High-dose subchronic imipramine treatment: effects on anxiety-like (conflict) behavior in rats

In the management of both anxiety and depression, agents such as imipramine (IMI) are noted for their 3-5 week delay to onset of clinical effect. A similar delay to onset has been reported for the anxiolytic-like (i.e., anticonflict) effect of chronic IMI treatment (2.5 mg/kg, BID for 5 weeks) in the Conditioned Suppression of Drinking (CSD) conflict paradigm; similar effects have been reported with other antidepressants and in other conflict procedures. In contrast, in the Forced Swim Test (FST) model of depression, antidepressant-like effects are reported immediately following subchronic treatment with relatively high doses of these agents (e.g., 30 mg/kg IMI, 3 times in 24 hr). The present study examined the effects of this high-dose, subchronic treatment with IMI on CSD conflict behavior. Conflict-trained female Sprague Dawley rats were divided into three groups with comparable pretreatment baselines for shocks received. Treatments (0, 15, and 30 mg/kg IMI) were administered intraperitoneally (IP) at 23, 5, and 1 hr prior to CSD conflict testing on day 1; CSD conflict behavior was then monitored daily (Mon-Fri) for 5 weeks following treatment. IMI treatment (30 and, to a lesser extent, 15 mg/kg) significantly reduced shocks received (punished responding) and water intake (unpunished responding) on day 1; although water intake was also slightly reduced in both IMI treatment groups for the remainder of test week 1, there was no difference in shocks received between the various treatments for this period. Subjects receiving 30 mg/kg IMI (but not those receiving 15 mg/kg IMI or vehicle) accepted significantly more shocks than controls on weeks 2-4 (maximal increase at week 3) and returned to pretreatment baseline levels by week 5. Thus, subchronic high-dose treatment with IMI (and perhaps other antidepressants) produces anxiolytic-like effects which are delayed in nature and persist for several weeks after treatment.