Regulation of cocaine reward by CREB.

Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.

Neurosteroid action at the GABAA receptor in fetal rat forebrain.

In utero exposure to diazepam (DZ), a positive modulator of the GABAA (gamma-aminobutyric acid type A) receptor exerts profound effects on the offspring that become most apparent after the maturation of the brain during puberty and that are often sex specific, suggesting that the early exposure might have interfered with organizing actions of sex steroids. In addition to genomic actions, many reduced steroids interact directly with membrane receptors, including the GABAA receptor. In the present study, the effect of in vitro exposure to neurosteroids on GABA-stimulated 36chloride uptake in synaptoneurosomes from adult cerebral cortex or fetal forebrain (gestation day 20) was examined. The initial study examined the effects of incubation with DZ (10 microM) and the neuroactive steroid, 3 alpha,5 beta-THP (500 nM), alone and in combination. In adult tissue, the presence of either drug alone decreased the EC50 for GABA stimulation, and incubation with both drugs had an additive effect. In fetal tissue, while both compounds decreased the EC50, an additive effect was apparent only when comparing the combined exposure to 3 alpha,5 beta-THP alone. DZ alone reduced the EC50 as much as both drugs together. In the second study, the effect of in vitro exposure to androsterone (2.5 microM) was evaluated in male and female fetal tissue separately as well as in the adult. Androsterone enhanced the sensitivity to GABA in all groups but also reduced the efficacy of GABA in fetal tissue, irrespective of gender. While neurosteroids and DZ elicited similar responses in fetal and adult tissue, the study identified a greater vulnerability of fetal GABAA receptors to modulatory compounds.