EFFECT OF CHRONIC TREATMENTS WITH TANDOSPIRONE AND IMIPRAMINE ON SEROTONIN-MEDIATED BEHAVIORAL-RESPONSES AND MONOAMINE RECEPTORS

The effects of acute and chronic treatment of rats with the tricyclic antidepressant imipramine, the 5-HT1A receptor partial agonist tandosp irone, or its metabolite 1-PP were compared on behavioral responses pr oduced by the activation of 5-HT receptors and on brain monoamine rece ptors. The behaviors examined were the 5-HT behavioral syndrome elicit ed by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake respons e produced by the 5-HT2 receptor agonist DOB. Drug treatments were adm inistered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were a ssessed when the drug was present and absent at the time of testing. T he infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug prese nt) and 24 hr after the drug was withdrawn (drug absent). When adminis tered by injection, tandospirone blocked the production of the 5-HT sy ndrome 1 hr (drug present), but not 24 hr (drug absent), following eit her 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections o f imipramine blocked the 5-HT syndrome when tested 1 hr but not 24 hr, after the final injection. Treatment with 1-PP did not alter the 5-HT syndrome. The head shake response was attenuated by acute and chronic injection of tandospirone either 1 or 24 hr after treatment, although chronic infusion of tandospirone did not alter this behavior, Head sh aking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chr onic injection of 1-PP also inhibited the head shake response 24 hr af ter injection, although 1-PP was ineffective at all other times and wh en given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in fr ontal cortex was reduced by the chronic infusion of either tandospiron e, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced followi ng chronic imipramine injections or infusion. The results suggest that both tandospirone and imipramine may regulate 5-HT-mediated responses and 5-HT2 receptor density, which may contribute to their efficacy as antidepressants, although their effects were dependent upon the metho d of administration and may involve different neuropharmacological mec hanisms.