Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons

Use of phencyclidine (PCP) can mimic some aspects of schizophrenia. However, the underlying mechanism is unclear. Administration of PCP is known to activate mesolimbic dopamine pathway. In this study, we focused on ventral tegmental area (VTA) of mesolimbic dopamine pathway as target of PCP for inducing schizophrenia-like symptoms. Single VTA neuron was isolated and its neural activity was monitored by measuring cytosolic Ca2+ concentration ([Ca2+]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca2+]i in dopamine neurons from control rats, and the [Ca2+]i increase was inhibited in the presence of PCP. In contrast, in VTA dopamine neurons from rats chronically treated with PCP for 7 days, administration of glutamate was able to induce [Ca2+]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca2+]i increase in the presence of PCP continued even after washout of glutamate and this effect lasted as long as PCP was present. This long-lasting glutamate-induced [Ca2+]i increase in the presence of PCP was not observed or significantly attenuated under Ca2+ free condition and by N-type Ca2+ channel blocker ω-conotoxin. The results indicate that chronic treatment with PCP reverses the acute PCP effect on VTA dopamine neurons from inhibitory to stimulatory tone, and consequently induces long-lasting activation of dopamine neurons by glutamate.