Effect of intracerebroventricular bradykinin and related peptides on rabbit operant behavior

The dose-effect relationships of intraventricularly injected bradykinin, Gly-Arg-Met-Lys-bradykinin (GAML-bradykinin), synthetic substance P and angiotensin II on lever-lifting behavior of rabbits in a variable-interval (VI) 72-second schedule of sweetened water presentation were determined. All peptides used caused dose-dependent decreases in overall rates of VI responding during the experimental session in the following order of potency: angiotensin II greater than bradykinin = substance P greater than GAML-bradykinin. The angiotensin II dose-effect curve was less steep than those of the other peptides. The administration of nearly equimolar doses of the bradykinin potentiating peptides, BPP5a and BPP9a, slightly decreased overall VI response rates and caused a 10- to 20-fold potentiation of the rate-decreasing effect of bradykinin on VI responding. Both angiotensin II and bradykinin caused pauses in responding of dose-dependent duration at the beginning of the experimental session that were followed by normal VI responding. The effect of GAML-bradykinin on VI performance was similar to that of bradykinin and angiotensin II but had a delay of onset of 3 to 6 minutes. In contrast, substance P caused actual decreases in response output and pauses of variable duration interspersed between periods of regular VI responding. At the doses used, both bradykinin-potentiating peptides caused uniform decreases in VI responding throughout the experimental session. Gross behavioral changes caused by the peptides were also observed. After the intraventricular injection of bradykinin or GAML-bradykinin, rabbits showed decreased motility, ptosis, miosis and lowered ears; after angiotensin II, animals remained motionless but with wide open eyes, fully raised ears and no miosis. In turn, substance P caused restlessness and increased locomotion. These results together with reported evidence on other powerful central actions of bradykinin, angiotensin and substance P and on the existence of components of their releasing and destroying enzymatic systems in the brain suggest that linear peptides may play a role in the functioning of the central nervous system.