Effects of recovery from immobilization stress on striatal preprodynorphin- and kappa opioid receptor-mRNA levels of the male rat.

Previously, we have reported that brain regions that are thought to be involved in motivated behavior are altered in animals undergoing repeated exposures to immobilization stress. The goal of the present study was to determine the effects of recovery from this type of stress on these same mesolimbic brain regions. For this purpose, adult male Sprague-Dawley rats were initially exposed to immobilization stress either once (2 h) or repeatedly (2 h×10 days). Rats were then either allowed to recover from the stressor for a shorter (2 days) or longer period of time (9 days) in their home cages. At the end of this recovery period, rats were euthanized and trunk blood and brains were processed for serum corticosterone (CORT) and neurochemistry, respectively. Brain mRNA levels were determined via in situ hybridization for the opioid preprodynorphin (DYN) and its cognate receptor (kappa, KOR), in striatal and accumbal subregions. A pattern of selective transcriptional activation emerged in the four resultant treatment conditions where a short recovery from either a single or repeated exposure to immobilization produced increases in KOR-mRNA levels in striatal and nucleus accumbens (Acb) subregions. Relative to controls, these differences were diminished after a longer recovery period. Interestingly, DYN-mRNA levels were unchanged after the shorter recovery period and after single or repeated immobilizations but appeared to be induced after a longer recovery period after repeated immobilizations. A relative amount of weight loss occurred after immobilization following repeated but not single exposure to stress. In addition, only those rats recovering from repeated stress exposures had higher CORT levels compared with non-immobilized controls. These results suggest that recovery from immobilization stress may alter the motivational system after as little as a single immobilization and that a possible dysphoric effect on appetitive behavior may be reflected by an altered striatal dynorphin system.

Minozac treatment prevents increased seizure susceptibility in a mouse "two-hit" model of closed skull traumatic brain injury and electroconvulsive shock-induced seizures.

The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a "two-hit" injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.