A role for noradrenergic transmission in the actions of phencyclidine and the antipsychotic and antistress effects of mGlu2/3 receptor agonists.

Activating mGlu2/3 receptors with the drug LY379268 reduces the behavioral effects of phencyclidine (PCP) in rats, and this effect is linked to changes in norepinephrine release. In rats undergoing brain microdialysis, LY379268 blocked PCP-induced hyperactivity for about three hours and transiently reduced PCP-induced dopamine release. PCP-induced norepinephrine release was reduced in a way that matched the timing of the behavioral reduction. Separately, the norepinephrine-related drugs clonidine (which reduces norepinephrine activity) blocked PCP behaviors, while reboxetine (which increases norepinephrine) worsened them. LY379268 reversed PCP effects even when reboxetine was present. These results suggest that mGlu2/3 receptor activation can normalize stress-related pathways affected by PCP.

Study at a glance

Abstract

Evidence suggests that glutamatergic neuronal transmission is involved in psychiatric and neurological disorders and that drugs that target glutamate systems may serve as novel therapeutics in humans. For example, agonists for group II mGlu receptors (mGlu2 and mGlu3) have been shown to be anxiolytic in certain animal models and have shown promise in early human trials. mGlu2/3 receptor agonists also block the neurochemical and behavioral actions of psychotogens, such as phencyclidine and amphetamine in rodents, suggesting that they may be useful to treat psychosis in humans. Recently, we have used in vivo microdialysis and behavioral methods to further explore the potential antipsychotic and antistress actions of mGlu2/3 receptor agonists in rats. In subjects undergoing brain microdialysis of the nucleus accumbens shell, we have shown that LY379268 (3 mg/kg s.c.) (a systemically active mGlu2/3 receptor agonist) blocks PCP-induced locomotor activations for approximately 3 hours. In these animals, PCP-induced dopamine release was reduced, but only in a transient fashion (15-75 min). PCP-induced norepinephrine release was also reduced, but unlike dopamine, in a manner that was temporally correlated with the reduction of PCP-induced behaviors. In separate experiments in rats not undergoing microdialysis, the alpha2-adrenergic receptor agonist, clonidine, was shown to block PCP behaviors, and the norepinephrine reuptake inhibitor reboxetine was shown to exacerbate PCP-induced ambulations. In the latter study, LY379268 pretreatment effectively reversed the PCP behaviors in both control and reboxetine-treated animals. These data support a role for noradrenergic neurotransmission in the actions of drugs such as phencyclidine and suggest that stress pathways associated with these drugs can be normalized by mGlu2/3 receptor activation.