Abstract
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-HT2B/2C antagonist SB 206553. Together, these findings suggest 5-HT2A receptors are critical regulators of learned fear, and that 5-HT2A receptors may be an important pharmacological target to normalize exaggerated learned fear resulting from chronic 5-HT-ergic disruption.
Highlights
The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) has been widely implicated in the modulation of emotional behavior
Overwhelming evidence shows that p-chlorophenylalanine (PCPA) decreases brain 5-HT, preliminary studies were conducted to confirm that the administration schedule used in this study has the intended effect of significantly lowering brain 5-HT
The major findings of the current study are 1) fear learning is enhanced in PCPA-treated rats, replicating results from our previous studies [8]; 2) the 5-HT2 receptor agonist Dimethoxy-4-iodoamphetamine hydrochloride (DOI) attenuates conditioned fear, normalizing the PCPA-induced increase in learned fear; and 3) 5-HT2A receptors have a critical role in the normalization of exaggerated fear behavior
Summary
The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) has been widely implicated in the modulation of emotional behavior. Numerous studies have shown abnormalities in 5-HT systems in patients with mood and anxiety disorders [1]. Compounds that enhance 5-HTergic activity, such as selective serotonin reuptake inhibitors (SSRIs), are first-line treatments for mood and anxiety disorders. Among the many known 5HT receptors the specific receptor subtypes involved in the pathophysiology of psychiatric illness or the amelioration of symptoms by 5-HT compounds are not clear. Some evidence suggests that 5-HT2 receptors are involved in emotional disturbance. 5-HT2A receptor antagonists are used as adjunct treatments with SSRIs for depression and anxiety [2]
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