Clenbuterol increases norepinephrine release from rat brain slices by a calcium- and receptor-independent mechanism

Clenbuterol (10-100 μM), a β₂-adrenergic agonist, potentiated basal (unstimulated) and electrical stimulation-evoked release of ³H- norepinephrine from cerebral cortical slices in a concentration-dependent manner. The β-adrenergic antagonists propranolol and ICI 118,551 did not antagonize the facilitatory effect of clenbuterol on basal ³H-norepinephrine efflux. Selective down-regulation of β₂-adrenergic receptors produced by chronic administration of clenbuterol also did not alter this effect of in vitro clenbuterol, despite marked reductions in the density of these receptors. These results suggest that the increase in basal efflux of ³H- norepinephrine observed with clenbuterol was not mediated by β₂-adrenergic receptors. The facilitatory effect of clenbuterol on basal ³H- norepinephrine efflux was Ca²⁺-independent, which may indicate an amphetamine-like mechanism of action. The enhanced basal efflux of ³H- norepinephrine produced by clenbuterol was stereoselective; there was a four- fold increase in basal ³H-norepinephrine efflux with the (+)-isomer of clenbuterol compared with that induced by the (-)-isomer; this contrasts with the stereoselectivity of the isomers for interacting with β₂-adrenergic receptors. The present results may explain some of the behavioral actions of clenbuterol, particularly those observed after long-term treatment, and may be relevant to the antidepressant actions of this compound.