The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

Abstract

Administration of noncompetitive NMDA ր glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animalsBiological psychiatric research has seen the development of many putative animal models of schizophrenia. The etiological bases of these models have varied widely from the administration of purportedly psychotomimetic drugs (Snyder 1988; Javitt and Zukin 1991; Jentsch et al. 1998a), to perinatal insults (Lipska et al. 1993;El-Khodor and Boksa 1997;Moore and Grace 1997; Bertolino et al. 1997), to chronic social isolation or stress (Jones et al. 1990), and beyond. The administration of psychotomimetic drugs to humans and animals represents probably the most widely accepted and utilized class of schizophrenia models. These "pharmacological" models seem to represent methods for the induction of psychopathology in humans and aberrant (potentially related) behavior in animals.At the behavioral level, there seems to be some heterogeneity in the effects of different psychotomimetic drug classes. The psychomotor stimulants, such as amphetamine and cocaine, can clearly induce a form of 20 , NO . 3 paranoid psychosis in human subjects after high-dose or long-term administration, but evidence regarding the ability of these agents to induce "deficit" state symptoms is conflicting (Angrist and Gershon 1970;Everitt et al., 1997); moreover, there is evidence that amphetamine may actually alleviate negative and cognitive symptoms in schizophrenic patients (Angrist et al. 1982;Goldberg et al. 1991; Carter et al. 1997). Psychotomimetic indoleamines, such as lysergic acid diethylamide, can induce profound sensory hallucinations without causing any apparent deficit state in normal subjects (Geyer and Markou 1994) and without precipitating symptomatology in schizophrenic patients (Cohen et al. 1962). In contrast, the noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) ր glutamate receptor, including phencyclidine (PCP) and ketamine, seem to be capable of inducing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans (Snyder 1980; Javitt and Zukin 1991;Tamminga 1998); these drugs also profoundly exacerbate both positive and negative symptoms in schizophrenic patients (Itil et al. 1967;Lahti et al. 1994;Malhotra et al. 1997a).Because of the more comprehensive psychopathology induced by PCP, many researchers have studied the effects of NMDA receptor antagonists in humans and animals to gain insights into the neurobiology of schizophrenia. In this review, the validity of NMDA receptor antagonist-induced models of schizophrenia in humans and animals are considered, and the applicability of acute versus chronic administration of PCP as a more precise model is assessed. The neurobiological substrates of the observed behavior...

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

“…It has been reported that there are qualitative and quantitative differences in the effects of acute vs chronic PCP exposure (Jentsch and Roth, 1999). For example, studies demonstrated that the chronic treatment selected here has been effective previously in inducing durable cognitive dysfunction, social withdrawal, and enhancement of immobility time in the forced swim test in rats or mice that are not observable after acute PCP (Noda et al, 1995(Noda et al, , 2000Jentsch et al, 1997c;Quiao et al, 2001).…”

“…Further it has been hypothesized that the negative symptoms of schizophrenia, such as anhedonia and avolition (ie lack of motivation; American Psychiatric Association, 1994) may be neurobiologically similar to depressive symptomatology, such as anhedonia and dysphoria, seen in both drug-and nondrug-induced depressions (Markou and Kenny, 2002). Withdrawal from PCP treatment induces in humans and rodents some longlasting behavioral and neurochemical perturbations that have been hypothesized to have relevance to schizophrenia symptomatology and neuropathologies, respectively (Jentsch and Roth, 1999). These observations have led to the hypothesis of hypofunctioning of the glutamatergic system as one of the pathophysiologies mediating schizophrenia (Javitt and Zukin, 1991;Carlsson et al, 2001).…”

“…Thus, it was important to characterize withdrawal from both high-dose bolus PCP administration and withdrawal from chronic sustained PCP exposure in the ICSS paradigm. Moreover, because the behavioral and neurochemical effects induced by withdrawal from chronic PCP treatment have been shown to be surprisingly long lasting, the argument has been made that withdrawal from chronic PCP exposure is likely to mimic the psychopathologies and neuropathologies associated with schizophrenia (Jentsch and Roth, 1999). Therefore, we tested the long-lasting effect of withdrawal from chronic PCP treatment on brain reward function in the context of its relevance to the anhedonia reported in the symptomatology of both schizophrenia and depression.…”

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

“…PCP and its structural analogue ketamine produce inactivation of inhibitory control by decreasing GABA release [58]. This disinhibition of excitatory neurotransmission is referred to as NMDA receptor hypofunction [32,45,46]. Acute administration of PCP in rats has been shown to produce deficits in the novel object recognition-NOR-task [21], an operant reversal learning paradigm [1,28] and attentional set-shifting [16].…”

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…In addition, we employed the well-validated subchronic phencyclidine (PCP)-administration paradigm (Jentsch and Roth, 1999;Cochran et al, 2003;Egerton et al, 2005;Abdul-Monim et al, 2006, 2007 to produce enduring cognitive deficits similar to those observed in schizophrenia (Javitt and Zukin, 1991). This permitted us to examine treatment effects of classical and second-generation antipsychotics that have different profiles and activity at multiple neurotransmitter receptors, including dopamine (DA) D 2 , 5-HT 2A , and 5-HT 6 .…”