Clozapine Preferentially Increases Dopamine Release in the Rhesus Monkey Prefrontal Cortex Compared with the Caudate Nucleus

Youngren, Kenneth D.; Inglis, Fiona M.; Pivirotto, Philip; Jedema, Hank P.; Bradberry, Charles W.; Goldman‐Rakic, Patricia S.; Roth, Robert H.; Moghaddam, Bita

doi:10.1016/s0893-133x(98)00082-7

Cited by 82 publications

(47 citation statements)

References 32 publications

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“…Both clozapine and haloperidol, given acutely, increase extracellular levels of dopamine in the prefrontal cortex and striatal complex. Acute clozapine treatment preferentially increased prefrontal dopamine release in the rat; whereas, haloperidol preferentially increased striatal dopamine efflux (Moghaddam and Bunney 1990;Pehek et al 1993;Youngren et al 1994), and our group has recently observed a similar effect in the monkey (Youngren et al 1998). Thus, clozapine (at doses that do not potently block D 1 -like receptors) may actually potentiate transmission at this receptor subtype.…”

Section: Response Of Pcp Effects To Antipsychotic Drugsmentioning

confidence: 75%

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

Jentsch

Roth²

1999

Neuropsychopharmacology

1,201

772

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Administration of noncompetitive NMDA ր glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animalsBiological psychiatric research has seen the development of many putative animal models of schizophrenia. The etiological bases of these models have varied widely from the administration of purportedly psychotomimetic drugs (Snyder 1988; Javitt and Zukin 1991; Jentsch et al. 1998a), to perinatal insults (Lipska et al. 1993;El-Khodor and Boksa 1997;Moore and Grace 1997; Bertolino et al. 1997), to chronic social isolation or stress (Jones et al. 1990), and beyond. The administration of psychotomimetic drugs to humans and animals represents probably the most widely accepted and utilized class of schizophrenia models. These "pharmacological" models seem to represent methods for the induction of psychopathology in humans and aberrant (potentially related) behavior in animals.At the behavioral level, there seems to be some heterogeneity in the effects of different psychotomimetic drug classes. The psychomotor stimulants, such as amphetamine and cocaine, can clearly induce a form of 20 , NO . 3 paranoid psychosis in human subjects after high-dose or long-term administration, but evidence regarding the ability of these agents to induce "deficit" state symptoms is conflicting (Angrist and Gershon 1970;Everitt et al., 1997); moreover, there is evidence that amphetamine may actually alleviate negative and cognitive symptoms in schizophrenic patients (Angrist et al. 1982;Goldberg et al. 1991; Carter et al. 1997). Psychotomimetic indoleamines, such as lysergic acid diethylamide, can induce profound sensory hallucinations without causing any apparent deficit state in normal subjects (Geyer and Markou 1994) and without precipitating symptomatology in schizophrenic patients (Cohen et al. 1962). In contrast, the noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) ր glutamate receptor, including phencyclidine (PCP) and ketamine, seem to be capable of inducing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans (Snyder 1980; Javitt and Zukin 1991;Tamminga 1998); these drugs also profoundly exacerbate both positive and negative symptoms in schizophrenic patients (Itil et al. 1967;Lahti et al. 1994;Malhotra et al. 1997a).Because of the more comprehensive psychopathology induced by PCP, many researchers have studied the effects of NMDA receptor antagonists in humans and animals to gain insights into the neurobiology of schizophrenia. In this review, the validity of NMDA receptor antagonist-induced models of schizophrenia in humans and animals are considered, and the applicability of acute versus chronic administration of PCP as a more precise model is assessed. The neurobiological substrates of the observed behavior...

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Section: Response Of Pcp Effects To Antipsychotic Drugsmentioning

confidence: 75%

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

Jentsch

Roth²

1999

Neuropsychopharmacology

1,201

772

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“…The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis.…”

Section: Tyrosine Availability Can Influence Dopamine (Da) Synthesis mentioning

confidence: 89%

“…Intriguingly, in rats pretreated with FG-7142, a beta-carboline known to preferentially increase MPFC synthesis, utilization and release Roth 1985, 1990;Bradberry et al 1991), administration of tyrosine robustly enhances MPFC DA synthesis (Tam et al 1990). We postulated that such precursor dependence would also be established by other drugs which activate mesocortical dopaminergic activity.The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis.…”

mentioning

confidence: 89%

Tyrosine Augments Acute Clozapine- but not Haloperidol-Induced Dopamine Release in the Medial Prefrontal Cortex of the Rat An in vivo Microdialysis Study

Jaskiw

Collins

Pehek

et al. 2001

Neuropsychopharmacology

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Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC).In most brain dopamine (DA) systems, levels of the DA precursor tyrosine do not significantly affect dopaminergic transmission. The availability of tyrosine in the brain normally exceeds the capacity of the enzyme tyrosine hydroxylase (TH) to convert it to DOPA (Carlsson and Lindqvist 1978;Morgenroth et al. 1976;Joh et al. 1978). Since the conversion of DOPA to DA is rapid and efficient, DA synthesis usually depends on TH activity and not on tyrosine levels (Wurtman et al. 1974;Carlsson and Lindqvist 1978). However, precursor dependence of DA synthesis has been demonstrated in the light-activated retina (Fernstrom et al. 1984(Fernstrom et al. , 1986 as well as in striatal DA neurons after administration of haloperidol, spiperone, reserpine or amfonelic acid (Scally et al. 1977;Sved et al. 1979;Fuller and Snoddy 1982) or after marked DA depletion (Melamed et al. 1980). The common feature of these paradigms is a marked increase in the electrophysiological activity of the relevant DA system. Such data suggest that precursor dependence of DA synthesis may be a latent property of all DA neurons, but one which emerges only under conditions of increased dopaminergic activity. (Chiodo et al. 1984;White and Wang 1984), precursor dependence of medial prefrontal cortical (MPFC) DA synthesis might be expected even under basal conditions. Even within the MPFC, however, tight feedback systems limit the ability of exogenous tyrosine administration to augment DA synthesis (Tam et al. 1990). Intriguingly, in rats pretreated with FG-7142, a beta-carboline known to preferentially increase MPFC synthesis, utilization and release Roth 1985, 1990;Bradberry et al. 1991), administration of tyrosine robustly enhances MPFC DA synthesis (Tam et al. 1990). We postulated that such precursor dependence would also be established by other drugs which activate mesocortical dopaminergic activity.The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al. 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al. 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis. We further postulated that if the increased DA synthesis were reflected in increased DA release, then administration of tyrosine to clozapine-pretreated rats would augment MPFC DA levels as measured by in vivo microdialysis. Finally, since haloperidol, but not clozapine, preferentially activates nigrostriatal DA synthesis and release, we anticipated that tyrosine would enhance dialysate DA concentrations in the striatum but not the MPFC of haloperi...

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“…Several laboratories have shown that clozapine releases dopamine in frontal cortex in animal preparations, an action possibly related to its serotonin and/or noradrenergic receptor affinity (Pehek et al, 1994;Pehek, 1996;Rollema et al, 1997;Moghaddam and Bunney, 1999;Hertel et al, 1999;Youngren et al, 1999). In electrophysiologic and immediate-early gene studies, clozapine and other secondgeneration antipsychotics demonstrate limbic selectivity in that they preferentially affect dopamine neurons projecting to limbic areas (Chiodo and Bunney, 1983;White and Wang, 1983;Robertson and Fibiger, 1992).…”

Section: Discussionmentioning

confidence: 99%

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Lahti

Holcomb

Weiler

et al. 2003

Neuropsychopharmacol

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Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with 15 O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n ¼ 6) and normal volunteers (NVs) (n ¼ 12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1) Rest, (2) sensory motor control (SMC) task, and (3) decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n ¼ 5) and/or clozapine (n ¼ 5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol-and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidoltreated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

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Clozapine Preferentially Increases Dopamine Release in the Rhesus Monkey Prefrontal Cortex Compared with the Caudate Nucleus

Abstract: Despite substantial differences between species in the organization and elaboration of the cortical dopamine

Cited by 82 publications

References 32 publications

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

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

Tyrosine Augments Acute Clozapine- but not Haloperidol-Induced Dopamine Release in the Medial Prefrontal Cortex of the Rat An in vivo Microdialysis Study

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

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