Activation of central 5-HT(2A) receptor signaling and its subsequent alterations have been implicated in the pathophysiological response to stress and the pathogenesis of stress-associated psychiatric disorders. To further examine the association between alterations in central 5-HT(2A) receptor signaling and the occurrence of stress-induced psychiatric symptoms, the present study, utilizing a learned helplessness stress model in rats, determined whether 5-HT(2A) receptor signaling blockade during stress could prevent the occurrence of stress-induced physical and behavioral abnormalities. Rats subjected to restraint/tail shock for three days developed long-lasting elevated acoustic startle response (ASR) and reduced body weight, compared to non-stressed control animals. However, administration of the selective 5-HT(2A) receptor antagonist, MDL 11,939 (α-phenyl-1-(2-phenylethyl)-4-piperidinemethanol), 30 min prior to exposure of the animals to the stress protocol prevented the subsequent occurrence of elevated ASR and reduced body weight in a dose-dependent manner in stressed subjects. Administration of MDL 11,939 to the animals immediately after exposure to the stress protocol also prevented the occurrence of exaggerated ASR, but was not able to normalize body weight. These findings suggest a critical role of the central 5-HT(2A) receptor activation in developing the pathophysiology associated with elevated ASR and reduced body weight during stress. The differential effects of MDL 11,939 on startle response and body weight and its potential clinical significance are discussed.