Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum

Abstract

The expression of immediate-early genes of the fos/jun leucine zipper family can be regulated in striatal neurons by stimuli affecting the dopaminergic nigrostriatal system. The regulatory effects are gene specific, region specific, and striatal compartment specific. In the experiments reported here, we have explored the possibility that dopaminergic stimulation might also affect striatal expression of NGFI-A, a member of the zinc finger family of immediate-early genes. We treated healthy adult rats with amphetamine or cocaine and monitored the acute response of striatal neurons by in situ hybridization with oligonucleotide probes for NGFI-A mRNA. Both drugs evoked rapid, anatomically patterned increases in NGFI-A mRNA expression in the dorsal striatum (caudoputamen) and in the ventral striatum (nucleus accumbens, olfactory tubercle). The main response to each drug was in medium-sized neurons, known to be the projection neurons of the striatum. At every dose of amphetamine eliciting a response, the increased NGFI-A mRNA expression was preferentially concentrated in striosomes of the rostral caudoputamen, whereas cocaine at each dose given induced expression of NGFI-A mRNA in both striosomes and matrix at these striatal levels. The two indirect agonists evoked NGFI-A expression in both striatal compartments farther caudally, especially in the central and medial caudoputamen. Activation by both drugs was blocked by pretreatment with the D1-selective dopamine receptor antagonist SCH23390. These patterns of NGFI-A activation are remarkably similar to those found for Fos-like immunoreactivity following acute amphetamine and cocaine treatments, suggesting that coordinate activation of members of at least two immediate-early gene families occurs in the striatum following catecholaminergic stimulation. Such patterns of induction strongly support the view that the genomic responsiveness of the striosome and of the matrix compartments of the rostral striatum are distinct at the level of early-response gene expression. These findings raise the interesting possibility that some of the well-known effects of dopaminergic stimulation on neuropeptide and neurotransmitter expression in the striatum may reflect particular combinatorial patterns of immediate-early gene activation.

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

“…The responsivity of EGR1, also known as NGFI-A, krox24, and zif268, to cocaine administration has been known for over a decade (Helton et al, 1993;Moratalla et al, 1992). More recently though, decreases in EGR1 mRNA expression have been documented during forced abstinence from highdose cocaine self-administration binges (Mutschler et al, 2000).…”

Dynamic interaction between medial prefrontal cortex and nucleus accumbens as a function of both motivational state and reinforcer magnitude: A c-Fos immunocytochemistry study

“…On the one hand, evidence suggests NAcc DA release can be inhibited by mPFC DA release, (Mitchell & Gratton, 1992) --a relationship that could be mediated by mPFC projections to VTA that innervate very specific populations of VTA cells, including GABAergic interneurons that have an inhibitory effect on the mesoaccumbens DA projection (Carr & Sesack, 2000). Such reductions in DA levels in the NAcc can explain the decreased c-Fos activity in this area, as dopamine and dopamine agonists were shown to stimulate the induction of c-Fos in the nucleus accumbens and striatum (Cole et al, 1994;Graybiel et al, 1990;Moratalla et al, 1992;Nguyen et al, 1992). Thus, this interaction between DA efflux in mPFC and NAcc could account for the negative correlations between mPFC and NAcc Fos immunoreactivity observed in animals deprived for 36h and allowed to feed on a small meal.…”

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

“…Cocaine acts as a competitive inhibitor of the monoamine transporters while METH reverses them [42,47]. Furthermore, the consequences produced by cocaine and METH, such as the expressions of opioid peptide mRNA [1,2] and immediate early genes [33,46] in some brain regions, are distinct. Therefore, the role of opioid receptors in the induction or expression of behavioral sensitization of these drugs may not be the same.…”