Adaptive responses of brain cyclic AMP-generating systems to alterations in synaptic input.

The concept of subsensitivity and supersensitivity as a mechanism of neuronal adaptation to alterations in synaptic activity in the brain is an attractive one. However, the complexity of the central nervous system has made it difficult to determine the cellular basis of apparent changes in neuronal excitability resulting from alterations in synaptic input (cf. ref. 83). It now seems that, at least for inhibitory central pathways in which cyclic AMP-generating systems mediate postsynaptic receptor-responses, alterations in synaptic input lead in rat cortex to predictable super- or subsensitivity of the norepinephrine-sensitive cyclic AMP-systems. Supersensitivity of histamine-sensitive cyclic AMP-systems also occurs in rat cortex as a result of apparent lesions of histaminergic tracts. The reason that supersensitivity does not develop to norepinephrine and histamine in guinea pig cortex after similar "denervations" is not known, but is central to an understanding of the factors involved in the role of cyclic AMP-mechanisms to the adaptive plasticity of the central nervous system. However, even before an understanding of all the factors involved in alterations in cyclic AMP-responses in brain tissue is obtained, studies on the effects of environmental and drug-manipulations can provide insights both into the central roles for cyclic AMP-mechanisms and into the nature of drug action. Clearly, an understanding of the interelationships of synaptic input and adaptive changes in postsynaptic cyclic AMP-systems and the exploitation of such knowledge for the elucidation of central adaptive function is an exciting challenge for future research.