NORADRENERGIC REGULATION OF IMMEDIATE-EARLY GENE-EXPRESSION IN RAT FOREBRAIN - DIFFERENTIAL-EFFECTS OF ALPHA(1)-ADRENOCEPTOR AND ALPHA(2)-ADRENOCEPTOR DRUGS

Noradrenergic (NAergic) transmission in the rat cerebral cortex has recently been shown to be involved in the regulation of the basal expression of NGFI-A, an immediate early gene (IEG) which encodes a zinc-finger transcription factor. The present study further investigated the role of the NAergic system in mediating cortical IEG expression and possible topographical changes in expression of NGFI-A mRNA in rat forebrain after alpha(1)-, and alpha(2)-adrenoceptor (AR) agonist and antagonist treatment. Expression of c-fos and c-jun, which encode leucine-zipper class transcription factors, was also studied. Male Sprague-Dawley rats were injected intraperitoneally with either an alpha(1)-AR agonist (methoxamine, 5 or 10 mg/kg); an alpha(1)-AR antagonist (prazosin, 5 mg/kg); an alpha(2)-AR agonist (clonidine, 0.5 mg/kg); or an alpha(2)-AR antagonist (methoxyidazoxan, 5 mg/kg) and killed after 1 h. IEG mRNA levels were detected by quantitative in situ hybridization histochemistry using S-35-labelled oligonucleotides. High basal levels of NGFI-A mRNA were present in cortical layers IV and VI, hippocampal CA1, piriform cortex, amygdala and caudate putamen. alpha(1)-AR agonist and antagonist treatment had essentially no effect on IEG mRNA, despite producing characteristic behavioral and peripheral effects at the doses used. Methoxyidazoxan significantly increased (mean%) NGFI-A mRNA in: cerebral cortex (44); caudate putamen (82); amygdala (92); and CA1 of hippocampus (48), while clonidine significantly decreased NGFI-A mRNA in the various cortical layers to a similar extent (27-37%). Basal c-fos mRNA expression was lower than that for NGFI-A in forebrain areas including cortex, caudate putamen and hippocampus. Methoxyidazoxan increased c-fos mRNA in cortex (30%), with no marked effect in other areas. Clonidine had no significant effect: on c-fos mRNA. In contrast, c-jun mRNA was not altered by any of the alpha-AR drugs used, although high basal c-jun mRNA levels were present in cortex, CA2-3, dentate gyrus and thalamus. These results suggest that alpha(2)-ARs normally mediate a strong inhibitory influence on NGFI-A expression in rat forebrain and that induction of the cellular transcription factor genes, NGFI-A and c-fos, mediate influences of the NAergic innervation on cortical and subcortical neuron activity.