Enduring Cognitive Deficits and Cortical Dopamine Dysfunction in Monkeys After Long-Term Administration of Phencyclidine

Abstract

The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function. Behavioral deficits and decreased dopamine utilization remained after phencyclidine treatment was stopped, an indication that these effects were not simply due to direct drug effects. The data suggest that repeated administration of phencyclidine in monkeys may be useful for studying psychiatric disorders associated with cognitive dysfunction and dopamine hypofunction in the prefrontal cortex, particularly schizophrenia.

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

“…These effects of PCP are blocked by antipsychotic drugs (Sharp et al, 1992;Johnson et al, 1998;Olney et al, 1999). No changes in absolute serotonin or dopamine concentrations have been reported with either acute or chronic treatment using high doses of PCP suggesting that there are no neurochemical lesions of these two important neurotransmitter innervations likely to be involved in the rewarding/ dysphoric actions of PCP (Jentsch et al, 1997b;Noda et al, 2000;Balla et al, 2001). Nevertheless, the irreversibility of the neurodegenerative and apoptotic actions of PCP observed in cortical and subcortical structures in which PCP acts to modulate neurotransmission may lead to the longlasting expression of the brain reward deficit observed during withdrawal from chronic high-dose PCP treatment.…”

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

“…Other human and animal studies DA modulates responses to positive/negative rewards, salient events and arousal-producing stimuli (Everitt et al, 2000;Liberzon et al, 2003;Horvitz, 2000) CSF HVA levels are related to impulsivity in BPD (Coccaro, 1998;Chotai et al, 1998); to self-injurious and violent behavior (Winchel and Stanley, 1991;Soderstrom et al, 2001) DA receptor activity in the DLPFC modulates working memory and cognition (Arnsten et al, 1994;Goldman-Rakic, 1996;Arnsten and Goldman-Rakic, 1998) DA modulates emotional responses mediated by the amygdala-VTA-PFC circuits (Horvitz, 2000) DA dysfunction is involved in drug addiction (Modell et al, 1993;Volkow and Fowler, 2000) PCP-induced cognitive impairment correlates with DA levels in the DLPFC (Jentsch et al, 1997) Stress alters DA activity in the amydala and PFC (Finlay and Zigmond, 1997;Doherty and Gratton, 1999) DA mediates aggression and attack in rats (Wade et al, 2000;Vukhac et al, 2001) DA modulates cognitive processes at NMDA receptors (Williams and Goldman-Rakic, 1995) DA modulates conditioned fear responses (Guarraci et al, 1999) DA stimulates impulsive behavior in rats (Harrison et al, 1997) D1 agonist dilhydrexidine enhances cognitive performance and stimulates Ach release in the PFC (Steele et al, 1997;Schneider et al, 1994) Microdialysates of the PFC and the NAC suggest DA dysfunction is a risk factor for impulsivity (Van Erp and Miczek, 2000;Dalley et al, 2002) DA dysfunction in the DLPFC is related to cognitive impairment in SCZ, SPD, and normal subjects (Goldberg et al, 2003;Siever et al, 2002) DAFdopamine; CSF HVAFspinal fluid homovanillic acid; DLPFCFdorsolateral prefrontal cortex; PCPFphencylclidine; VTAFventral tegmental area; PFCFprefrontal cortex; AchFacetylcholine; NACFnucleus accumbens; SCZFschizophrenia; SPDFschizotypal personality disorder.…”

“…Cognitive impairment in monkeys can be produced by repeated treatment with phencyclidine (PCP) (Jentsch et al, 1997). The impairment produced by PCP, a glutamatergic antagonist, correlates significantly with a decrease in DA levels only in the DLPC and in the prelimbic cortex, and is reversed by clozapine.…”

“…Glutamate upregulates DA D1 receptors by NMDA receptor activation (Scott et al, 2002). Any alteration in these mechanisms could cause an impairment of DA-modulated cognitive function (Jentsch et al, 1997). In addition, the D1 agonist dihydrexidine releases acetylcholine in the PFC and enhances cognitive performance in rats (Steele et al, 1997) and in monkeys (Schneider et al, 1994), effects blocked by SCH 23390.…”

Impairments of Reversal Learning and Response Perseveration after Repeated, Intermittent Cocaine Administrations to Monkeys

“…Volkow and Fowler 2000;London et al 2000). Second, chronic drug administration affects the neurochemistry and anatomy of these brain regions in animal models (Nestler and Aghajanian 1997;Robinson and Kolb 1997;Wolf 1998;Berke and Hyman 2000; Vandershuren and Kalivas 2000;Robinson et al 2001 (Post et al 1976), altered incentive motivation (Shippenberg and Heidbreder 1995;Taylor and Horger 1999;Robbins and Everitt 1999) and impaired cognitive and executive function (Jentsch et al 1997(Jentsch et al , 2000Rogers et al 1999;Robbins and Everitt 1999;Grant et al 2000;Ornstein et al 2000) after chronic stimulant drug administration.Because of its important role in decision-making (Bechara et al 2000) and inhibitory control over pre-potent behavior (Roberts and Wallis 2000), an involvement of ventromedial regions of the frontal cortex in drug abuse has been proposed. In essence, impairments of frontal lobe function are thought to effectively 'un-gate' subcortically-mediated, conditioned tendencies (such as established instrumental responses to obtain and consume drugs), resulting in the compulsive drug seeking and taking that characterize addiction (Jentsch and Taylor 1999).…”