Cocaine differentially regulates activator protein-1 mRNA levels and DNA-binding complexes in the rat striatum and cerebellum

P Couceyro, KM Pollock, K Drews and J Douglass

Vollum Institute, Oregon Health Sciences University, Portland 97201.

Cocaine is a psychomotor stimulant that exerts many of its behavioral and physiological effects through alteration of catecholamine reuptake systems. One early cellular response to cocaine administration is a brain region-specific alteration in the transcriptional pattern of immediate early genes belonging to the Fos/Jun family of nucleotide sequence-specific [activator protein-1 (AP-1)] DNA-binding proteins. The work described here compares cocaine-induced transcriptional regulation of immediate early gene mRNA levels, as well as AP-1 DNA- binding activity, within the striatum and cerebellum. In the striatum, acute cocaine administration increases cellular levels of c-fos and jun- B mRNA, whereas transcriptional effects in the cerebellum are limited to c-fos mRNA. After chronic cocaine treatment a desensitization of c- fos mRNA induction is observed in the striatum, with sensitization of the same transcriptional effect occurring in the cerebellum. Pharmacological studies further reveal that the dopamine D1, dopamine D2, gamma-aminobutyric acid type B, and N-methyl-D-aspartate receptor systems mediate the effects of cocaine on cerebellar neurons, whereas striatal effects are modulated through D1 and N-methyl-D-aspartate receptors. Gel retention analysis using antibodies to the various Fos and Jun proteins was used to characterize cocaine-dependent alterations in the composition of striatal and cerebellar AP-1 DNA-binding complexes. In striatum, cocaine increases the relative levels of c-Fos, Fos-B, Jun-B, and Jun-D proteins that bind the AP-1 DNA sequence element, whereas in the cerebellum only c-Fos and Jun-D binding activities are increased. These data suggest two possible neuroanatomical sites where tolerance and sensitization to cocaine can be examined at the genomic level.

Volume 46, Issue 4, pp. 667-676, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				J. D. Alvaro, J. R. Taylor, and R. S. Duman Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 391 - 399. [Abstract] [Full Text] [PDF]

				G. Torres and J. M. Horowitz Drugs of Abuse and Brain Gene Expression Psychosom Med, September 1, 1999; 61(5): 630 - 650. [Abstract] [Full Text] [PDF]

				J. J. Lucas, L. Segu, and R. Hen 5-Hydroxytryptamine1B Receptors Modulate the Effect of Cocaine on c-fos Expression: Converging Evidence Using 5-Hydroxytryptamine1B Knockout Mice and the 5-Hydroxytryptamine1B/1D Antagonist GR127935 Mol. Pharmacol., May 1, 1997; 51(5): 755 - 763. [Abstract] [Full Text]