Melatonin and Diazepam Affect Anxiety-Like and Depression-Like Behavior in Wistar Rats: Possible Interaction with Central GABA Neurotransmission

Etienne Challet,Fatima Zahra El Mrabet,Ali Ouichou,Aboubaker El Hessni,Paul Pévet,Abdelhalem Mesfioui,Sihame Ouakki,Ibtissam Lagbouri

doi:10.4236/jbbs.2013.37055

Abstract

Recent studies have shown the importance of the GABA-ergic transmission in the pathophysiology of anxiety and depressive disorders in humans. Our present study aims to investigate the interaction of melatonin (MEL) with this system by exploring the effects of MEL with or without a facilitator of GABA-ergic neurotransmission, diazepam (DZ) on the levels of depression and anxiety in Wistar rats. For this purpose, different doses of MEL (2, 4 or 16 mg/kg) or DZ (2 mg/kg) are subchronically administered during 15 days. After pharmacological treatments, anxiety levels are evaluated in behavioral tests of Open Field (OFT) and elevated plus maze (EPM) and depression levels are evaluated by the forced swim test (FST). The results showed that MEL produces anxiolytic-like and antidepressant-like effects in a dose-dependent manner; the maximum effect was obtained at a dose of 16 mg/kg. However, a dose of 4 mg/kg is necessary to induce an effect. The effect of MEL and DZ reported in this study concerns selective modulation of behavioral anxiety and depression since locomotor activity assessed by the OFT and EPM was not affected. The subchronic injection of MEL at 4 mg/kg, DZ at 2 mg/kg or the two combined molecules also induces also anxiety-like and antidepressant-like behavior. In addition, a potentiating effect between MEL and DZ was observed. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to improve the central GABA-ergic transmission.

Highlights

Melatonin (MEL) is synthesized primarily in the pin- eal gland and retina, since the pinealectomy abolishes its synthesis and suppresses endogenous rhythm of its secretion in all mammals [1].The MEL synthesis in pinealocytes depends on the availability of its precursor, L-tryptophan (L-TRP) an essential amino acid
Time spent in the central area (TCA) (Table 1): The results summarized in Table 1 show that MEL stimulates TCA in dose-dependent manner, since at doses of 4 and 16 mg/kg it increases the TCA in comparison with the control group (p < 0.01 and p < 0.001 respectively), whereas at 2 mg/kg MEL was is ineffective (p > 0.05)
At doses of 4 and 16 mg/kg, MEL increases the Number of returns to the center (NRC) compared with the control group, while the dose of 2 mg/kg did not induce any significant change in this parameter (p < 0.01, p < 0.001 and p > 0.05)

Summary

Introduction

Melatonin (MEL) is synthesized primarily in the pin- eal gland and retina, since the pinealectomy abolishes its synthesis and suppresses endogenous rhythm of its secretion in all mammals [1]. The MEL synthesis in pinealocytes depends on the availability of its precursor, L-tryptophan (L-TRP) an essential amino acid. The first step of the biosynthesis of this indolamine involves L-TRP absorption into pinealocytes and its conversion to 5-hydroxytryptophan (5HTRP) by the TRP-hydroxylase. Decarboxylation of 5HTRP by L-aromatic decarboxylase leads to the formation of 5-hydroxytryptamine or serotonin (5-HT). Acetylation of 5-HT by arylalkylamine N-acetyltransferase (AA-NAT) leads to the formation of N-acetylserotonin (NAS) [2]. Methylation of NAS by hydroxyindole-O-methyltransferase (HIOMT) leads to the synthesis of the final product, the MEL. The pineal hormone can cross the blood-brain barrier to enter the central nervous system [3]

Methods

Results

Conclusion