Activation of arc, a Putative “Effector” Immediate Early Gene, by Cocaine in Rat Brain

Abstract

As immediate early genes (IEGs) are thought to play a critical role in mediating stimulus‐induced neuronal plasticity, several laboratories have characterized the IEG response induced by cocaine to help define the changes in gene expression that may underlie its long‐lasting behavioral effects. Although activation of several transcription factor IEGs has been described, little is known about which “effector” IEGs, if any, are also induced. In the present study, we have examined whether cocaine administration affects expression of a recently identified “effector” IEG, referred to as arc (activity‐regulated, cytoskeleton‐associated). This IEG encodes a protein with homology to spectrin that appears to be associated with the actin cytoskeleton. Using in situ hybridization, we have found that systemic cocaine administration elicits a robust, transient rise in arc mRNA levels in striatum, which is suppressed by D1 dopamine receptor blockade, reserpine treatment, or striatal 6‐hydroxydopamine lesions. D2 receptor antagonists triggered arc expression when administered alone. Immunohistochemical studies indicated that Arc protein induced by cocaine is expressed in neuronal cell bodies and dendrites. As Arc appears to be a component of the neuronal cytoskeleton, it may be involved in structural alterations underlying neuronal plasticity triggered by cocaine.

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…Arc induction was first reported by Fosnaugh et al (1995). Previously, we found increases in Arc protein in the mPFC after chronic noncontingent (Freeman et al, 2002a), but not self-administered, cocaine (Freeman et al, 2002b).…”

“…The set of transcripts examined, while not comprehensive, represent well-characterized gene alterations from several cocaine administration procedures. Specifically, the immediate early genes Fos (Graybiel et al, 1990), EGR1 (Daunais and McGinty, 1995), Arc (Fosnaugh et al, 1995), and Nr4a1 (Freeman et al, 2002b); neuropeptides CART (Douglass et al, 1995) and Neuropeptide Y (NPY; Westwood and Hanson, 1999); glutamate receptors (Carlezon and Nestler, 2002;Boudreau and Wolf, 2005), and homer genes (Szumlinski et al, 2006) were examined. Furthermore, for those genes that demonstrated persistent changes in mPFC mRNA abundance, histone H3 hyperacetylation was examined as a potential regulatory mechanism.…”

Cytoskeletal Genes Regulation by Chronic Morphine Treatment in Rat Striatum

“…Chronic morphine produced a significant increase in the mRNA and protein levels of Arc in rat striatum. The modulation of this protein in different rat brain structures by several drugs of abuse has been previously described (Ammon et al, 2003;Fosnaugh et al, 1995;Freeman et al, 2002;Kodama et al, 1998;Tan et al, 2000). The exact function of Arc is unknown but its induction and localization in dendrites and soma (Steward and Worley, 2001;Wallace et al, 1998) led to the hypothesis of its involvement in cytoskeletal rearrangements during the process of synaptic plasticity (Lyford et al, 1995).…”

Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence

“…IEGs, like the transcription factors, c-fos and zif/268, and the effector, activity-regulated cytoskeleton-associated gene (arc), contribute to the promotion and maintenance of synaptic plasticity (Rial Verde et al 2006), associative learning Malkani et al 2004), and long-term storage and retrieval of memories (Guzowski et al 2000;Hall et al 2001;Thomas et al 2002;Bozon et al 2003;Plath et al 2006). The expression of all of these IEGs is transiently induced by cocaine (Graybiel et al 1990;Young et al 1991;Moratalla et al 1992;Bhat and Baraban 1993;McGinty 1994, 1995;Fosnaugh et al 1995;Tan et al 2000;Fumagalli et al 2006) and cocaineassociated cues (Brown et al 1992;Crawford et al 1995;Everitt and Robbins 2000;Neisewander et al 2000;Ciccocioppo et al 2001;Thomas et al 2003: Zavala et al 2007). Moreover, cocaine-induced behavioral sensitization and conditioned place preference are absent in zif/268 knockout mice (Valjent et al 2006).…”