Anti-depressant action of melatonin in chronic forced swimming-induced behavioral despair in mice, role of peripheral benzodiazepine receptor modulation

The possible antidepressant effect of physiological and pharmacological dos es of melatonin was investigated in the Porsolt forced swimming-induced beh avioral despair test. The duration of immobility period of BALB/c and C57BL /6J mice during a 6-min swim test was measured at noon (11:00-12:00 h), ear ly dark (20:00-21:00 h) and at midnight (1:00-2:00 h), respectively. The ci rcadian time cycle did not alter the duration of immobility in either strai ns of mice. Similarly, exogenously administered melatonin (10-1000 mug/kg c ongruent to 50 nM to 5 muM/mouse), a dose that could act on high affinity m elatonin receptors, did not modify the duration of immobility period at any of the time intervals studied in either strains of the mice. This suggeste d that neither circadian variation influenced the duration of immobility pe riod of BALB/c and C57BL/6J mice nor at physiological doses melatonin showe d any anti-depressant action. Acute administration of higher doses of melat onin (2.5-10 mg/kg) failed to induce any anti-depressant activity in mice w hich were subjected to forced swimming test for the first time. However, da ily administration of melatonin (2.5-10 mg/kg) prior to swimming test signi ficantly reversed the increase in immobility period that was observed on ch ronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAegic dr ugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test. The anti-dep ressant action of melatonin was sensitive to reversal by peripheral BZ rece ptor antagonist, PK11195. Whereas, flumazenil failed to reverse the anti-de pressant action of melatonin, thereby suggesting that central BZ receptor w ere not involved in its action. In conclusion the study showed that at phar macological doses melatonin has anti-depressant action in chronic forced sw imming-induced despair behavior by an action involving peripheral BZ recept ors. (C) 2000 Elsevier Science B.V. All rights reserved.