Ultra-low doses of methamphetamine suppress 5-hydroxytryptophan-induced head-twitch response in mice during aging

The head-twitch response (HTR) in mice is considered a behavioral assay for activation of 5-HT 2A receptors in rodents. It can be evoked by direct-acting 5-HT 2A receptor agonists such as (±)-2,5-dimethoxy-4-iodoamphetamine, 5-hydroxytryptamine precursors [e.g. 5-hydroxytryptophan (5-HTP)], and selective 5-hydroxytryptamine releasers (e.g. d -fenfluramine). The nonselective monoamine releaser methamphetamine by itself does not produce the HTR but can suppress both (±)-2,5-dimethoxy-4-iodoamphetamine- and d -fenfluramine-evoked HTRs across ages via concomitant activation of the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors. Currently, we investigated: (1) the ontogenic development of 5-HTP-induced HTR in 20-, 30-, and 60-day-old mice; (2) whether pretreatment with ultra-low doses of methamphetamine (0.1, 0.25, and 0.5 mg/kg, intraperitoneally) can suppress the frequency of 5-HTP-induced HTR at different ages; and (3) whether the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors may account for the potential inhibitory effect of methamphetamine on 5-HTP-induced HTR. In the presence of a peripheral decarboxylase inhibitor (carbidopa), 5-HTP produced maximal frequency of HTRs in 20-day-old mice which rapidly subsided during aging. Methamphetamine dose-dependently suppressed 5-HTP-evoked HTR in 20- and 30-day-old mice. The selective 5-HT 1A -receptor antagonist WAY 100635 reversed the inhibitory effect of methamphetamine on 5-HTP-induced HTR in 30-day-old mice, whereas the selective adrenergic α 2 -receptor antagonist RS 79948 failed to reverse methamphetamine's inhibition at any tested age. These findings suggest an ontogenic rationale for methamphetamine's inhibitory 5-HT 1A receptor component of action in its suppressive effect on 5-HTP-induced HTR during development which is not maximally active at a very early age.