Dopamine D 4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys

The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.

Section: Discussionmentioning

confidence: 99%

Clozapine Normalizes Prefrontal Cortex Dopamine Transmission in Monkeys Subchronically Exposed to Phencyclidine

Elsworth

Jentsch

Morrow

et al. 2007

“…Several previous studies have examined cognitive effects of D 4 antagonists. Using an object retrieval/detour task in monkeys (a test of frontostriatal function), Jentsch et al (1999) found that behavioral deficits induced by the NMDA antagonist phencyclidine could be reversed with the selective D 4 antagonist NGD94-1. The D 4 -selective antagonist PNU-101,387G has been reported to prevent working memory deficits induced by the benzodiazepine inverse agonist FG-7142 in monkeys (Arnsten et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

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.

“…However, there have been a number of previous reports that systemic administration of D4 antagonists can improve performance on tasks dependent on the PFC. For example, administration of the D4 antagonist NGD94-1 in monkeys reverses the phencyclidine-induced impairments on an object retrieval/detour task (Jentsch et al, 1999). Similarly, impairments in working memory induced by FG-7142, a pharmacological stressor that selectively increases PFC DA release, were attenuated by coadministration of the D4-selective antagonist PNU-101,387G (Arnsten et al, 2000).…”

Section: Opposing Effects Of D4 Receptor Agonists and Antagonists On mentioning

confidence: 97%

Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

Floresco

Magyar

Ghods-Sharifi

et al. 2005

358

290

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired setshifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.