Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET

147

Previous studies have shown that repeated exposures to phencyclidine (PCP) induces prefrontal cortical dopaminergic and cognitive deficits in rats and (Javitt and Zukin 1991); that is, administration of PCP or its congeners ketamine or dizocilpine can induce schizophrenic-like symptomatology in people (Luby et al. 1959;Krystal et al. 1994; Bunney et al. 1994) and precipitate psychosis in schizophrenics (Ital et al. 1967;Lahti et al. 1994). These compounds can stimulate both positive and negative symptoms of schizophrenia (Javitt and Zukin), including cognitive dysfunction (Cosgrove and Newell 1991). As such, PCP administration has been suggested to represent a drug-induced model of schizophrenia (Javitt and Zukin;Steinpreis 1996).The ability of PCP to simulate the symptomatology of schizophrenia in humans has led to the proposal that the behavioral pathologies evident in schizophrenia and PCP-exposed humans are caused by dysfunction of common neural substrates (Luby et al. 1959;Javitt and Zukin 1991). The effects of PCP on brain dopamine systems has received particular attention (Meltzer et al. 1980;Bowers and Hoffman 1984;Deutch et al. 1987;Hertel et al. 1996;Jentsch et al. 1997a) since alterations in dopaminergic systems have been hypothesized in schizophrenia (reviewed in Davis et al. 1991;Deutch 1992 Recent work has shown that long-term administration of PCP causes enduring cognitive dysfunction and cortical dopamine deficits in rats and monkeys (Jentsch et al. 1997b,c). These data correspond to reports of cognitive disturbances in schizophrenic subjects (Fey 1951;Goldman-Rakic 1991;Park and Holzman 1992), and recent in vivo imaging studies of the schizophrenic brain have revealed a failure of activation of frontal cortex during cognitive performance (termed "hypofrontality" by Weinberger and Berman 1996), effects that may be mediated by dopaminergic dysfunction Daniel et al. 1989 Daniel et al. , 1991Dolan et al. 1995). These data are also consistent with studies in nonhuman primates that have revealed that lesions of the prefrontal cortical dopamine innervation lead to working memory impairments (Brozoski et al. 1979), a cognitive process closely associated with this brain region (Goldman-Rakic 1987).Moreover, prefrontal cortical dopaminergic deficiencies may result in enhancement of activity of subcortical dopamine systems. Destruction of prefrontal cortical dopamine terminals has been shown to augment the response of the mesolimbic dopamine systems to stress ), amphetamine sensitization (Banks and Gratton 1994), high K ϩ -stimulation (Roberts et al. 1994), or haloperidol administration (Rosin et al. 1994). These data have supported an emerging neurochemical hypothesis of schizophrenia: cortical dopaminergic hypoactivity and subcortical dopaminergic hyperactivity (Robbins 1990;Grace 1991;Deutch 1992). Recent in vivo studies of the schizophrenic brain have revealed evidence for the subcortical component of this hypothesis; heightened responsivity to the dopamine-releasing properties of amphetamine ha...

Section: Validity Of the Subchronic Pcp-based Animal Model Of Schizopsupporting

confidence: 77%

Subchronic Phencyclidine Administration Increases Mesolimbic Dopaminergic System Responsivity and Augments Stress- and Psychostimulant-Induced Hyperlocomotion

Jentsch

Taylor

Roth

1998

147

“…Second, hypofrontality in schizophrenia is alleviated by systemic administration of indirect or direct dopaminergic agonists, such as amphetamine (Daniel et al 1991) or apomorphine (Daniel et al 1989;Dolan et al 1995). Finally, a recent positron emission tomographic (PET) study has suggested that the dopamine D 1 -receptor may be downregulated in schizophrenia (Okubo et al 1997). Thus, it seems that one component of the cognitive dysfunction of schizophrenia is associated with reduced frontal dopaminergic transmission.…”

Section: Neurochemistry Cortical Dopamine Dysfunctionmentioning

confidence: 99%

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

Jentsch

Roth²

1999

1,207

772

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...

“…First, many clinically efficacious antipsychotics are potent dopamine receptor antagonists (Seeman 1992). Second, dopamine receptors (Okubo et al 1997) or the release dynamics of dopamine terminals (Wong et al 1997) are markedly altered in living schizophrenic brains. Third, several psychoactive substances (e.g., amphetamine, phencyclidine) abnormally augment dopamine transmission and induce psychotic symptoms indistinguishable from schizophrenia.…”

mentioning

confidence: 99%

Developing a Neuronal Model for the Pathophysiology of Schizophrenia Based on the Nature of Electrophysiological Actions of Dopamine in the Prefrontal Cortex

Yang

Seamans

Gorelova

1999

164

This review covers some recent findings of the electrophysiological mechanisms through which mesocortical dopamine modulates prefrontal cortical neurons. Dopamine has been shown to modulate several ionic conductances located along the soma-dendritic axis of prefrontal cortical pyramidal neurons. These ionic currents include high-voltage-activated calcium currents and slowly inactivating NaReceived May 12, 1998; revised May 27, 1998; accepted May 29, 1998. 162 C.R. Yang et al. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO Schizophrenia strikes one in one hundred people worldwide, regardless of cultural or racial origins. As the illness progresses and if it remains unattended, patients are frequently trapped in psychological, social, and economic devastation (Gottesman 1991;Jablensky 1995). Currently, our incomplete understanding of the neurobiological bases of schizophrenia suggests that defects in the genetic controls of brain development in such limbic regions (including temporal lobe structures such as hippocampus and the amygdala) as well as the prefrontal cortex (PFC) lead to cell loss or deformation, cytoarchitectural disorganization, and abnormal innervation in these brain regions (Roberts and Bruton 1990;Stevens 1992; Bogerts 1993;Shapiro 1993; Akbarian et al. 1993 Akbarian et al. , 1996Ross and Pearlson 1996;Weinberger 1996; Karayiorgou and Gogos 1997; Lewis 1997;Selemon et al. 1995Selemon et al. , 1998.Some results from recent imaging studies of brains from living schizophrenics have suggested that there are defective functional communications between the interconnected cortical (PFC and cingulate cortex) and limbic subcortical structures (thalamus, striatum, and temporal lobe limbic structures)(see reviews of Liddle 1996; Pfefferbaum and Marsh 1995; Andreasen 1997; Heckers et al. 1998). Findings from these studies suggest that in schizophrenics, abnormal recruitment of several interconnected cortical and subcortical structures may underlie such symptom clusters as psychomotor poverty, thought disorganization, and reality distortion (Liddle et al. 1992; Liddle 1996; Fletcher 1998; Heckers et al. 1998).As noted in Figure 1, the PFC receives converging limbic, association cortical, and mesocortical dopamine inputs. These inputs interact in the PFC and are involved functionally in high-level cognitive processes (Fuster 1995). Among the many brain regions that PFC output innervates, two important subcortical regions are emphasized in this review. These are the nucleus accumbens (where mesoaccumbens dopamine neurons terminate) and the ventral tegmental area (VTA, where the midbrain dopamine neurons reside) Groenewegen et al. 1990; Berendse et al. 1992a Berendse et al. , 1992bSesack and Pickel 1992;Gorelova and Yang 1997b). Several of the interconnected limbic, cortical, and subcortical structures known to be affected in schizophrenia are targets of the ascending midbrain dopamine systems that normally provide functional modulation of neurotransmission (Björklund and Lindvall 1984;Mogenson et ...