The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat

Abstract

The possible functional interaction between angiotensin and dopamine mechanisms in the rat was investigated by examining the effects of the angiotensin converting enzyme inhibitors captopril and enalapril on apomorphine-induced stereotypy. Apomorphine-induced behaviour was observed, and recorded using a keypad linked to a microcomputer. In agreement with previous findings, low doses of apomorphine induced a syndrome of vacuous mouth movements, penile grooming, yawning and immobility whereas at higher doses the yawning syndrome disappeared to be replaced with sniffing, licking and gnawing. Two antagonism studies were carried out. In the first the effects of captopril on apomorphine-induced behaviour were compared with those of the classical neuroleptic haloperidol, and in the second dose—response curves for the effects of captopril and enalapril on apomorphine-induced behaviour were determined. Captopril had no effect on the apomorphine-induced yawning syndrome whereas this was blocked by haloperidol. In contrast, both captopril and haloperidol blocked oral stereotypy (licking and gnawing) induced by apomorphine but had no effect on sniffing induced by the dopamine agonist. Selective blockade of apomorphine-induced oral stereotypy by angiotensin converting enzyme inhibition was confirmed in the second study in which both captopril and enalapril were observed to antagonize apomorphine-induced gnawing. The inhibition of apomorphine-induced gnawing by enalapril correlated with inhibition of brain angiotensin converting enzyme, but not lung angiotensin converting enzyme, by the drug as assessed by ex vivo penetration studies. These data suggest that angiotensin converting enzyme inhibition modulates the expression of apomorphine-induced oral stereotypy, a response that is thought to be mediated by postsynaptic dopamine receptors. In contrast, the yawning syndrome induced by low doses of apomorphine which is thought to be due to selective stimulation of dopamine autoreceptors is unaffected by the angiotensin converting enzyme inhibitors. Thus the pharmacological interaction between inhibition of brain angiotensin converting enzyme and blockade of apomorphine-induced oral stereotypy probably occurs at postsynaptic dopamine receptors or at downstream sites innervated by striatal neurones (e.g., substantia nigra or superior colliculus).