Increased tonic activation of rat forebrain 5-HT(1A) receptors by lithium addition to antidepressant treatments

Neuropsychopharmacology. 2000 Apr;22(4):346-56. doi: 10.1016/S0893-133X(99)00138-4.


The present study was undertaken to determine whether lithium addition to long-term treatment with different classes of antidepressant drugs could induce a greater effect on the serotonin (5-HT) system than the drugs given alone. Because 5-HT(1A) receptor activation hyperpolarizes and inhibits the firing activity of CA(3) pyramidal neurons in the dorsal hippocampus, the degree of disinhibition produced by the selective 5-HT(1A) receptor antagonist WAY 100635 was determined using in vivo extracellular recordings. In controls, as well as in rats receiving a lithium diet for 3 days, the administration of WAY 100635 (25-100 microg/kg, IV) did not modify the firing activity of dorsal hippocampus CA(3) pyramidal neurons. When the tricyclic antidepressant imipramine (10 mg/kg/day, SC), the monoamine oxidase inhibitor tranylcypromine (2.5 mg/kg/day, SC) and the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day, SC) were administered alone for 21 days, a dose of 50 microg/kg of WAY 100635 was needed to increase significantly the firing activity of these neurons. On the other hand, WAY 100635, at a dose of only 25 microg/kg, increased significantly the firing rate of CA(3) pyramidal neurons in rats receiving both a long-term antidepressant treatment and a short-term lithium diet. It is concluded that the addition of lithium to antidepressant treatments produced a greater disinhibition of dorsal hippocampus CA(3) pyramidal neurons than any treatments given alone. The present results support the notion that the addition of lithium to antidepressants may produce a therapeutic response in treatment-resistant depression by enhancing 5-HT neurotransmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents, Second-Generation / pharmacology
  • Depressive Disorder / drug therapy
  • Depressive Disorder / physiopathology
  • Drug Therapy, Combination
  • Free Radical Scavengers / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • Imipramine / pharmacology
  • Lithium / pharmacology*
  • Male
  • Monoamine Oxidase Inhibitors / pharmacology
  • Paroxetine / pharmacology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin / pharmacology
  • Tranylcypromine / pharmacology


  • Antidepressive Agents
  • Antidepressive Agents, Second-Generation
  • Free Radical Scavengers
  • Monoamine Oxidase Inhibitors
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin
  • Tranylcypromine
  • Paroxetine
  • Lithium
  • Imipramine