Antagonism of baclofen's effects on rat striatal 5‐HT metabolism: A model for 5‐HT agonistic properties?

Abstract

AbstractThe increase in the rat striatal concentration of 5‐hydroxyindoleacetic acid (5‐HIAA) elicited by baclofen was antagonized by the 5‐HT antagonists pipamperone (10/30 mg/kg i.p.), cyproheptadine (30 mg/kg i.p.), methiothepin (1 mg/kg i.p.), and GP 50 302 (1/3 mg/kg i.p.), but not by cinanserin (1–30 mg/kg i.p.), pizotifen (1–10 mg/kg i.p.), spiroperdol (0.1–1 mg/kg i.p.), or haloperidol (0.1–1 mg/kg i.p.). The 5‐HT agonists, m‐chlorophenylpiperazine (1 mg/kg i.p.) and MK 212 (3/10 mg/kg i.p.) also showed an antagonistic effect. Methysergide (5–20 mg/kg i.p.) and quipazine (2.5/5 mg/kg i.p.) were previously shown to act similarly, whereas mianserin (5–20 mg/kg i.p.) was inactive and methergoline at lower doses (0.25–0.5 mg/kg i.p.) increased the effect of baclofen, which was reversed at higher doses (1 mg/kg i.p.). The alterations by these compounds of the 5‐HT increase elicited by baclofen were more or less similar; however, they were less clear‐cut and occurred at higher doses. These interactions were not the result of interferences of the compounds with the absorption, distribution, or metabolism of baclofen nor with its effect on the nigrostriatal dopaminergic system, since the increase in dopamine concentrations it caused was not affected by any of the compounds. A comparison of our results with published data on the antagonism of 5‐hydroxytryptophan‐induced head twitches, on spiroperidol or 5‐HT displacement, on 5‐HT‐stimulated adenylate cyclase, and with electrophysiological results suggests that the antagonistic effect of compounds interfering with the 5‐HIAA elevating action of baclofen is not related to 5‐HT receptor blocking properties of these drugs, Instead, it seems to be much more related to 5‐HT agonists properties. It is speculated that this model might reveal presynaptic agonistic properties of drugs, but more data are needed to confirm or reject this.