Differential modulatory effects of alpha- and beta-adrenoceptor agonists and antagonists on cortical immediate-early gene expression following focal cerebrocortical lesion-induced spreading depression.

Abstract

Unilateral, focal cerebrocortical lesion (FCL) and associated spreading depression (SD) increase immediate-early gene (IEG) expression throughout the ipsilateral hemisphere. Noradrenergic transmission is involved in the regulation of basal- and stimulation-induced expression of IEGs in cerebral cortex; and is modulated by both injury and SD. The present study further investigated the association between the noradrenergic system and cortical adaptive responses, by examining basal and FCL(SD)-induced cortical IEG expression following acute treatment with alpha(1)-, alpha(2)- and beta(1/2)-adrenoceptor (AR) agonists or antagonists. Activation of alpha(1)-ARs by NVI-085, or beta-ARs by salbutamol, increased cortical NGFI-A, c-jun and c-fos mRNA levels, whereas inhibition of alpha(1)-ARs by prazosin, or beta-ARs by propranolol, had no marked effect. The alpha(2)-AR agonists, clonidine and UK14304 also had no effect on basal IEG levels, while blockade of alpha(2)-ARs by methoxyidazoxan significantly increased NGFI-A and c-fos expression, but decreased c-jun mRNA levels. This latter effect confirms the complex and differential nature of IEG regulation in brain. In FCL(SD) rats, all AR agonists generally produced a supra-additive (synergistic) effect on expression of the examined IEGs, compared with drug-treatment or FCL alone. Prazosin reduced FCL(SD)-induced elevations of c-jun and c-fos, but not NGFI-A, mRNA. Methoxyidazoxan enhanced NGFI-A and c-fos mRNA expression after FCL(SD), but reduced c-jun. Propranolol enhanced all lesion-induced IEG levels. These results confirm that alpha(1)- and beta-ARs normally mediate a stimulatory, and alpha(2)-ARs a net inhibitory, influence on cortical cell activity (reflected by NGFI-A, c-fos expression); and demonstrate that alterations in noradrenergic tone modulate the level of cellular activation during and after SD, which is primarily elicited by K(+)/glutamate via NMDA receptors and Ca(2+)-associated mechanisms. In turn, noradrenergic transmission and interactions with excitatory systems are likely to be important in responses to brain injury, including regulation of IEGs and their downstream target genes.