The second extracellular loop of the beta-adrenergic and muscarinic acetylcholine receptors was shown to be an autoimmune target for antibodies in several autoimmune diseases. These autoantibodies and the antibodies induced against synthetic peptides corresponding to this loop have pharmacological and physiological properties upon receptor recognition which could explain their pathophysiological role. We here describe the immune properties of the first and second extracellular loops of another G protein-coupled receptor, the serotonin 5-HT1A receptor. The injection in rabbits of the free peptides Y16L and G21G corresponding to the first and second extracellular loops respectively induced anti-peptide antibodies with high titer, demonstrating the presence of a T-cell epitope on each peptide. Interestingly, in contrast to the G21G peptide that induced only anti-G21G antibodies (Ab-2 antibodies), the Y16L peptide induced two populations of antibodies. One recognized only the Y16L peptide (Ab-1 antibodies), the other recognized both peptides (Ab-12 antibodies). This reflects the presence on the two peptides of at least two B-cell epitopes. The fact that the G21G peptide induces only one antibody population might indicate that it possesses one immunodominant epitope involved in the Ab-2 antibody production and one cryptic epitope involved in the cross-reaction with the anti-Y16L antibodies. But only Ab-2 antibodies were able to recognize specifically the human protein receptor expressed in E coli in immunoblot.