Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT 2 receptor function

Abstract

The acute and chronic effects of cocaine were evaluated on the 5-hydroxytryptamine (5-HT)-receptor 5-HT 2 mediated behavioral function, the head-twitch response (HTR), in mice. In a recent study, we reported that the (±)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane HCl (DOI)-induced HTR was dose dependently reduced by cocaine via indirect stimulation of serotonergic 5-HT 1A and adrenergic α 2 receptors. In the present investigation, the HTR was evoked by the nonselective 5-HT agonist 5-methoxy- N, N-dimethyltryptamine hydrogen oxolate (5-MeO-DMT). Cocaine by itself failed to produce HTR but dose dependently inhibited the 5-MeO-DMT-induced behavior. Cocaine's effects were not due to 5-HT 3 antagonism since acute administration of the more potent 5-HT 3 antagonist (ICS-205,930) failed to produce or modify the 5-MeO-DMT-induced behavior. During withdrawal from chronic cocaine treatment (5–20 mg/kg). 5-MeO-DMT-induced HTR was enhanced. Depending upon the cocaine dose used, the induced supersensitivity persisted up to 172 h following cessation of cocaine treatment. The mechanisms of cocaine-induced supersensitivity were further investigated using the more selective 5-HT 2 agonist DOI. Withdrawal from a low-dose (0.03–1.25 mg/kg) chronic cocaine treatment caused the DOI-induced HTR to increase, whereas withdrawal from a 5- and 10-mg/kg cocaine regimen had no significant effect. The maximal effect persisted up to 36 h following termination of cocaine treatment. Relative to vehicle-exposed controls, withdrawal from cocaine treatment enhanced the inhibitory potency of the 5-HT 1A agonist (±)-8-hydroxy-2-(di- n-propylamino)tetralin HBr (8-OH-DPAT) on DOI-induced HTR. Moreover, the 5-HT 1B/1C agonist 1-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP) and the 5-HT 3 agonist m-chlorophenylbiguanide HCl (mCPBG) failed to modify DOI-induced HTR in chronically vehicle-exposed mice but both agents reduced the induced behavior in the cocaine-treated group. Unlike changes in the sensitivity of serotonergic receptor subtypes, cocaine exposure failed to modify α 2 adrenoceptor sensitivity because clonidine was equipotent in inhibiting DOI-induced behavior in both groups treated chronically with vehicle and cocaine. Thus, the present study demonstrates a serotonergic component of cocaine's action in that low-dose chronic exposure enhances the functional sensitivity of serotonergic 5-HT 1A, 5-HT 2, and 5-HT 3 receptors.