Effect of Nerve Degeneration by 6-Hydroxydopamine on Catecholamine-Stimulated Adenosine 3',5'-Monophosphate Formation in Rat Cerebral Cortex

Intraventricular injection of 6-hydroxydopamine leads to two types of alterations in the effect of norepinephrine on the cyclic 3',5'-AMP content of slices of rat cerebral cortex: an early-developing, presynaptic effect and a late-developing, postsynaptic effect. The early effect is attributed to the destruction of adrenergic nerve terminals by 6-hydroxydopamine and the resultant loss of presynaptic catecholamine uptake sites. This conclusion is based on three primary observations: (a) the potentiation of the effect of a threshold concentration of norepinephrine (1 µM) by 6-hydroxydopamine followed approximately the same time course as the loss of ability of the slices to accumulate [ 3 H]norepinephrine; (b) cocaine, which inhibits the presynaptic accumulation of [ 3 H]norepinephrine, potentiated the effects of low concentrations of norepinephrine in slices from control rats but did not alter the effect of norepinephrine in slices from 6-hydroxydopamine-treated animals; (c) the EC 50 for norepinephrine was reduced from 5.2 to 1.7 µM by treatment with 6-hydroxydopamine, but the EC 50 for isoproterenol (which is not accumulated presynaptically) was not altered. Also, cocaine did not potentiate the increase in cyclic AMP content induced by isoproterenol in slices from control animals. The increase in the effect (of high concentrations (30 µM) of norepinephrine did not occur until 96 hr after treatment of the rats with 6-hydroxydopamine. This late-developing increase in responsiveness would appear to be a postsynaptic phenomenon, since it occurs during a time span (72-96 hr) when there is no further change in inhibition of the uptake of [ 3 H]norepinephrine. Furthermore, there is an increase in responsiveness to isoproterenol as well as to norepinephrine. Adenosine also causes an increase in the cyclic AMP content of rat cortext slices, but its effects are not altered by prior treatment with 6-hydroxydopamine.