Perturbations in serotonin [5-hydroxytryptamine (5-HT)] neurotransmission have been implicated in several psychiatric illnesses including depression and anxiety disorders. It is not yet clear, however, which of the 14 currently identified 5-HT receptor subtypes in the brain participate in the regulation of emotional states. This study investigates a role for the 5-HT(1B) receptor subtype in anxiety-related behaviors using the elevated plus-maze paradigm in rats. The selective 5-HT(1B) receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253; 1--5.6 mg/kg) dose-dependently decreased the amount of exploration on the open arms of the plus-maze without altering overall locomotor activity. This 5-HT(1B) agonist-induced increase in anxiety-like behavior was dose-dependently reversed by coadministration of the selective 5-HT(1B/1D) receptor antagonist 2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl]-amide (GR 127,935). There was no significant effect of GR 127,935 administration alone on plus-maze behavior. These results indicate that 5-HT(1B) receptor activation increases anxiety-like behavioral responses as measured by the elevated plus-maze. Since 5-HT(1B) receptors modulate the activity of multiple neurotransmitter systems that have been implicated in anxiety disorders, these findings suggest that this receptor subtype may represent an important therapeutic target for the treatment of anxiety.