Phosphoethanolamine (PE) is a metabolite of the phospholipid metabolism which is decreased in Alzheimer's disease brain. PE shows a strong structural similarity to the inhibitory neurotransmitter, GABA, and the GABAB receptor partial agonist, 3-amino-propylphosphonic acid. The ability of PE to compete for binding to GABAA and GABAB binding sites was investigated. GABAA sites were studied using [3H]SR-95531 and [3H]muscimol. GABAB sites were studied using [3H]GABA in the presence of isoguvacine to saturate GABAA sites. Total [3H]GABA binding was also examined. PE showed little activity at any of the GABA binding sites investigated. PE was most potent at GABAB sites, but the IC50 of 7.5 +/- 0.75 mM was considerably higher than its maximal physiologic concentration of approximately 1.5 mM. The efficient exclusion of PE from GABA binding sites may be an important physiologic mechanism in the control of inhibitory neurotransmission. The structural basis for this exclusion is discussed in reference to the GABAB partial agonist 3-amino-propylphosphonic acid.