg/kg SC or IP) were also tested. Locomotion was recorded during CPP conditioning and testing. RESULTS: Early and late postpartum females expressed strikingly similar preference for the cocaine-associated chamber across all administration routes and doses. IP cocaine produced an orderly, inverted U-shaped dose-preference curve, with preference peaking at the 5 mg/kg dose (83% of females). While many postpartum females preferred 10mg/kg cocaine administered either SC or IP, both virgin females and males expressed strong aversion to SC cocaine and, while virgin females strongly preferred IP cocaine, males remained relatively indifferent. Across 10mg/kg IP cocaine-conditioning sessions, locomotor sensitization occurred exclusively in cocaine- but not saline-preferring postpartum females. Locomotor rate was lower in preferred versus nonpreferred chambers at CPP test. CONCLUSIONS: Early and late postpartum females may be equally and uniquely susceptible to sampling and/or abuse of modestly salient doses of cocaine (10mg/kg SC; 5mg/kg IP) compared to virgin females and/or males.

Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats.

Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect.