ACUTE AND CHRONIC COCAINE ADMINISTRATION DIFFERENTIALLY ALTERS STRIATAL OPIOID AND NUCLEAR TRANSCRIPTION FACTOR MESSENGER-RNAS

The effects of short- and long-term cocaine exposure on the expression of the nuclear transcription factor genes, c-fos and zif/268, as well as the opioid peptides, preprodynorphin (PPD) and preproenkephalin (P PE), in various regions of rat brain were evaluated by injecting i.p. saline or 10, 20, or 30 mg/kg cocaine HCl once daily for 1 or 10 days. In situ hybridization histochemistry was performed using 40mer oligon ucleotides coding for c-fos and zif/268, or 48mers coding for PPD and PPE, followed by quantitative image analysis. Behavioral ratings demon strated that on day 1 cocaine-induced activity increased in a dose-dep endent manner. Statistical analysis revealed that repeated administrat ion of cocaine for 10 days resulted in an augmentation of the behavior al response elicited by acute exposure to cocaine. Image analysis of f ilm autoradiograms demonstrated that 1 h after a single injection of c ocaine, the expression of c-fos and zif/268, but not PPD or PPE in the dorsal striatum and cortex, was enhanced in a dose-dependent manner a s compared to that in saline controls. In contrast, administration of 30, but not 10 or 20, mg/kg cocaine for 10 days increased the expressi on of PPD but not PPE, mRNA and downregulated that of c-fos and zif/26 8 as compared to acute cocaine. These data indicate that repeated, hig h dose cocaine administration induces an increased PPD but not PPE gen omic response and that the expression of c-fos and zif/268 is dissocia ble from that of PPD. (C) 1994 Wiley-Liss, Inc.