Clozapine Reverses the Spatial Working Memory Deficits Induced by FG7142 in Monkeys
NeuropsychopharmacologyPublished 1 June 1997Open access
Beth L. Murphy
Citations47
SJR quartileQ1
SJR score2.94
SNIP1.99
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TL;DR
The results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.
Abstract
The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.
Keywords
MedicineNeuroscience
Archives of General PsychiatryPhysiologic Dysfunction of Dorsolateral Prefrontal Cortex in Schizophrenia
2,019 Citations1986Daniel R. Weinberger
Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.
NatureCloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine
2,017 Citations1991Hubert H.M. Van Tol, James R. Bunzow +5 more
The cloning of a gene that encodes a dopamine receptor gene that has high homology to the human dopamine D2 and D3 receptor genes is reported, which suggests the existence of other types of dopamine receptors which are more sensitive to clozapine.
NatureModulation of memory fields by dopamine Dl receptors in prefrontal cortex
1,610 Citations1995Graham V. Williams, Patricia S. Goldman‐Rakic
The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.
ScienceCognitive Deficit Caused by Regional Depletion of Dopamine in Prefrontal Cortex of Rhesus Monkey
1,521 Citations1979Thomas J. Brozoski, Roger M. Brown +2 more
Evidence is provided that dopamine plays an important role in a specific cortical function in rhesus monkeys and that this role can be pharmacologically reversed with dopamine agonists.
ScienceD1 Dopamine Receptors in Prefrontal Cortex: Involvement in Working Memory
1,381 Citations1991Toshiyuki Sawaguchi, Patricia S. Goldman‐Rakic
D1 dopamine receptors play a selective role in the mnemonic, predictive functions of the primate prefrontal cortex, and local injections of SCH23390 and SCH39166 induced errors and increased latency in performance on an oculomotor task that required memory-guided saccades.
Journal of Pharmacology and Experimental TherapeuticsClassification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
1,348 Citations1989Herbert Y. Meltzer, Shin Matsubara +1 more
The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptors binding sites and cortical serotonin (5-HT2) receptor binding sites were determined.
NatureSelective activation of the mesocortical DA system by stress
1,036 Citations1976A.M. Thierry, Jean‐Pol Tassin +2 more
The results suggest that the mesocortical DA system is selectively activated by this stress induced by electric foot shocks, and the antipsychotic effects of neuroleptics are in part related to the blockade of postsynaptic DA receptors localised in areas innervated by the mesolimbic and mesocORTical DA systems.
Proceedings of the National Academy of SciencesIncreased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.
595 Citations1996Beth L. Murphy, AFT Arnsten +2 more
Analysis of the effects of FG7142 on the performance of spatial working memory tasks in rats and monkeys indicates that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the cortex.
PsychopharmacologyDopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys
578 Citations1994Amy F.T. Arnsten, Jingxia Cai +2 more
Results underscore the importance of DA D1 mechanisms in cognitive function, and provide functional evidence of DA system degeneration in aged monkeys, suggesting that excessive D1 stimulation may be deleterious to cognitive function.
Journal of PsychopharmacologyCatecholamine regulation of the prefrontal cortex
482 Citations1997Amy F.T. Arnsten
Evidence that catecholamine release during stress may serve to take the PFC 'off-line' to allow faster, more habitual responses mediated by the posterior and/or subcortical structures to regulate behavior is reviewed.
Journal of NeuroscienceNMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine
454 Citations1996Anita Verma, Bita Moghaddam
Findings indicate that attenuation of glutamatergic neurotransmission at the NMDA receptor impairs PFC- dependent cognitive functions and activation of dopamine neurotransmission contributes, at least in part, to this impairment.
Biological PsychiatryImprovement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine
399 Citations1993Corinne Hagger, P.F. Buckley +4 more
The improvement in cognitive function during clozapine treatment could have consequences for capacity to work and social function and there was some evidence for a relationship between improvement in psychopathology and cognitive function.
NatureDopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia
376 Citations1995Raymond J. Dolan, Paul C. Fletcher +4 more
PET 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.
Progress in brain researchChapter 19 The determinants of stress-induced activation of the prefrontal cortical dopamine system
367 Citations1991Ariel Y. Deutch, Robert H. Roth
This chapter explores the features of mesoprefrontal cortical DA neurons that render their response characteristics to a number of pharmacological and environmental challenges different from those of other mesotelencephalic DA neurons by using stress-induced alterations in mesotechnical DA neurons as a model.
The British Journal of PsychiatryThe Effect of Clozapine on Cognition and Psychiatric Symptoms in Patients with Schizophrenia
293 Citations1993Terry E. Goldberg, Richard D. Greenberg +6 more
Despite improvements in psychiatric symptoms, attention, memory, and higher-level problem-solving were essentially unchanged, suggesting that certain cognitive deficits are relatively independent of psychotic symptoms in schizophrenia, and are probably central and enduring features of the disorder.
The British Journal of PsychiatryLife Events and Psychosis
266 Citations1993Paul Bebbington, Soraya Wilkins +5 more
This study provides some of the strongest evidence for a link between life events and the emergence of psychotic symptoms, particularly in the three months before onset of psychosis.
Journal of Psychiatric ResearchFrontal lobe dysfunctions in schizophrenia—I. Eye movement impairments
258 Citations1984Smadar Levin
The phenomena of eye movement impairments in schizophrenia are interpreted in this paper, Part I of a two-paper series, in the context of neural mechanisms of attention and eye movement control in terms of a dysfunction of temporo-parietal mechanisms of task-engagement.
The British Journal of PsychiatryDimensions of Outcome with Clozapine
255 Citations1992Herbert Y. Meltzer
There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function, and tardive dyskinesia following clozapine administration to neuroleptic-resistant schizophrenic patients.
The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia
218 Citations1992Ariel Y. Deutch
In light of the importance that such DA system interactions may have in the pathogenesis of schizophrenia, the effects of cortical DA lesions on subcortical DA function are reinvestigated.
PubMedEffects of clozapine on cognitive function in schizophrenia.
200 Citations1994M A Lee, Paul A. Thompson +1 more
Clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia, especially attention and verbal fluency in both treatment- resistant schizophrenia and non-treatment-resistant schizophrenia.
Biological PsychiatryChanges in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: A tyrosine hydroxylase immunohistochemical study
175 Citations1994David R. Rosenberg, David A. Lewis
In this study, immunohistochemical techniques and antibodies against tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, are used to examine the relative density and laminar distribution of labeled axons in the prefrontal cortex of preadolescent, adolescent and adult monkeys.
PubMedBrain region effects of clozapine on amino acid and monoamine transmission.
80 Citations1994Bryan K. Yamamoto, Elizabeth A. Pehek +1 more
Overall, clozapine has a preferential effect on mesocorticolimbic neurotransmission whereas haloperidol alters glutamate and GABA efflux within the extrapyramidal motor system.
PubMedThe effects of clozapine on neurocognition: an overview.
68 Citations1994T E Goldberg, D.R. Weinberger
Clozapine appears to has a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions.
Journal of Mental ScienceCase of Mental Feebleness Associated with Pseudo-Muscular Hypertrophy
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