Effects of clenbuterol and antidepressant drugs on beta adrenergic receptor/N-protein coupling in the cerebral cortex of the rat

Repeated administration of the centrally acting beta adrenergic agonist clenbuterol to rats reduced the ability of isoproterenol to increase levels of cyclic AMP in slices of cerebral cortex. This lessened response to isoproterenol was not due to a reduction in beta receptor density but appeared to be due to diminished receptor/N-protein coupling. This was determined by measuring the ability of isoproterenol to inhibit the binding of the beta adrenergic antagonist [¹²⁵I]iodopindolol to membranes prepared from cerebral cortex. Using membranes prepared from vehicle-treated rats, isoproterenol, in the absence of GTP, inhibited the binding of [¹²⁵I]iodopindolol with an IC₅₀ value of 85 nM and a Hill coefficient of 0.65. GTP (250 μM) increased the IC₅₀ value to 290 nM and the Hill coefficient to 0.98. After repeated administration of 10 mg/kg of clenbuterol to rats for 8 days, isoproterenol inhibited the binding of [¹²⁵I]iodopindolol with an IC₅₀ value of 125 nM and a Hill coefficient of 0.90; GTP increased the IC₅₀ value to 170 nM and the Hill coefficient to 0.98. It was inferred from the results of modeling of the isoproterenol competition curves that the repeated administration of clenbuterol reduced or eliminated the high-affinity component of isoproterenol binding. These effects of clenbuterol were found to depend on dose and duration of treatment and were reversible. Repeated administration of the antidepressant drugs desipramine, imipramine, phenelzine, zimelidine and mianserin twice daily for 21 days, by contrast, did not affect receptor/N-protein coupling. All of these antidepressant drugs previously have been reported to reduce norepinephrine- or isoproterenol-stimulated adenylate cyclase activity in the rat brain. It appears that repeated administration of the lipophilic beta adrenergic agonist clenbuterol, but not of the antidepressant drugs tested, reduces or eliminates the ability of the beta adrenergic agonist isoproterenol to promote receptor/N-protein coupling.