The 5-HT3 receptor is thought to play a role in the reward pathway and the phenomena of drug abuse by modulating dopamine release in the mesolimbic pathway. Studies involving this receptor have been hampered due to the low level of 5-HT3 receptors in the CNS. A 5-HT3 receptor over-expressing mouse was produced to study the role of this receptor in the rewarding properties of drugs of abuse. Over-expression was restricted to the forebrain by controlling gene expression with the Ca2+ calmodulin (CAM) kinase IIalpha promoter. No over-expression was detected in other body organs nor the cerebellum, as measured by ligand binding and Northern analysis. 5-HT3 receptor over-expressing mice drank less alcohol than non-transgenic mice in a two-bottle free choice test. Over-expression of the 5-HT3 receptor in these mice resulted in a decrease in ethanol consumption. These mice should prove useful in testing hypothesis regarding a common reward pathway for drugs of abuse and the role 5-HT3 receptors play in this pathway.