Subchronic Phencyclidine Administration Increases Mesolimbic Dopaminergic System Responsivity and Augments Stress- and Psychostimulant-Induced Hyperlocomotion

Abstract

Previous studies have shown that repeated exposures to phencyclidine (PCP) induces prefrontal cortical dopaminergic and cognitive deficits in rats and (Javitt and Zukin 1991); that is, administration of PCP or its congeners ketamine or dizocilpine can induce schizophrenic-like symptomatology in people (Luby et al. 1959;Krystal et al. 1994; Bunney et al. 1994) and precipitate psychosis in schizophrenics (Ital et al. 1967;Lahti et al. 1994). These compounds can stimulate both positive and negative symptoms of schizophrenia (Javitt and Zukin), including cognitive dysfunction (Cosgrove and Newell 1991). As such, PCP administration has been suggested to represent a drug-induced model of schizophrenia (Javitt and Zukin;Steinpreis 1996).The ability of PCP to simulate the symptomatology of schizophrenia in humans has led to the proposal that the behavioral pathologies evident in schizophrenia and PCP-exposed humans are caused by dysfunction of common neural substrates (Luby et al. 1959;Javitt and Zukin 1991). The effects of PCP on brain dopamine systems has received particular attention (Meltzer et al. 1980;Bowers and Hoffman 1984;Deutch et al. 1987;Hertel et al. 1996;Jentsch et al. 1997a) since alterations in dopaminergic systems have been hypothesized in schizophrenia (reviewed in Davis et al. 1991;Deutch 1992 Recent work has shown that long-term administration of PCP causes enduring cognitive dysfunction and cortical dopamine deficits in rats and monkeys (Jentsch et al. 1997b,c). These data correspond to reports of cognitive disturbances in schizophrenic subjects (Fey 1951;Goldman-Rakic 1991;Park and Holzman 1992), and recent in vivo imaging studies of the schizophrenic brain have revealed a failure of activation of frontal cortex during cognitive performance (termed "hypofrontality" by Weinberger and Berman 1996), effects that may be mediated by dopaminergic dysfunction Daniel et al. 1989 Daniel et al. , 1991Dolan et al. 1995). These data are also consistent with studies in nonhuman primates that have revealed that lesions of the prefrontal cortical dopamine innervation lead to working memory impairments (Brozoski et al. 1979), a cognitive process closely associated with this brain region (Goldman-Rakic 1987).Moreover, prefrontal cortical dopaminergic deficiencies may result in enhancement of activity of subcortical dopamine systems. Destruction of prefrontal cortical dopamine terminals has been shown to augment the response of the mesolimbic dopamine systems to stress ), amphetamine sensitization (Banks and Gratton 1994), high K ϩ -stimulation (Roberts et al. 1994), or haloperidol administration (Rosin et al. 1994). These data have supported an emerging neurochemical hypothesis of schizophrenia: cortical dopaminergic hypoactivity and subcortical dopaminergic hyperactivity (Robbins 1990;Grace 1991;Deutch 1992). Recent in vivo studies of the schizophrenic brain have revealed evidence for the subcortical component of this hypothesis; heightened responsivity to the dopamine-releasing properties of amphetamine ha...

Subchronic Continuous Phencyclidine Administration Potentiates Amphetamine-Induced Frontal Cortex Dopamine Release

“…PCP doses of 10-20 mg/kg/day in rodents have also been found to be effective by other groups (Jentsch et al, 1998a;Martinez et al, 1999;Sams-Dodd, 1998). Ehrhardt et al (1999) found no significant effect of 5 mg/kg/day PCP, similar to the observations in the present study.…”

“…For example, Jentsch et al (1998a) found no significant alterations in absolute PFC dopamine levels 1 or 3 weeks following a 7-day subchronic treatment with 10 mg/kg/day PCP, although the DOPAC/dopamine ratio was altered. Similarly, Lannes et al (1991) found no change in tissue levels of dopamine or DOPAC following a 60-day treatment repeatedly with 15 mg/kg/day ketamine administered orally, despite the fact that animals showed increased behavioral sensitivity to both apomorphine and haloperidol.…”

“…Amphetamineinduced activity was monitored in order to evaluate the relationship between alterations in dopamine levels and known chronic PCP-induced potentiation of amphetamineinduced locomotor activity (Jentsch et al, 1998a). Activity measurements were obtained for 210 min following amphetamine administration.…”

“…Both amphetamine-and PCP-induced hyperactivity have traditionally been associated with alterations in dopamine release within NAc (Clarke et al, 1988;French and Vantini, 1984;Jentsch et al, 1998a;Kelley and Throne, 1992;McCullough and Salamone, 1992;Nabeshima et al, 1983;Ouagazzal et al, 1994). Recently, it has been demonstrated that increased PFC dopamine levels also correlate with the time course of hyperactivity following PCP administration (Adams and Moghaddam, 1998).…”

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

“…It has been observed that withdrawal from PCP treatment is associated with an upregulation of 5-HT 2A receptors (Kitaichi et al, , 1999) and a progressive increase in serotonin utilization in the prefrontal cortex, indicating an overstimulation of serotonin neurotransmission in this brain area during withdrawal; the amplitude of this effect is proportional to the duration of the preceding PCP treatment and is reversed by antipsychotic drugs having 5-HT 2A receptor antagonist activity (eg clozapine) (Noda et al, 1995(Noda et al, , 2000Quiao et al, 2001). Moreover, two laboratories showed that during PCP withdrawal, depending on the duration of PCP treatment, there is a progressive decrease in basal-or stress-evoked dopamine utilization in the prefrontal cortex associated with an increase in subcortical dopamine turnover induced by amphetamine or a stressor (Jentsch et al, 1997c(Jentsch et al, , 1998bNoda et al, 2000;Balla et al, 2001). Therefore, sustained PCP exposure seems to establish imbalances between serotonin and dopamine transmission in cortical brain regions as well as in the functioning of these two neurotransmitter systems between cortical and subcortical brain regions that may lead to the expression of a long-lasting dysphoric effect of the drug at the cessation of treatment.…”