Phencyclidine-induced head-twitch response in rats treated chronically with methysergide.

Withdrawal from chronic methysergide, a 5-HT2 receptor blocker, potentiates phencyclidine (PCP)-induced head-twitch behavior in rats, while repeated PCP treatment leads to tolerance that is blocked by methysergide. PCP-induced behaviors (head-twitch, head-weaving, turning, backpedalling) were attenuated after 12 days of daily PCP, but head-twitch increased significantly after stopping methysergide. Binding studies showed increased Bmax of 5-HT2 and PCP receptors after methysergide withdrawal, and decreased Bmax of 5-HT2 receptors after PCP tolerance, with no affinity changes. PCP displaced [3H]ketanserin at 5-HT2 but not [3H]5-HT at 5-HT1 sites, indicating PCP produces head-twitch through agonistic action at 5-HT2 receptors.

Study at a glance

Abstract

This study was designed to assess whether phencyclidine (PCP)-induced behaviors in rats were potentiated after two days' withdrawal from chronic methysergide (a 5-HT2 receptor blocker) treatment (10 mg/kg per day i.p. for 12 days), in order to confirm the involvement of 5-hydroxytryptamine (5-HT) neurons in PCP actions. The PCP (10 mg/kg)-induced behaviors (head-twitch, head-weaving, turning and backpedalling) were attenuated by successive pretreatment with PCP (10 mg/kg per day i.p. for 12 days), while PCP- and 5-methoxy-N,N-dimethyltryptamine (2 mg/kg)-induced head-twitch increased significantly after the repeated methysergide treatment was stopped. The development of tolerance to PCP-induced head-twitch was antagonized by pretreatment with methysergide. Furthermore, Scatchard plots of specific [3H]ketanserin binding at the 5-HT2 receptors and [3H]PCP binding at the PCP receptors in the methysergide group revealed significant increases in binding capacity (Bmax) with no change in affinity (Kd). On the contrary, after development of tolerance to PCP, there were significant decreases in Bmax of [3H]ketanserin binding with no change in affinity. PCP can thus displace [3H]ketanserin at the 5-HT2 receptor site, but not [3H]5-HT at the 5-HT1 receptor site. These facts indicate that PCP may produce head-twitch via an agonistic interaction with 5-HT2 receptor sites.