Differential Spatiotemporal Alterations in Adrenoceptor mRNAs and Binding Sites in Cerebral Cortex Following Spreading Depression: Selective and Prolonged Up-Regulation of α1B-Adrenoceptors

Noradrenaline, an important transmitter in the CNS, is involved in cerebral plasticity and functional recovery after injury. Experimental brain injury, including KCl application onto the brain surface, induces a slow-moving cortical depolarization/depression wave called cortical spreading depression (CSD). Interestingly, CSD does not produce neuronal damage but can protect cortical neurons against subsequent neurotoxic insults, although the mechanisms involved are unknown. This study examined the status of α- and β-adrenoceptors (ARs) in cerebral cortex following CSD. Anesthetized rats had unilateral CSD induced by a 10-min topical application of KCl to the frontoparietal cortex and were killed at various times thereafter. Levels of α₁-, α₂-, β₁-, and β₂-AR mRNA and binding were examined usingin situhybridization histochemistry and radioligand autoradiography. Levels of α_1b-AR mRNA in the affected neocortex were significantly increased by 20–40% at 1, 2, and 7 days (P ≤ 0.01) compared with contralateral levels, but were not significantly above control values at 2 and 4 weeks after CSD induction. Cortical α_1B-AR binding sites were also increased by 45–65% 1 and 2 weeks (P ≤ 0.01) after CSD in a similar, but delayed, profile to α_1b-AR mRNA. CSD rapidly increased β₁-AR mRNA by 45% at 1 h (P ≤ 0.01) and produced a delayed decrease of 25% in α_2a-AR mRNA at 2 days and 1 week (P ≤ 0.05), but had no effect on corresponding levels of binding sites. In contrast, CSD had no effect on the remaining AR-subtype mRNAs or binding levels in neocortex under identical conditions. These results reveal a long-term up-regulation of α_1B-ARs induced by an acute cortical stimulation/depression. Subtype-selective responses of ARs to CSD reflect an important differential regulation of expression of each receptorin vivoand suggest that α_1B-ARs are particularly likely to be involved in cortical adaptive responses to physical injury at both local and distant locations.