Effect of dopaminergic agonists and antagonists on in vivo cyclic nucleotide content: Relation of guanosine 3':5'-monophosphate (cGMP) changes in cerebellum to behavior

Apomorphine was shown to increase guanosine 3'-5'-monophosphate (cGMP) levels in the cerebellum in a dose-related fashion without consistently affecting content in the striatum. The elevation in cerebellar cGMP induced by apomorphine was antagonized by the cis, but not the trans, isomer of flupenthixol and was enhanced by 6-hydroxydopamine treatments which reduced dopamine. Furthermore, selected antipsychotic compounds were shown to antagonize the increase in cerebellar cGMP after apomorphine administration in proportion to their potency to block dopaminergic receptors. These observations provided evidence that apomorphine was activating dopaminergic receptors resulting in increases in cerebellar cGMP. However, neither apomorphine nor antipsychotic drugs altered cAMP content in the cerebellum or in the striatum. While d-amphetamine and methylphenidate also increased cerebellar cGMP, other drugs proposed to be dopaminergic agonists, such as bromocriptine, lergotrile and piribedil, did not alter the content of this cyclic nucleotide in the cerebellum unless administered to 6-hydroxydopamine-treated rats. These data suggest that drugs such as d-amphetamine and apomorphine have properties which differentiate them from other dopaminergic agonists investigated. Experiments also demonstrated that paralysis with d-tubocurarine attenuated the action of apomorphine on cerebellar cGMP in both control and 6-hydroxydopamine-treated rats and reduced control levels of cerebellar cGMP. These latter results indicate that secondary effects, such as alterations in behavioral activity, can contribute to the magnitude of change observed in cerebellar cGMP content after drug administration.