Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction

Goldman‐Rakic, Patricia S.; Castner, Stacy A.; Svensson, Torgny H.; Siever, Larry J.; Williams, Graham V.

doi:10.1007/s00213-004-1793-y

Cited by 455 publications

(351 citation statements)

References 191 publications

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“…component of the evoked EPSP (ie altering the EPSP time course) is consistent with a postsynaptic interaction of D1 and NMDA receptors (Zheng et al, 1999;Seamans et al, 2001a;Chen et al, 2003;Tseng and O'Donnell, 2004). Consistently, anatomical evidence shows that D1 receptor immunoreactivity is frequently associated postsynaptically with dendritic spines and shafts that are in close proximity to asymmetrical synapses characteristic of glutamate receptors (Simley et al, 1994;Goldman-Rakic et al, 2004). In the Type II deep layer pyramidal neurons, we also observed a DA-mediated depression of afferent-evoked synaptic responses in slices that was attributed to activation of D2/D4 receptors.…”

Section: Discussionsupporting

confidence: 67%

“…The pharmacological roles of D4 receptors have begun to be elucidated, including a role in the performance of cognitive functions involving the prefrontostriatal system in rats (Jentsch et al, 1999;Zhang et al, 2004) and monkeys (Arnsten et al, 2000), and D4 receptors may be overexpressed in schizophrenia subjects (Seeman et al, 1993;Sumiyoshi et al, 1995; but also see Lahti et al, 1996;Reynolds and Mason, 1995), in which a primary DA dysfunction is implicated (Grace, 2000;Lewis, 2000;Goldman-Rakic et al, 2004). The recent demonstration of a preferential localization of D4 receptors on parvalbumin (PV)-containing GABAergic interneurons in the PFC (Mrzljak et al, 1996;Wedzony et al, 2000) suggests a potential involvement of D4 receptors in the regulation of activity of intrinsic GABAergic neurons that may exert a powerful feedforward inhibitory influence on pyramidal neurons.…”

Section: Introductionmentioning

confidence: 99%

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Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Onn

Wang

Lin

et al. 2005

Neuropsychopharmacol

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Although dopamine (DA) effects in the prefrontal cortex (PFC) have been studied extensively, the function of steady-state ambient levels of DA in the regulation of afferent excitatory transmission in PFC pyramidal neurons remains relatively unexplored. Using intracellular sharp-electrode and whole-cell recordings combined with intracellular labeling in brain slices, we found that D1/D5 receptor blockade did not alter synaptic responses in the PFC, but D1/D5 receptor activation consistently enhanced recurrent synaptic excitation in the majority of pyramidal neurons tested. In contrast, D4 receptor blockade resulted in an evoked complex multiple spike discharge pattern that contained both early and late (presumably multisynaptic) components of the evoked response that is contingent upon the preservation of axon collaterals of the neuron under study. Moreover, GABAergic interneurons were found to play a role in both responses; blockade of GABA a -mediated inhibition caused bath application of DA to convert monosynaptic excitatory postsynaptic potentials (EPSPs) to complex spike bursts riding on the late component of the EPSP. On the other hand, during the blockade of GABA amediated conductances, administration of a D4 receptor antagonist failed to facilitate evoked multiple spike discharge. Morphological analysis of axon collaterals of labeled neurons revealed that neurons in which the D4 receptor blockade induced the putative polysynaptic response had axon collaterals that were largely preserved. These data suggest that DA exerts a bidirectional modulation of PFC pyramidal neurons in brain slices provided that local network connections with interneurons are preserved, with D4 receptors under tonic stimulation by ambient low levels of DA, whereas D1/D5 receptors activated upon phasic DA input.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Onn

Wang

Lin

et al. 2005

Neuropsychopharmacol

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“…37 Dysregulation of DA transmission of the pFCx has been mainly related to working memory deficits seen in schizophrenic patients. 38 However, cognitive impairments in schizophrenia involve a spectrum of functions including impaired emotional learning. 39 Schizophrenic patients are known to display abnormalities in emotional learning but it is unclear whether deficits in emotional memory are part of a general cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

et al. 2007

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The transcription factor Nurr1 (NR4A2) has been found to play a critical role in the development of midbrain dopaminergic neurons. Nurr1 heterozygous ( þ /À) male and female mice expressing 35-40% of normal levels of Nurr1 were generated and examined in animal models related to symptoms of schizophrenia. The Nurr1 ( þ /À) mice displayed hyperactivity in a novel environment, which persisted after administration of the dopamine-mimetic amphetamine and the N-methyl-D-aspartate receptor antagonist phencyclidine. The Nurr1 ( þ /À) mice were deficient in the retention of emotional memory and showed an enhanced response to swim stress. In addition, Nurr1 ( þ /À) male mice displayed a reduced dopamine turnover in the striatum and an enhanced dopamine turnover in the prefrontal cortex, while female mice showed an opposite pattern. These results show that Nurr1 ( þ /À) mice display a pattern of behaviors indicative of potential relevance for symptoms of schizophrenia combined with a gender-specific abnormal dopamine transmission in the striatum and prefrontal cortex, respectively. This suggests that the Nurr1 mutant mouse may be a potential animal model for studies on some of the behavioral and molecular mechanisms underlying schizophrenia.

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“…In contrast to D 2 antagonist effects, manipulations of dopamine D 1 receptors was considered one of the most promising possible targets for pro-cognitive agents in schizophrenia by the MATRICS Neuropharmacology group (Goldman-Rakic et al, 2004). The effects of dopamine agonists on PPI in rats are clearly due largely to actions at the dopamine D 2 -family of receptors , which is quite consistent with the actions of existing antipsychotic drugs.…”

Section: The Dopamine Prepulse Inhibition Model In Ratsmentioning

confidence: 96%

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

2006

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Prepulse inhibition (PPI) of startle is an operational measure of the pre-attentive filtering process known as sensorimotor gating. Originally identified in patients with schizophrenia, PPI deficits have been observed in multiple but not all psychiatric disorders. Thus, as with most signs and symptoms of psychiatric disorders, deficits in PPI cut across diagnostic categories. It remains unclear whether the diversity of disorders exhibiting deficient PPI bespeaks diagnostic overlaps or comorbidities. Given the recent focus on treatments for cognitive deficits of schizophrenia independently of treating psychosis, the relationship of PPI deficits to cognitive deficits becomes of interest. Although PPI cannot be considered to be a cognitive process per se, abnormalities in pre-attentive information processing may be predictive of or lead to complex cognitive deficits. Animal models of PPI deficits produced by dopamine agonists reliably predict existing antipsychotics. Nevertheless, since neither PPI nor cognitive deficits in schizophrenia are ameliorated by standard antipsychotics, current research is exploring the predictive value of non-dopaminergic PPI models in identifying treatments for gating disturbances independently of their relevance to specific disorders. Both PPI and cognitive deficits in schizophrenia patients are not reversed by first generation antipsychotics but may be attenuated by clozapine. Similarly, effects of glutamate antagonists on symptoms in patients and PPI in animals appear to be reduced by clozapine. Hence, treatment-induced reversals of deficits in PPI produced by glutamate antagonists may provide animal, and human, models to aid in the discovery of treatments of cognitive deficits in patients already treated with existing antipsychotics.

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Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction

Cited by 455 publications

References 191 publications

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

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