en Behavioral Neuroscience Behavioral Neuroscience Original Original <strong>Introduction</strong>: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway.<br> <strong>Methods</strong>: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30&ndash;300 mg/kg, orally [PO]), imipramine (3&ndash;30 mg/kg, PO), fluoxetine (3&ndash;30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration.<br> <strong>Results</strong>: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK- and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice.<br> <strong>Conclusion</strong>: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect. Glycine/NMDA receptor, Open space swim test, Rapid-acting antidepressant, Trichilia, Alkaloids 395 408 http://bcn.iums.ac.ir/browse.php?a_code=A-10-2838-1&slc_lang=en&sid=1 Kennedy Kwami Edem Kukuia edemkennedy@yahoo.com 13700319475328460035989 13700319475328460035989 Yes Department of Medical Pharmacology, University of Ghana Medical School, College of Health Sciences, University of Ghana, Korle Bu-Accra, Ghana. Jeffrey Amoako Mensah jeffreyamoako.mensah@utah.edu 13700319475328460035990 13700319475328460035990 No Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, U.S. A. Patrick Amoateng pamoateng@ug.edu.gh 13700319475328460035991 13700319475328460035991 No Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon-Accra, Ghana. Dorcas Osei-Safo doseisafo@ug.edu.gh 13700319475328460035992 13700319475328460035992 No Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon-Accra, Ghana. Awo Efua Koomson diamondefua@ymail.com 13700319475328460035993 13700319475328460035993 No Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon-Accra, Ghana. Joseph Torbi jtorbi@st.ug.edu.gh 13700319475328460035994 13700319475328460035994 No Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon-Accra, Ghana. Donatus Wewura Adongo donatusadongo@yahoo.com 13700319475328460035995 13700319475328460035995 No Department of Pharmacology and Toxicology, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana. Elvis Ofori Ameyaw 13700319475328460035996 13700319475328460035996 No Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana. Inemesit Okon Ben 13700319475328460035997 13700319475328460035997 No Department of Pharmacology and Toxicology, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana. Seth Kwabena Amponsah 13700319475328460035998 13700319475328460035998 No Department of Medical Pharmacology, University of Ghana Medical School, College of Health Sciences, University of Ghana, Korle Bu-Accra, Ghana. Kwasi Agyei Bugyei 13700319475328460035999 13700319475328460035999 No Department of Medical Pharmacology, University of Ghana Medical School, College of Health Sciences, University of Ghana, Korle Bu-Accra, Ghana. Isaac Julius Asiedu-Gyekye 13700319475328460036000 13700319475328460036000 No Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon-Accra, Ghana.