ROLE OF THE INHIBITORY ADRENERGIC ALPHA-2 AND SEROTONERGIC 5-HT(1A) COMPONENTS OF COCAINE ACTIONS ON THE DOI-INDUCED HEAD-TWITCH RESPONSE IN 5-HT2- RECEPTOR SUPERSENSITIVE MICE

It was recently reported that acute cocaine pretreatment can reduce th e +/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced 5-h ydroxytryptamine2 (5-HT2)-receptor mediated head-twitch response (HTR) in mice via indirect stimulation of adrenergic alpha2- and serotonerg ic 5-HT1A-receptors. The aim of the present investigation was to deter mine whether cocaine can alter the DOI-induced HTR in 5-HT2-receptor s upersensitive mice. Supersensitivity was induced by a single injection of DOI 48 h prior to experimentation. These supersensitive mice exhib ited a greater frequency of HTR to a challenge dose of DOI 48 h after its initial administration. Cocaine pretreatment dose-dependently redu ced the DOI-induced HTR in the supersensitive mice. The stimulant was approximately four times more potent in the 5-HT2-receptor supersensit ive mice relative to its reported effects in normal mice. Receptor blo ckade studies with yohimbine and alprenolol revealed that both of the inhibitory components of cocaine's actions (i.e., adrenergic alpha2- a nd serotonergic 5-HT1A-receptor effects, respectively) were more effic ient in reducing the DOI-induced HTR in supersensitive mice compared t o normosensitive animals. The present results further support the prev iously suggested hypothesis that acute cocaine administration inhibits the 5-HT2-receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and the refore indirectly stimulating the respective inhibitory adrenergic alp ha2- and serotonergic 5-HT1A-receptors.