Modulation in the sensitivity of noradrenergic receptors in the CNS studied by the responsiveness of the cyclic AMP system

Abstract

Various characteristics of the altered responsiveness to noradrenaline (NA) of the cyclic Amp (cAMP) generating system of cortical brain slices have been studied in rat after chronic reserpine treatment and in mice after chronic D-amphetamine treatment. Supersensitivity of the cAMP system to NA following reserpine treatment and subsensitivity after D-amphetamine treatment exhibit many common features. Firstly, in both cases the modified responsiveness to NA occurs rapidly after the beginning of the treatment (one day for reserpine and 5 h after amphetamine) and recovers slowly after the end of the treatment. Additionally, the altered states of sensitivity of the cAMP system to NA are the result of a modification of the maximal response rather than of an altered affinity of the system to NA. Since, following D-amphetamine treatment the change of sensitivity is still apparent in the presence of a potent phosphodiesterase inhibitor, the involvement of a gross alteration of phosphodiesterase activity is unlikely. In this case too, while the response to adenosine is slightly decreased, the responses to dopamine and serotonin of the cAMP system observed in brain slices following D-amphetamine treatment is not detected in a cell-free preparation. Thus, it appears that drug treatments, modifying synaptic transmission in opposite directions, lead also to changes in opposite directions of the responsiveness of the cAMP system to NA. The hypothesis that the mechanisms underlying such phenomena are related to a modified number of functional noradrenergic receptors is discussed.