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.
The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.
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