Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia

Abstract

Publisher Summary Phencyclidine (PCP) induces several distinct behavioral effects in humans and animals that appear to represent schizophrenia-like symptomatology. In humans, acute PCP exposure can induce both positive and negative symptoms of schizophrenia. In contrast, repeated exposure to PCP in humans can lead to enduring presentation of both negative and positive symptoms of schizophrenia. Thus, repeated PCP administration may induce neurobiological defects that mimic those present in the brain of patients with schizophrenia. This chapter discusses some of the recent studies on the effects of acute and repeated PCP administration on the rodent and nonhuman primate dopamine (DA) systems and how these neurobiological effects may underlie the psychotomimetic properties of PCP. The chapter also evaluates the relevance of DAergic dysfunction for the hypoglutamatergic and neuropathological hypotheses of PCP's effects. In the primate, acute PCP administration causes a selective activation of DA metabolism in the frontal cortex, while sparing subcortical DA systems. It is suggested that activation of DA systems by PCP may be involved in the development of neuropathology after acute PCP administration. Taken together, these studies indicate that repeated PCP administration may model the cognitive dysfunction of schizophrenia and suggest that this dysfunction may be because of an inhibition of DAergic function in the PFC. Further, this paradigm may represent a step forward in biological psychiatric research by offering a tool for evaluating the pathophysiology of the deficits of schizophrenia and a mechanism for the evaluation of novel agents that may be able to ameliorate the typically treatment-refractory negative symptoms in this debilitating disorders.