Context-driven cocaine-seeking in abstinent rats increases activity-regulated gene expression in the basolateral amygdala and dorsal hippocampus differentially following short and long periods of abstinence.

In this study, the expression patterns of zif268 and activity-regulated cytoskeleton-associated gene (arc) were investigated in the basolateral amygdala (BLA) and dorsal hippocampal (dHPC) subregions during context-induced drug-seeking following 22 h or 15 d abstinence from cocaine self-administration. Arc and zif/268 mRNA in BLA and dHPC increased after re-exposure to the cocaine-paired chamber at both timepoints; however, only the BLA increases (with one exception-see below) were differentially affected by the presence or absence of the cocaine-paired lever in the chamber. Following 22 h of abstinence, arc mRNA was significantly increased in the BLA of cocaine-treated rats re-exposed to the chamber only with levers extended, whereas following 15 d of abstinence, arc mRNA in the BLA was increased in cocaine-treated rats returned to the chamber with or without levers extended. In contrast, zif268 mRNA in the BLA was greater in cocaine-treated rats returned to the chamber with levers extended vs. levers retracted only after 15 d of abstinence. In the dentate gyrus (DG) following 22 h of abstinence, zif268 mRNA was greater in rats returned to the chamber where levers were absent regardless of drug treatment whereas arc mRNA was increased in CA1 (cell bodies and dendrites) and CA3 only in cocaine-treated groups. Following 15 d of abstinence, arc mRNA was significantly greater in CA1 and CA3 of both cocaine-treated groups returned to the chamber than in those placed into a familiar, non-salient alternate environment; however, only in CA1 cell bodies the cocaine context-induced increases significantly greater than in yoked-saline controls. In contrast, zif/268 mRNA in all dHPC regions was significantly greater in both cocaine-treated groups returned to the cocaine context than in the cocaine-treated group returned to an alternative environment or saline-treated groups. These data suggest that the temporal dynamics of arc and zif268 gene expression in the BLA and dHPC encode different key elements of drug context-induced cocaine-seeking.

Differential expression of arc mRNA and other plasticity-related genes induced by nicotine in adolescent rat forebrain.

Relatively little attention has been focused on mechanisms related to neural plasticity and drug abuse in adolescence, compared with abundant research using adult animal models. As smoking is typically initiated in adolescence, an important question to address is whether the adolescent brain responds differently to nicotine compared with the adult. To investigate this question, we examined the expression of a number of early response genes (arc, c-fos and NGFI-B) that have been implicated in synaptic plasticity and addiction, following acute nicotine in adolescent and adult rats. Baseline expression of arc and c-fos was higher in adolescent brains compared with adults. Following acute nicotine treatment (0.1, 0.4mg/kg), we found a marked induction of arc mRNA in the prefrontal cortex of nicotine-treated adolescents compared with a less pronounced increase of arc in the adult. c-fos and NGFI-B were also upregulated by nicotine, but not in an age-related manner. In contrast, nicotine induced less arc, c-fos, and NGFI-B expression in the somatosensory cortex of adolescents compared with adults. A fourth gene, quinoid dihydropteridine reductase was expressed at lower levels in white matter of the adolescent forebrain compared with the adult, but was not affected by nicotine. These results suggest that in adolescence, the activity of specific early response genes is higher in brain regions critical for emotional regulation and decision-making. Further, nicotine affects key plasticity molecules in these areas in a manner different from the adult. Thus, adolescence may represent a neurobiologically vulnerable period with regard to nicotine exposure.

Interleukin-6 promotes post-traumatic healing in the central nervous system.

The central nervous system (CNS) is an immune-privileged site where the role of immune cells and mediators in traumatic brain injury is poorly understood. Previously we have demonstrated that interleukin (IL)-6, a cytokine that acts on a wide range of tissues influencing cell growth and differentiation, is an agonist for vascular endothelial growth factor (VEGF), in in vitro vascularization assays for brain microvessel endothelial cells. In this present work we focus on the role of IL-6 in promoting tissue repair in the CNS in vivo. An aseptic cerebral injury (ACI) was created in the right parietal cortex, using both wild type (C57Bl/6J) and IL-6-deficient (C57Bl/6J-IL-6-/-) mice to study the consequences of the absence of IL-6 on the pathology of brain injuries. We monitored the immediate, early, and late responses to this traumatic injury by characterizing several histologic features in the CNS at days 1, 4, 7 and 14 following injury. Acellular necrosis, cellular infiltration, and re-vascularization were characterized in the injured tissues, and each of these histologic features was individually graded and totaled to assign a healing index. IL-6-deficient mice were found to have a comparatively slower rate of recovery and healing. Furthermore, fluorescein isothiocyanate (FITC)-dextran intravenous injection demonstrated leaky vessels in IL-6-deficient but not in wild type animals following ACI. Additionally, chronic expression of IL-6 in the CNS using transgenic GFAP-IL-6 mice resulted in more rapid healing following ACI. The accelerated tissue repair in GFAP-IL-6 transgenic animals is primarily due to extensive re-vascularization as detected by endothelial cell markers. Combined, this data suggests an important role of IL-6 in tissue repair processes following traumatic injury in the CNS.