CHRONIC, COMBINED TREATMENT WITH DESIPRAMINE AND MIANSERIN - ENHANCED 5-HT(1A) RECEPTOR FUNCTION AND ALTERED 5-HT(1A)/5-HT(2) RECEPTOR INTERACTION IN RATS

A greater percentage of depressed patients respond to combined treatment with a tricyclic antidepressant and the tetracyclic antidepressant mianserin than to treatment with these drugs given alone. The functional sensitivity of the 5-hydroxytryptamine (5-HT)1A receptor, and the functional interaction between the 5-HT1A and the 5-HT2 receptors were investigated after treatment with desipramine and mianserin either alone or combined for 21-28 days. Pretreatment with desipramine and mianserin in combination induced the most intense 5-HT syndrome and the greatest fall in colonic temperature after injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). The rats pretreated with desipramine alone had the largest elevation of the response temperature in the increasing temperature hot-plate test after injection of 8-OH-DPAT . After the combined pretreatment with desipramine and mianserin, no enhanced functional response in these tests was found when the 5-HT1A and the 5-HT2 receptors were stimulated simultaneously using 8-OH-DPAT and the 5-HT2 agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCI (DOI), contrasting the findings for desipramine or mianserin treatments given alone, where an increased functional response was found for the colonic temperature and the response temperature in the increasing temperature hot-plate test. In vitro receptor binding using [H-3]-8-OH-DPAT as ligand revealed an increase in K(d) and B(max) in the spinal cord after chronic treatment with the combination of desipramine and mianserin. In the hippocampus and the frontal cortex the changes were small. Thus, the combination of desipramine and mianserin increased the functional response to 5-HT1A receptor stimulation, and decreased the response to simultaneous stimulation of the 5-HT1A and 5-HT2 receptors, when compared to treatments with either one of the antidepressants alone, or controls. These rather large functional changes were not clearly reflected in the receptor binding study, indicating that changes in the postreceptor signal transduction may be of importance.