Prefrontal Dopamine D₁Receptors and Working Memory in Schizophrenia

Abstract

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

“…Phasic PFC DA function appears to be magnified in schizophrenia patients (Laruelle et al, 1999) and basal cortical DA function possibly diminished (see Molina et al, 2005a, b). Indeed, PFC D1 receptors are upregulated in these patients (Abi-Dargham et al, 2002). Phasic release of DA by stress or drugs under these conditions would induce a magnified effect.…”

Chronic NMDA Antagonism Impairs Working Memory, Decreases Extracellular Dopamine, and Increases D1 Receptor Binding in Prefrontal Cortex of Conscious Monkeys

“…The role of the antagonistic effects of NMDA receptors has been of interest because of hypofunction of glutamatergic neurotransmission in the PFC (Carlsson et al, 1997), and its relationship to dopaminergic dysfunction (Robbins, 1990;Grace, 1991;Deutch, 1992), which has been hypothesized in schizophrenic patients. Recent PET studies have supported dysfunction of the extrastriatal dopaminergic system in schizophrenic patients (Okubo et al, 1997;Abi-Dargham et al, 2002;Suhara et al, 2002). The Okubo et al (1997) The PFC dopaminergic system is also vulnerable to stress.…”

“…[ 11 C]NNC112 (Halldin et al, 1998) and [ 11 C]FLB457 (Halldin et al, 1995) have been developed to assess the extrastriatal neocortical receptor D 1 (D 1 R) and D 2 (D 2 R), respectively. Recent PET studies have suggested the dysfunction of the extrastriatal dopaminergic system in schizophrenic patients (Okubo et al, 1997;Abi-Dargham et al, 2002;Suhara et al, 2002).…”

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

“…Previous studies have shown the critical importance of optimal dopamine transmission in the prefrontal cortex for certain aspects of cognition, such as working memory, and indicate that dysfunctional dopamine D 1 receptors may contribute to cognitive impairments in schizophrenia (see Abi-Dargham et al, 2002;Goldman-Rakic et al, 2004;AbiDargham and Moore, 2003). Moreover, glutamate, the excitatory transmitter in cortical pyramidal cells, is involved in higher mental functions, such as cognition, memory and learning, and a glutamatergic synaptic hypofunction in schizophrenia seems indicated (see Coyle et al, 2003), a notion recently supported by the demonstration of a reduced prefrontal expression of the N-methyl-D-aspartate (NMDA) receptor subunits NR1, NR2A and NR2C in schizophrenic patients (Beneyto and Meador-Woodruff, 2008).…”