Additive subthreshold dose effects of cannabinoid CB(1) receptor antagonist and selective serotonin reuptake inhibitor in antidepressant behavioral tests.
The main clinically used antidepressant drugs are selective monoamine reuptake inhibitors, including selective serotonin reuptake inhibitors (citalopram, sertraline), selective dopamine reuptake inhibitor (nomifensine) and selective noradrenaline reuptake inhibitor (reboxetine), but they have various side effects. Because cannabinoid CB(1) receptor antagonists (SR141716A, AM251) enhance monoamine release, they might be beneficial in the therapy of affective disorders. We hypothesized that the use of monoamine reuptake inhibitors in combination with cannabinoid CB(1) receptor antagonists would allow a lower dose of monoamine reuptake inhibitors to be used in the therapy of depression, thereby reducing or eliminating the side effects. To test this hypothesis, we examined the combination of SR141716A or AM251 with citalopram, sertraline, nomifensine or reboxetine at subthreshold doses to see whether these combinations would show an additive effect in the forced swimming test and the tail suspension test with mice. Subthreshold doses of cannabinoid CB(1) receptor antagonist and selective serotonin reuptake inhibitors, which separately had no effect on the immobility of mice in the tests, showed a clear effect when the drugs were administered at 40 and 30 min, respectively, before the tests, without any change of motor activity. Therefore, the use of subthreshold doses of these agents in combination might be useful to enhance mainly serotonergic neurotransmission, and to reduce or eliminate the side effects of citalopram and sertraline.
Research Resources Center, RIKEN Brain Science Institute, Wako, Saitama, Japan. etakahashi@brain.riken.jp <etakahashi@brain.riken.jp>
Eiki
E
Takahashi
Mariko
M
Katayama
Kimie
K
Niimi
Chitoshi
C
Itakura
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D015283:Citalopram / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009627:Nomifensine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077593:Reboxetine; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology; D013550:Swimming
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D015283:Citalopram; D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; D009627:Nomifensine; D010880:Piperidines; D011720:Pyrazoles; D000077593:Reboxetine; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C103505:AM 251