Reversal of Antipsychotic-Induced Working Memory Deficits by Short-Term Dopamine D1 Receptor Stimulation

Castner, Stacy A.; Williams, Graham V.; Goldman‐Rakic, Patricia S.

doi:10.1126/science.287.5460.2020

Cited by 361 publications

(242 citation statements)

References 37 publications

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“…Moreover, the reduced performance was reversed by dopamine receptor agonists. A number of more recent studies have shown that mainly dopamine D 1 , but not D 2 , receptors are involved in the modulation of tasks relying on intact prefrontal cortical functioning Goldman-Rakic, 1991, 1994;Williams and Goldman-Rakic, 1995;Goldman-Rakic, 1996;Castner et al, 2000). Moreover, D 1 receptor density exceeds D 2 density by a factor of 10-20 in animal (Camps et al, 1990;Lidow et al, 1991) and human (De et al, 1988) cerebral cortex.…”

Section: The Effect Of Haloperidol On Neuropsychological Performancementioning

confidence: 99%

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Csomor

Stadler

Feldon

et al. 2007

Neuropsychopharmacol

101

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Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D 2 -like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebocontrolled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D 2 -like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.

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Section: The Effect Of Haloperidol On Neuropsychological Performancementioning

confidence: 99%

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Csomor

Stadler

Feldon

et al. 2007

Neuropsychopharmacol

101

View full text Add to dashboard Cite

show abstract

“…It is well known that dopamine (DA) neurotransmission plays a pivotal role in WM (Castner et al, 2000;McNab et al, 2009). Pharmacological studies on both animals (Vijayraghavan et al, 2007) and humans (Kimberg and D'Esposito, 2003) have indicated that dopamine (DA) in the brain modulates WM.…”

Section: Introductionmentioning

confidence: 99%

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

Jin¹,

Lei²,

Wang³

et al. 2013

NeuroImage

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The genetic and neural basis of working memory (WM) has been extensively studied. Many dopamine (DA) related genes, including the NTSR1 gene (a DA modulator gene), have been reported to be associated with WM performance. The NTSR1 protein is predominantly expressed in the cerebral cortex and the hippocampus, the latter of which is closely involved in WM processing based on both lesion and fMRI studies. Thus far, however, no study has examined the joint effects of NTSR1 gene polymorphism and hippocampal morphology on WM performance. Participants of the current study were 330 healthy Chinese college students. WM performance was measured with a 2-back WM paradigm. Structural MRI data were acquired and then analyzed using an automated procedure with atlas-based FreeSurfer segmentation software (v 4.5.0) package. Linear regression analyses were conducted with a NTSR1 C/T polymorphism which was previously reported to be associated with WM (rs4334545), hippocampal volume, and their interaction as predictors of WM performance, with gender and intracranial volume (ICV) as covariates. Results showed a significant interaction between NTSR1 genotype and hippocampal volume (p b .05 for both the left and right hippocampi). Further analysis showed that the correlation between hippocampal volume and WM scores was significant for carriers of the NTSR1 T-allele (p b .05 for both hippocampi), but not for CC homozygotes. These results indicate that the association between hippocampal structure and WM performance was modulated by variation in the NTSR1 gene, and suggest that further studies of brain-behavior associations should take genetic background information into account.

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“…Chronic exposure to the D 2 -like receptor antagonist haloperidol results in disrupted working memory (Castner et al, 2000). Acute challenge with various D 2 -like receptor antagonists has been reported to impair working memory and delayspecific PFC neuronal activity in some studies (Arnsten and Goldman-Rakic, 1998;Didriksen, 1995;Murphy et al, 1996), but not others (Aultman and Moghaddam, 2001;Bushnell and Levin, 1993;Sawaguchi and Goldman-Rakic, 1994;Verma and Moghaddam, 1996;Williams and GoldmanRakic, 1995).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

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Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D 1 and D 2 receptors, with most evidence suggesting a dominant role for the D 1 receptor. Since the dopamine D 4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D 4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D 4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D 4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D 4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D 4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D 4 receptor in working memory, and suggest innovative, D 4 -based, treatment of cognitive deficits associated with neuropsychiatric disorders.

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Reversal of Antipsychotic-Induced Working Memory Deficits by Short-Term Dopamine D1 Receptor Stimulation

Cited by 361 publications

References 37 publications

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

Regulation of Working Memory by Dopamine D4 Receptor in Rats

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