Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia

Abstract

Dopaminergic dysregulation remains an empirical cornerstone for theories concerning the causation of schizophrenia. Evidence for a dopamine system dysfunction in schizophrenia includes the psychosis-inducing effects of dopaminergic agonists and the antipsychotic potency of dopaminergic antagonists. Here we use positron emission tomography (PET) to examine the regulatory role of dopamine on cortical function in normal subjects and unmedicated schizophrenic patients. Using a factorial experimental design, we compared the effect of dopaminergic manipulation with apomorphine on a neural response to a cognitive task. In the schizophrenic patients, relative to controls, an impaired cognitive activation of the anterior cingulate cortex was significantly modulated by a manipulation of dopaminergic neurotransmission. Thus, after apomorphine, the schizophrenic subjects displayed a significantly enhanced cognitive activation of the anterior cingulate cortex relative to the controls. These data provide in vivo evidence that an impaired cognitive-task-induced activation of the anterior cingulate cortex in schizophrenic patients can be significantly modulated by a dopaminergic manipulation.

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

“…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).…”

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

“…e Cosgrove and Newell (1991 Deutch et al 1987;Verma and Moghaddam 1996; Jentsch et al 1997a); whereas, longterm PCP administration reduces frontal dopamine transmission (Jentsch et al 1997b,c; see below). Because hypofrontality and some cognitive deficits of schizophrenia have been associated with reduced dopamine transmission within the prefrontal cortex (Weinberger et al 1988; Daniel et al 1989Daniel et al , 1991Dolan et al 1995; reviewed in Davis et al 1991;Knable and Weinberger 1997), these findings suggest that long-term administration of NMDA receptor antagonists produces effects that are most consistent with schizophrenia. Later in this review, the validity of acute versus long-term PCP exposure as models of schizophrenia is revisited.…”

“…First, the reduction in metabolic activity in the prefrontal cortex of schizophrenic patients is inversely correlated with cerebrospinal fluid concentrations of homovanillic acid, a measure of central dopaminergic transmission (Weinberger et al 1988). 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).…”

Functional connectivity in fMRI: A modeling approach for estimation and for relating to local circuits

“…A leftsided insufficiency need not necessarily be reflected as lower activations. Rather, it is possible that this insufficiency is due to a functional disconnection between frontal and posterior regions, as has been shown to be the case in schizophrenia in a number of imaging tasks that involve language (Dolan et al, 1995;Fletcher et al, 1996;Lawrie et al, 2002;Ragland et al, 2004). In particular, we hypothesize that such a functional disconnection can arise from a disturbance in local circuitry in the frontal cortex.…”

“…For example, reduction in functional connectivity between frontal and posterior has been found in a number of imaging studies of schizophrenia (Dolan et al, 1995;Fletcher et al, 1996;Lawrie et al, 2002;Ragland et al, 2004). While evidence for deficits in white matter tracts between these regions is inconsistent (McGuire & Frith, 1996), there is evidence of local circuit disturbances in frontal cortex (Lewis & Gonzalez-Burgos, 2000;Glantz & Lewis, 2000;Kolluri et al, 2005).…”