Prepulse inhibition (PPI) is a measure of sensorimotor gating and an endophenotype of schizophrenia. We have shown previously in rats that estrogen treatment prevents disruption of PPI by the 5-HT_1A/5-HT₇ receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D₁ and D₂ and serotonin 5-HT_1A, 5-HT_2A, and 5-HT₇ receptors in these effects. Part 1 of this study investigated the ability of estrogen treatment to reverse PPI disruption induced by 8-OH-DPAT or the dopamine D₁/D₂ receptor agonist apomorphine. Part 2 of this study compared these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apomorphine on PPI. Female Sprague-Dawley rats were ovariectomized (OVX), and, where appropriate, they received silastic implants containing either a low (E20) or high dose (E100) of estrogen. Two weeks later, PPI was assessed using automated startle boxes. The disruption of PPI by either treatment with 8-OH-DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg) was similarly prevented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pretreatment with the 5-HT_1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg) and the typical antipsychotic and dopamine D₂ receptor antagonist haloperidol (0.25 mg/kg), but it was not reversed by pretreatment with the dopamine D₁ receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.1 mg/kg), the 5-HT_2A/2C receptor antagonist ketanserin (2 mg/kg), or the 5-HT₇ receptor antagonist SB-269970 (10 mg/kg). Apomorphine-induced disruptions of PPI were reversed by haloperidol and SCH 23390 only. Estrogen may prevent disruptions of PPI induced by both 8-OH-DPAT and apomorphine by an action on dopamine D₂ receptors downstream of 5-HT_1A receptors.

We determined whether genetic deficiency of angiotensin II Type 1A (AT _1A ) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT _1A ^−/− (85±2 mm Hg) than in AT _1A ^+/+ (112±2 mm Hg) mice; heart rate was not different between groups. Cage-switch stress for 90 minutes elevated blood pressure by +24±2 mm Hg in AT _1A ^+/+ and +17±2 mm Hg in AT _1A ^−/− mice ( P <0.01), and heart rate increased by +203±9 bpm in AT _1A ^+/+ and +121±9 bpm in AT _1A ^−/− mice ( P <0.001). Locomotor activation was less in AT _1A ^−/− (3.0±0.4 U) than in AT _1A ^+/+ animals (6.0±0.4 U), but differences in blood pressure and heart rate persisted during nonactive periods. In contrast to wild-type mice, spontaneous baroreflex sensitivity was not inhibited by stress in AT _1A ^−/− mice. After cage-switch stress, c-Fos immunoreactivity was less in the paraventricular ( P <0.001) and dorsomedial ( P =0.001) nuclei of the hypothalamus and rostral ventrolateral medulla ( P <0.001) in AT _1A ^−/− compared with AT _1A ^+/+ mice. Conversely, greater c-Fos immunoreactivity was observed in the medial nucleus of the amygdala, caudal ventrolateral medulla, and nucleus of the solitary tract ( P <0.001) of AT _1A ^−/− compared with AT _1A ^+/+ mice. Greater activation of the amygdala suggests that AT _1A receptors normally inhibit the degree of stress-induced anxiety, whereas the lesser activation of the hypothalamus and rostral ventrolateral medulla suggests that AT _1A receptors play a key role in autonomic cardiovascular reactions to acute aversive stress, as well as for stress-induced inhibition of the baroreflex.