Β-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling

Abstract The central levels of endogenous tryptophan metabolite kynurenic acid (KYNA), an antagonist of N -methyl- d -aspartate (NMDA) and α7-nicotinic receptors, affect glutamatergic and dopaminergic neurotransmission. Here, we demonstrate that selective agonists of β 1 -receptors (xamoterol and denopamine), β 2 -receptors (formoterol and albuterol), α- and β-receptors (epinephrine), 8pCPT-cAMP and 8-Br-cAMP (analogues of cAMP) increase the production of KYNA in rat brain cortical slices and in mixed glial cultures. Neither betaxolol, β 1 -adrenergic antagonist, nor timolol, a non-selective β 1,2 -adrenergic antagonist has influenced synthesis of KYNA in both paradigms. In contrast, KT5720, a selective inhibitor of protein kinase A (PKA), strongly reduced KYNA formation in cortical slices (2–10 µM) and in glial cultures (100 nM). β-adrenergic antagonists and KT5720 prevented the β-adrenoceptor agonists-induced increases of KYNA synthesis. In vivo , β-adrenergic agonist clenbuterol (0.1–1.0 mg/kg) increased the cortical endogenous level of KYNA; the effect was blocked with propranolol (10 mg/kg). β-adrenoceptors agonists, cAMP analogues and KT5720 did not affect directly the activity of KAT I or KAT II measured in partially purified cortical homogenate. In contrast, the exposure of intact cultured glial cells to pCPT-cAMP, 8-Br-cAMP and formoterol has lead to an enhanced action of KATs. These findings demonstrate that β-adrenoceptor-mediated enhancement of KYNA production is a cAMP- and PKA-dependent event. PKA activity appears to be an essential signal affecting KYNA formation. Described here novel mechanism regulating KYNA availability may be of a potential importance, considering that various stimuli, among them clinically used drugs, activate cAMP/PKA pathway, and thus could counteract the central deficits of KYNA.