Imipramine as a discriminative stimulus

The tricyclic antidepressant imipramine was established as a discriminative stimulus in pigeons at two doses (3.0 or 5.6 mg/kg). Because imipramine has multiple effects on different neurotransmitter systems, a range of compounds from several pharmacological classes were tested for substitution. The tricyclic antidepressants desipramine, amitriptyline and doxepin, all of which block serotonin (5-HT) and norepinephrine (NE) reuptake, resulted in imipramine-key responding. The psychomotor stimulants cocaine and d-amphetamine also occasioned responding on the imipramine key, as did the NE reuptake inhibitor tomoxetine; nomifensine, which blocks the reuptake of both NE and dopamine (DA), also resulted in responding on the key correlated with imipramine injections. Bupropion, a DA reuptake inhibitor, resulted in drug key responding but substitution did not occur with another DA uptake inhibitor GBR 12909. The alpha-2 agonist clonidine, the 5-HT₂ antagonist ritanserin or the 5-HT reuptake inhibitor fluoxetine also did not occasion drug-key responding. Drug-appropriate responding occurred in pigeons trained at the lower dose of imipramine with the 5-HT(1A) compounds 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide and gepirone; partial substitution occurred in pigeons trained with the higher dose of impramine. Substitution for the imipramine stimulus by gepirone, an antidepressant with actions mediated by the 5-HT(1A) receptor, as well as with 8-hydroxy-2-(dl-n-propylamino)tetralin hydrobromide, suggests that imipramine may have effects at this receptor site and confirms reports that compounds active at this receptor may have antidepressant activity. This appears to be the first report of the successful, long-term establishment of imipramine as a discriminative stimulus without the development of toxicity. These results indicate that the discriminative stimulus effects of imipramine are complex and involve at least NE reuptake and a specific 5-HT receptor subtype (1A). Generalization to the imipramine stimulus by cocaine and d-amphetamine also suggests that further analyses of these drugs as discriminative stimuli, with particular attention to the possible role of the 5-HT(1A) receptor and NE systems, may aid in clarifying their neurochemical and behavioral actions as abused drugs.