Dibutyryl Adenosine Cyclic 3′:5′-Monophosphate Effects on Goldfish Behavior and Brain RNA Metabolism

Abstract

Intraventricular administration of dibutyryl adenosine cyclic 3':5'-monophosphate into goldfish brains produced hyperactive animals. A study of the effects of the drug (25-50 mg/kg) on the incorporation of [5-'Hlorotic acid, as a precursor of labeled uridine and cytidine, into newly synthesized RNA showed the formation of an RNA with a uridine to cytidine ratio 20-50% higher than that of the control. In double-labeling experiments with uridine as the labeled precursor, the synthesis of a nuclear RNA fraction (not produced in the absence of drug) was demonstrated. Some of this RNA was found to migrate into the cytoplasmic fraction and to become associated-with polysomes. The results suggest that cyclic AMP might function as a "metabolic demand signal" for eliciting new RNA synthesis in goldfish brain.Adenosine cyclic 3':5'-monophosphate (cAMP) has been implicated as a mediator of hormonal responses in many cell functions. Sutherland et al. (1, 2) have proposed the general concept that cAMP acts as the "second messenger" inside cells. According to this postulate, the external receptor molecules are coupled with adenylate cyclase molecules situated on the internal surface of the cell membrane. Inputs, hormonal or otherwise, at the external receptors would promote some type of conformational change to activate the synthesis of cAMP by adenylate cyclase. By this means, environmental inputs would be transduced by the surface receptors into an increased intracellular concentration of cAMP. The cAMP molecules within the cell then participate in various functions.A number of observations have suggested that cAMP also plays a key role in brain metabolism. Sutherland, Rall, and Menon (3) found that adenylate cyclase is widely distributed in brain tissue; the concentration was highest in the cortex and the lowest in the spinal cord of rat brain. Kakiuchi and Rall (4) showed that tissue slices from brain can be stimulated to synthesize cAMP by catecholamines, particularly norepinephrine. In addition, electrical stimulation of nervous-tissue slices (5) or of intact superior cervical sympathetic ganglia (6) produces a 10-fold and a 5-fold increase in the concentration of cAMP, respectively. Electrophoretic administrations of cAMP to cerebellar Purkinje cells causes a rapid decrease in the firing rate of the neurons (7), suggesting a post synaptic role for the molecules.In a previous paper (8) RNA changes in the brain of goldfish were correlated with the acquisition and storage of new behavioral patterns. It was suggested (8) that the RNA changes might result from a "biochemical demand signal" that was characteristic of the response of the nervous system to the acquisition of new behavioral patterns. In the present paper, the possibility that cAMP may function as such a "biochemi-2835 cal demand signal" was examined. Two experimental methods were used in-the study. In the first series of experiments, intracerebral injections of N6,021-dibutyryl adenosine cyclic havior was studied by injection of 10-IA aliquots of an aqu...

Letters to the Editor

“…In this way the specialized information recording function of nervous tissue can utilize processes and substrates which may be common to all cells, but maximally developed in brain. Thus, the search for biochemical correlates of the process of information storage becomes one of two types, (1) a search for the neural response to new information Barondes 1967;Flexner 1970;Hyden 1962;Glassman 1969 andShashoua 1968), and (2) the search for trigger substances which can activate the metabolism of specific classes of neural circuits (Shashoua, 1971 …”