Imipramine as a discriminative stimulus

L Zhang and JE Barrett

Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

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- HT1A compounds 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide and gepirone; partial substitution occurred in pigeons trained with the higher dose of imipramine. Substitution for the imipramine stimulus by gepirone, an antidepressant with actions mediated by the 5-HT1A receptor, as well as with 8-hydroxy-2-(di-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.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 259, Issue 3, pp. 1088-1093, 12/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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