THE JOURNAL OF COMPARATIVE NEUROLOGY 353:200-212 (1995) Dynorphin Opioid Inhibition of Cocaine-Induced,D l Dopamine Receptor-Mediated Immediate-Early Gene Expression in the Striatum HEINZ STEINER AND CHARLES R. GERFEN zyxw Section of Neuroanatomy, Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892-4068 ABSTRACT Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zzf 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that 1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5-250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mgikg); 2) systemic administration of the kappa opioid receptor agonist spiradoline (0.5-10.0 mgikg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; 3) intrastriatal infusion of spiradoline (1-50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and 4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D l dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum. zyxw c 1995 Wiley-Liss, he.* Indexing terms: kappa opioid, zyxwvut c-fos, zyxwvutsrqp zif268, striatonigral, cocaine Striatal output neurons can be classified into two major subtypes based on their projection targets (Kawaguchi et al., 1990). One subtype, striatopallidal neurons, projects to the globus pallidus, and the other subtype, striatonigral neurons, sends a minor axon collateral to the globus pallidus and more extensive axon projections to the entope- duncular nucleus andlor to the substantia nigra. A charac- teristic of these neurons is that they contain opioid peptides in addition to the main transmitter, y-aminobutyric acid (GABA). Generally, striatopallidal projection neurons ex- press the neuropeptide enkephalin, whereas striatonigral neurons express the peptide dynorphin (see, e.g., Vincent et al., 1982; Beckstead and Kersey, 1985; Gerfen and Young, 1988). Little is known about the functional role of these opioid peptides. However, it has been shown that striatal Accepted August 1,1994 Address reprint requests to C.R. Gerfen, Section of Neuroanatomy, Laboratory of Systems Neuroscience, National Institute of Mental Health, Building 36, Room 2D-10, Bethesda, MD 20892-4068. zyxw o 1995 WILEY-LISS, INC. *This article is a US govern- ment work and, as such, is in the public domain in the United States of America.