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 tandospirone, or its metabolite 1-PP were compared on behavioral responses produced by the activation of 5-HT receptors and on brain monoamine receptors. The behaviors examined were the 5-HT behavioral syndrome elicited by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake response produced by the 5-HT2 receptor agonist DOB. Drug treatments were administered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were assessed when the drug was present and absent at the time of testing. The infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug present) and 24 hr after the drug was withdrawn (drug absent). When administered by injection, tandospirone blocked the production of the 5-HT syndrome 1 hr (drug present), but not 24 hr (drug absent), following either 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections of 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 shaking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chronic injection of 1-PP also inhibited the head shake response 24 hr after injection, although 1-PP was ineffective at all other times and when given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in frontal cortex was reduced by the chronic infusion of either tandospirone, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced following 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 method of administration and may involve different neuropharmacological mechanisms.
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104.
S
S
Wieland
C T
CT
Fischette
I
I
Lucki
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D007099:Imipramine / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D017981:Receptors, Neurotransmitter; D017366:Serotonin Receptor Agonists; C055267:tandospirone; D007099:Imipramine