This project examines behavioral and molecular aspects of sensitization to repeated cocaine administration and kindling. c-fos mRNA and the Fos protein have been shown to increase dramatically in the striatum following an acute injection of cocaine. With daily repeated injections, the Fos response returns to baseline levels. Paradoxically, this is at a time when the rats are behaviorally sensitized to cocaine; that is, following repeated administration more locomotion is induced in these rats with cocaine than in rats who receive cocaine for the first time. We have also found that while the induction of c-fos mRNA and the Fos protein are diminished with repeated exposure to cocaine, induction of another Fos-related protein (Fra) is not reduced. This may have important implications for switching of molecular responses with repeated cocaine and the manifested behavioral sensitization. The behavioral effects of sensitization induced by amygdala kindling are also studied. Kindling induces a hyperexcitability in the region stimulated. Because the amygdala is known to be necessary for the acquisition and expression of fear-related behaviors such as fear- potentiated startle, we asked whether amygdala kindling would facilitate the startle response. Rats that received kindling stimulation in the amygdala displayed exaggerated fear-potentiated startle, whereas rats with hippocampal kindling demonstrated normal levels of fear-potentiated startle. In addition, amygdala kindling induced c-fos mRNA expression in the amygdala and limbic cortices, while c-fos mRNA expression following hippocampal kindling was restricted to the hippocampus. These data suggest that the hyperactivity in limbic regions induced by amygdala kindling may be responsible for the expression of abnormal levels of fear and anxiety.
