5-HT_2A receptor antagonism by MDL 11,939 during inescapable stress prevents subsequent exaggeration of acoustic startle response and reduced body weight in rats

Abstract

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.

Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat-induced anxiety and the acquisition of conditioned defeat in Syrian hamsters

“…Systemic blockade of 5-HT2a receptors prevents the occurrence elevated acoustic startle following inescapable tailshock stress (Jiang et al, 2011). Also, 5-HT2a receptor blockade prevents the potentiation of anxiety-like behavior following predator stress (Adamec et al, 2004).…”

“…Three consecutive days of immobilization with tail-shocks has been shown to down regulate 5-HT2a receptors and lead to hyperexcitability of BLA pyramidal cells (Jiang et al, 2009). Also, systemic blockade of 5-HT2a receptors has been shown to prevent stress-induced elevation of acoustic startle possibly by preventing the down-regulation of 5-HT2a receptors (Jiang et al, 2011). Furthermore, anxiogenic drugs targeting 5-HT2a receptors were found to increase c-Fos expression in PV-positive interneurons in the BLA, which correlated with the number of c-Fos immunoreactive 5-HT cells in the DRN and levels of anxiety-like behavior (Hale et al, 2010).…”

Predator odor stress alters corticotropin-releasing factor-1 receptor (CRF1R)-dependent behaviors in rats

“…Other modalities of stress (e.g., footshock or restraint) also produce increases in arousal in rodents as measured by the acoustic startle test (Chester et al, 2008; Jiang et al, 2011; Rasmussen et al, 2008). Similar to our results, others have reported stress-induced increases in startle amplitude that last up to ten days post stress exposure (Jiang et al, 2011; Rasmussen et al, 2008). …”

5-hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior

“…Finally, a 5-HT receptor in the BLA other than the 5-HT 2C R may be responsible for exaggerated freezing following uncontrollable stress. The 5-HT 2A receptor is one candidate, as systemic 5-HT 2A blockade prevents stress-induced potentiation of acoustic startle (Jiang et al, 2009). …”