A 5-HT(2C) receptor-mediated interaction between 2,5-dimethoxy-4-methylamphetamine and citalopram in the rat

Previous studies conducted in our laboratory have shown that acute administration of the selective serotonin re-uptake inhibitor (SSRI), citalopram, potentiates the stimulus effects of the phenethylamine hallucinogen [-]-2,5-dimethoxy-4-methylamphetamine (DOM) in the rat while neither substituting for the DOM stimulus when administered alone nor altering brain levels of DOM. The present investigation was designed to determine the mechanism by which citalopram acts on DOM-induced stimulus control. To that end, we tested the following hypotheses: (a) citalopram blocks the transport of DOM by the serotonin transporter, (b) citalopram acts via the 5-HT(1A) receptor, and (c) citalopram acts via the 5-HT(2C) receptor. Hypothesis (a) was rejected on the basis of equilibrium saturation studies of [3H]citalopram binding, which revealed no significant affinity of DOM for the 5-HT transporter of rat brain membranes. Hypotheses (b) and (c) were tested in a group of 20 rats in which stimulus control was established with DOM (0.6 mg/kg; 75 min pretreatment time). A two-lever, fixed ratio 10 (FR10), positively reinforced task with saline controls was employed. Hypothesis (b), a role for the 5-HT(1A) receptor, was rejected on the basis of an absence of antagonism of the effects of citalopram on DOM by the selective 5-HT(1A) receptor antagonist, WAY-100635. In contrast, Hypothesis (c), a role for the 5-HT(2C) receptor, gained support from the observation of significant antagonism of the effects of citalopram on DOM by the selective 5-HT(2C) receptor antagonist, SB-242084.