Feeding elicited by injection of the cholecystokinin antagonist dibutyryl cyclic GMP into the cerebral ventricles of sheep

Dibutyryl cyclic GMP (Bt₂cGMP) is a specific competitive antagonist of the action of cholecystokinin (CCK) on dispersed pancreatic acini and on gall bladder smooth muscle, and it exerts its effects at the CCK receptor level. CCK peptides in brain are proposed to have a role in satiety, and because (1) brain CCK receptors have characteristics similar to those of peripheral CCK receptors, and (2) injections of CCK-octapeptide (CCK-OP) into the cerebrospinal fluid (CSF) of sheep decreased feeding, we tested the ability of Bt₂cGMP to inhibit satiety when injected into the cerebral ventricles of sheep. Feed intakes were increased by more than 150% during the first hour of a two hour continuous injection of 2.9 nmole/min Bt₂cGMP (N=20, p<0.05). Although 29 and 290 nmoles/min Bt₂cGMP caused agitation and no increase in feeding, only normal behaviors were observed with the 2.9 nmole/min dose. A lower dose (0.72 nmole/min) had no effect on behavior or feed intake. The increase in feed intake caused by injection of 2.9 nmole/min Bt₂cGMP into the cerebral ventricles suggests that this nucleotide, acting as an antagonist of CNS CCK receptors, inhibited satiety and thus elicited feeding. These results, in conjunction with those demonstrating an increase in feeding following the binding of CCK in CSF by CCK antibody, support the hypothesis that brain CCK is released during feeding and acts on CCK receptors which are involved in the control of feed intake.