Role of the inhibitory adrenergic α2 and serotonergic 5-HT 1A components of cocaine's actions on the DOI-induced head-twitch response in 5-HT 2-receptor supersensitive mice

Abstract

It was recently reported that acute cocaine pretreatment can reduce the (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced 5-hydroxytryptamine 2 (5-HT 2)-receptor mediated head-twitch response (HTR) in mice via indirect stimulation of adrenergic α 2- and serotonergic 5-HT 1A-receptors. The aim of the present investigation was to determine whether cocaine can alter the DOI-induced HTR in 5-HT 2-receptor supersensitive mice. Supersensitivity was induced by a single injection of DOI 48 h prior to experimentation. These supersensitive mice exhibited a greater frequency of HTR to a challenge dose of DOI 48 h after its initial administration. Cocaine pretreatment dose-dependently reduced the DOI-induced HTR in the supersensitive mice. The stimulant was approximately four times more potent in the 5-HT 2-receptor supersensitive mice relative to its reported effects in normal mice. Receptor blockade studies with yohimbine and alprenolol revealed that both of the inhibitory components of cocaine's actions (i.e., adrenergic α 2- and serotonergic 5-HT 1A-receptor effects, respectively) were more efficient in reducing the DOI-induced HTR in supersensitive mice compared to normosensitive animals. The present results further support the previously suggested hypothesis that acute cocaine administration inhibits the 5-HT 2-receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and therefore indirectly stimulating the respective inhibitory adrenergic α 2- and serotonergic 5-HT 1A-receptors.