Nefazodone in the rat: Mimicry and antagonism of [-]-DOM-induced stimulus control

Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT₂) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed psychoactive medications in the world and are likely to be ingested in the presence of hallucinogens with increased frequency; the consequences are largely unknown. The present investigation examined the interaction between the serotonergic phenethylamine hallucinogen [-]-2,5-dimethoxy-4-methylamphetamine ([-]-DOM), and nefazodone, in rats trained with [-]-DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. The data indicate that maximal substitution of nefazodone for the [-]-DOM stimulus was present using a 45-min pretreatment time before testing. Using this pretreatment time, a dose of nefazodone of 12.0 mg/kg administered alone resulted in 76% DOM-appropriate responding. When a range of doses of nefazodone was combined with the training dose of [-]-DOM, a pattern of responding compatible with partial agonism was observed. The intermediate degree of [-]-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT₂, SR 46349B (5HT_2A/2C), and M100907 (5-HT_2A). Taken together, the present data suggest that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT_2A receptor.