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

Abstract

Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.

Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists

“…This finding has been replicated in several cohorts using in vivo PET and SPECT imaging (Abi-Dargham et al, 1998;Breier et al, 1998Breier et al, , 1997Kegeles et al, 1999;Laruelle et al, 1998Laruelle et al, , 1999Laruelle et al, , 1996Laruelle et al, , 1995Laruelle et al, , 1997a. Similar abnormalities are observed in humans following ketamine administration (Kegeles et al, 2000), and in rodents following acute (Balla et al, 2003;Miller and Abercrombie, 1996) or chronic (Balla et al, 2001b(Balla et al, , 2003 NMDA antagonist administration.…”

“…NMDA antagonists induce dopaminergic hyperactivity similar to that observed in schizophrenia in both human (Kegeles et al, 2000) and rodent (Balla et al, 2001b(Balla et al, , 2003Miller and Abercrombie, 1996) studies. In schizophrenia, treatment with NMDA co-agonists such as glycine, D-serine, and D-cycloserine produce significant amelioration of treatment-refractory symptoms, including improvement in both negative and positive symptoms (Javitt, 2002).…”

Amphetamine-Induced Fos is Reduced in Limbic Cortical Regions but not in the Caudate or Accumbens in a Genetic Model of NMDA Receptor Hypofunction

“…The striatal dopaminergic system in NR1 hypomorphic mice, including basal, unstimulated concentration of extracellular dopamine, the tissue contents of dopamine, and its metabolites, appears to be fairly intact (Mohn et al, 1999). In contrast to the apparent lack of effect of the NR1 hypomorphic mutation on striatal dopamine release, chronic treatment with PCP enhanced amphetamineinduced dopamine release in the striatum and medial frontal cortex (Balla et al, 2001;Balla et al, 2003). It will be of interest to assess dopamine release in the NR1-deficient mice in response to amphetamine in future studies.…”

“…For example, amphetamine-induced behavioral responses, including hyperactivity and stereotypies, can be either enhanced (Balla et al, 2003;Turgeon and Roche, 1999), inhibited (Greenberg and Segal, 1985), or unchanged (Wang et al, 1994) by NMDA-R antagonists such as PCP in rodents. The different effects observed probably relate to different doses, patterns of exposure, and the time interval examined after the administration of the NMDA antagonists.…”

Glutamate as a therapeutic target in psychiatric disorders

“…In humans, acute treatment with ketamine induces high levels of anxiety that are not typically seen in established schizophrenia, but fails to reproduce the hallucinatory behavior that emerges over time during the schizophrenia prodrome 73,74 As an alternative to acute treatment models, neurodevelopmental and chronic treatment models may provide a more appropriate vehicle for drug development. Prolonged NMDAR blockade can be induced by repeated or continuous administration of NMDAR antagonists in rodents 75,76 or primates. 77,78 As compared with acute treatment in humans, chronic treatment in monkeys leads to appearance of hallucinatory-like behavior, 77 suggesting that dysregulation of relevant brain systems may emerge gradually over time.…”