5-HT2A Receptor Activation Normalizes Exaggerated Fear Behavior in p-Chlorophenylalanine (PCPA)-Treated Rats.

Deficits in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission are implicated in abnormal emotional behaviors such as aggression, anxiety, and depression. However, the specific 5-HT receptor mechanisms involved are not well understood. The role of 5-HT₂ receptors in fear potentiated startle, (FPS) was examined in rats chronically treated with p-chlorophenylalanine (PCPA) to reduce brain 5-HT. PCPA-treated rats show an enhanced magnitude of FPS. Systemic administration of the 5-HT₂ receptor agonist (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) reduced FPS in both PCPA-treated and saline (SAL)-treated control animals, normalizing the exaggerated fear response in PCPA-treated rats. In both SAL- and PCPA-treated animals, the DOI-induced reduction of learned fear was reversed by the 5-HT₂ antagonist ketanserin, but not by the 5-HT_2B/2C antagonist SB 206553. Together, these findings suggest 5-HT_2A receptors are critical regulators of learned fear, and that 5-HT_2A receptors may be an important pharmacological target to normalize exaggerated learned fear resulting from chronic 5-HT-ergic disruption.