Metabolite involvement in bromocriptine-induced circling behaviour in rodents

Bromocriptine and apomorphine produced identical circling responses in rodents with medial forebrain bundle lesions. Rotation induced by bromocriptine, but not by apomorphine, was inhibited by prior treatment with reserpine or alpha-methyl-p-tyrosine suggesting a requirement for intact presynpatic events. Bromocriptine-induced circling also was inhibited by the catecholamine re-uptake blockers nomifensine and desmethylimipramine, supporting the role of presynaptic mechanisms. Bromocriptine-induced circling, but not apomorphine circling, was reduced by pre-treatment with SKF 525A, an inhibitor of monooxygenase enzymes, suggesting metabolite involvement in the turning response. This compound prolonged hexobarbitone sleeping times and zoxazolamine paralysis times in mice. These indices of drug metabolizing activity also were prolonged by pre-treatment with desmethylimipramine while nomifensine prolonged only hexobarbitone sleeping times and alpha-methyl-p-tyrosine had no effect on either index. The data suggest that a metabolite of bromocriptine may be of importance in causing circling and that uptake of bromocriptine (or a metabolite) into presynaptic catecholamine terminals may be necessary.