Molecular Pharmacology, Vol 13, 1170-1180, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Supersensitivity in Rat Cerebral Cortex: Pre- and Postsynaptic Effects of 6-Hydroxydopamine at Noradrenergic Synapses

¹ Department of Pharmacology, University of Colorado Medical Center, Denver, Colorado 80262

The intraventricular administration of 6-hydroxydopamine resulted in the destruction of noradrenergic nerve terminals in the rat cerebral cortex and a 90% decrease in norepinephrine content. The time courses of the effects of this treatment on catecholamine-stimulated cyclic 3',5'-AMP accumulation in slices of cerebral cortex and on beta adrenergic receptors were determined to investigate the mechanisms underlying supersensitivity in this system. The EC₅₀ for norepinephrine stimulation of cyclic AMP accumulation decreased following 6-hydroxydopamine administration. This decrease was apparent within 1 day and was probably due to the loss of the presynaptic uptake system for norepinephrine. The density of beta adrenergic receptors, as determined by measuring the binding of the high-affinity beta adrenergic receptor antagonist [¹²⁵I]iodohydroxybenzylpindolol, and maximal levels of catecholamine-stimulated cyclic AMP accumulation increased with a slower time course, reaching peak levels approximately 16 days after treatment with 6-hydroxydopamine. The maximal increase in the density of beta adrenergic receptors was 50%, while maximal levels of cyclic AMP accumulation in treated rats were approximately twice those measured in control animals. The K_D of [¹²⁵I]iodohydroxybenzylpindolol for beta adrenergic receptors and the EC₅₀ of isoproterenol for stimulation of cyclic AMP accumulation were unchanged following 6-hydroxydopamine administration, suggesting that the intrinsic properties of the postsynaptic receptor were not affected by denervation. The administration of 6-hydroxydopamine did not affect fluoride-sensitive adenylate cyclase activity. The results are consistent with the idea that the supersensitivity to catecholamines that occurs in the cerebral cortex following 6-hydroxydopamine administration had both pre- and postsynaptic components. The slowly developing postsynaptic component can be at least partially explained by an increase in the density of beta adrenergic receptors.

Note:
ACKNOWLEDGMENT Ms. Jane Andrews provided excellent technical assistance.

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