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Abstract

Phencyclidine (PCP) administration in rodents has been used to model aspects of schizophrenia. One aspect of such treatment has been the enhancement of amphetamine-induced increase of dopamine in the prefrontal cortex and striatum. To further characterize this mechanism rats were treated for 2 weeks with continuous PCP (15 mg/kg per day via Alzet minipump). Rats were implanted with a microdialysis probe into the prefrontal cortex (PFC) or striatum. Amphetamine was administered locally via the dialysis probe during one collection period and changes in extracellular dopamine were monitored. The effect of local administration of the dopamine uptake blocker nomifensine was also measured. Amphetamine (10 microM) and nomifensine (10 microM) increased the level of dopamine in both the PFC and striatum. PCP administration did not alter the response to amphetamine or nomifensine in the PFC, but reduced this response about 2-fold in striatum. To examine effects of continuous PCP administration on dopamine autoreceptor function, release of [3H]dopamine in response to electrical stimulation and in the presence of a dopamine agonist or antagonist was tested in striatal and prefrontal cortical tissue. Autoreceptor responses were similar in control and PCP-treated tissues. We conclude that the brain region-specific enhancement of dopamine release by peripheral amphetamine administration in rats after PCP is not likely mediated by alterations in the dopamine autoreceptors or changes in the dopamine transporter. The selective local responses of amphetamine indicates heterogeneous regional effects of continuous PCP on NMDA receptor function; effects that influence both regional excitatory responses and the overall dynamics of tonic excitatory/inhibitory inputs to the PFC and striatum.

Thinking Glutamatergically: Changing Concepts of Schizophrenia Based Upon Changing Neurochemical Models

“…In normal volunteers, pretreatment with ketamine leads to dopaminergic dysregulation similar to that observed in schizophrenia (121), even under conditions where no effect on basal DA release is observed. Similar augmentation of amphetamine-induced DA release is observed in rodents treated with NMDA antagonists (122–124). A primary site of NMDA appears to be local inhibitory interneurons within key brain regions (125).…”

Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia

“…An advantage of these compounds vs. previous agents is their tolerability during subchronic systemic administration. As in earlier studies with NMDAR antagonists, significant enhancement in prefrontal DA release was observed following subchronic PCP treatment at concentrations relevant to PCP-induced psychosis in humans (Balla et al, 2001a; Balla et al, 2001b; Balla et al, 2003). Furthermore, as in subchronic studies with the NMDAR modulator glycine or an acute study with the prototype GlyT1 inhibitor NFPS (Javitt et al, 2004), significant effects were observed on AMPH-induced DA release in PFC.…”

Neurophysiological and neurochemical animal models of schizophrenia: Focus on glutamate☆

“…Potentiation of amphetamine-induced DA release is also observed following administration of the NMDA antagonist MK-801 [90]. In both preparations, increases are seen to systemic but not local amphetamine administration, suggesting that effects are not mediated by direct interaction of NMDA antagonists with the receptors on the presynaptic terminal or by interaction with the DAT itself [6]. Rather, effects appear to depend upon more complex neural interactions.…”