Development of tolerance and supersensitivity to phencyclidine in rats after repeated administration of phencyclidine.
European journal of pharmacology – March 03, 1987
Source: PubMed
Summary
Repeated administration of phencyclidine (PCP) at 10 mg/kg for 14 days led to notable behavioral changes in rats. Tolerance was observed in back-pedaling and head-weaving behaviors, while sniffing, rearing, and ambulation increased by 25-50%. Additionally, dopamine activity surged, with elevated levels in the nucleus accumbens and a higher HVA-to-DA ratio in the striatum. Despite these changes, sleep duration induced by pentobarbital remained unchanged. These findings highlight significant shifts in dopaminergic and serotonergic systems without affecting drug metabolism.
Abstract
In rats treated with phencyclidine (PCP) repeatedly (PCP 10 mg/kg per day for 14 days), the back-pedalling, head-weaving and turning induced by PCP were attenuated (tolerance), while PCP-induced sniffing, rearing and ambulation were potentiated (supersensitivity). The behavior induced by the direct and indirect serotonin (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine and p-chloroamphetamine, was attenuated, while the sniffing, rearing or licking induced by the direct and indirect dopamine (DA) agonists, apomorphine and methamphetamine, were potentiated in the chronic PCP-treated rats. The DA and 5-HT contents in the nucleus accumbens and the ratio of HVA to DA in the striatum increased following the repeated PCP administration. Pentobarbital-induced sleep time did not change in the chronic PCP-treated rats as compared with the control rats. In addition, there was no significant difference between the disappearance rate of PCP in the brain of the rats treated with PCP repeatedly and the rate in the control rats. These results suggest that functional changes in the dopaminergic and serotonergic neuronal systems develop on repeated administration of PCP but that such changes do not develop in the hepatic drug-metabolizing system. In addition, tolerance develops in the serotonergic neuronal system while supersensitivity develops in the dopaminergic neuronal system. Biochemical findings suggest that increased mesolimbic dopaminergic neuronal function plays an important role in the development of the supersensitivity.