Dopaminergic and serotonergic properties of fluoxetine

1. Rats were trained to discriminate i.p. injections of a 5-HT agonist, LSD (0.08 mg/kg, n = 12) or a DA agonist, cocaine (10 mg/kg; n = 16) in a two lever, drug discrimination situation. 2. Animals were tested with fluoxetine (0.625-10 mg/kg) alone and in combination with low doses of the training drugs. 3. Fluoxetine did not substitute for either LSD or cocaine at any dose tested. A relatively low dose of fluoxetine (2.5 mg/kg) potentiated the discriminability of cocaine (2.5 mg/kg) from saline. A higher dose of fluoxetine (5.0 mg/kg) significantly enhanced the effects of a low dose of LSD (0.02 mg/kg), but only to 41.7% responses on the LSD-appropriate lever. 4. The data suggest that fluoxetine alters the discriminative stimulus properties of cocaine to a greater extent than those of LSD. 5. The ability of fluoxetine to potentiate the cocaine cue (but not to substitute for cocaine) suggests that both of those drugs affect DA systems, but do so through different mechanisms. For example, fluoxetine may not inhibit DA reuptake (to the same extent as cocaine), but may have other dopaminergic actions such as increasing DA receptor density.