Single or repeated exposure to psychostimulants such as amphetamines and cocaine after postnatal week 3 leads to an enduring enhancement in the psychotomimetic responses elicited by a subsequent challenge of a stimulant in rodents. This behavioral sensitization phenomenon has been considered to be the neural consequences of stimulant-induced alterations in gene expression in the brain after a critical period of postnatal development. Using a differential cloning technique, RNA arbitrarily primed PCR, we have now identified from the rat neocortex a novel and developmentally regulated methamphetamine (MAP)-inducible gene mrt1 (MAP responsive transcript 1). mrt1 encodes two major types of PDZ-and PX-domains containing proteins of approximately 62 kDa in size with different carboxy termini, Mrt1a and Mrt1b. The mrt1 mRNAs for Mrt1a, mrt1a, and for Mrt1b, mrt1b, are predominantly expressed in various brain regions and the testes, respectively. Acute MAP injection upregulated mrt1b expression in the neocortex after postnatal week 3 in a D1 receptor antagonist-sensitive manner without affecting mrt1a expression. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to change the mrt1b transcript levels. Moreover, repeated daily treatment of MAP, but not MAP plus D1 antagonist, for 5 days caused an augmentation of the basal expression of mrt1b 2 and 3 weeks after the drug discontinuation. These late-developing, cocaine-crossreactive, D1 antagonist-sensitive and long-term regulations of mrt1b by MAP are similar to the pharmacological profiles of stimulant-induced behavioral sensitization, and therefore may be associated with the initiation and/or maintenance of the long-term neuronal adaptation.

We have examined the effects of schizophrenomimetic drugs including phencyclidine (PCP) and methamphetamine (MAP) on cortical and striatal dopamine (DA) metabolism using an in vivo dialysis technique in the rat. An acute systemic injection of PCP (2.5–10 mg/kg, intraperitoneally (i.p.)) dramatically increased concentrations of DA, 3,4‐dihydroxy‐phenylacetic acid, and homovanillic acid in the dialysates from the medial frontal cortex in a dose‐dependent fashion. However, PCP (2.5–10 mg/kg, i.p.) caused a much lower augmentation of extracellular DA release, with a significant decrease in dialysate DOPAC levels in the striatum. Moreover, continuous infusion of tetrodotoxin (TTX, 10−5 M) into the prefrontal or striatal region through the microdialysis tube completely blocked the ability of PCP (10 mg/kg, i.p.) to alter the extracellular release of DA and its metabolites in the respective areas. In contrast, MAP (4.8 mg/kg, i.p.) elicited a marked and tetrodotoxin‐resistant increase in DA levels with a significant loss of DOPAC contents in the extracellular space of both the frontal cortex and the striatum. The present results clearly demonstrate the differential effects of PCP on cortical and striatal DA transmission, suggesting that PCP may facilitate DA release in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the cortical area, whereas PCP‐induced elevation of extracellular DA in the striatum may be caused mainly by reuptake inhibition of DA liberated by basal activity of the striatal DA neurons. The regional variation in PCP‐induced DA release would be due to the combination of NMDA (N‐methyl‐D‐aspartate) receptor blocking and DA reuptake inhibition by the drug. The uniform and TTX‐resistant nature of MAP‐induced changes in brain DA metabolism may result from the direct actions of MAP at DA nerve terminals. © 1996 Wiley‐Liss, Inc.

The onset of schizophrenia and the schizophrenomimetic effects of an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, rarely occur during infancy and childhood, suggesting that schizophrenia-related neuron circuits and molecules in the brain might show an age-related response to an NMDA receptor antagonist. By using a DNA microarray technique, we have identified the developmentally regulated PCP-inducible gene leiomodin2 (Lmod2) that encodes a tropomyosin-binding actin-capping protein enriched in the cardiac and skeletal muscles. PCP caused an increase in the thalamic amounts of Lmod2 transcripts at postnatal days (PD) 32 and 50 without affecting them at PD 8, 13, 20 and 24, while the NMDA antagonist failed to produce a significant change in the gene expression in the adult heart. In-situ hybridization analysis revealed that the basal and PCP-induced expression of the Lmod2 gene is almost confined to the lateral and anterior nuclei of the thalamus among the brain regions at PD 50. The PCP-induced up-regulation of Lmod2 mRNAs in the adult thalamus was mimicked totally (also up-regulated) by another NMDA antagonist, dizocilpine, and partly by the indirect dopamine agonist, methamphetamine. Moreover, pretreatment with a D(2)-preferring dopamine receptor antagonist, haloperidol, partially antagonizes the increasing effects of PCP on thalamic Lmod2 gene expression. These findings suggest that Lmod2 might be involved in the pathophysiology of the age-dependent onset of drug-induced schizophrenia-like psychosis and schizophrenia and that the limited thalamic nuclei expressing the Lmod2 gene could compose the neuron circuits that are specifically disturbed in these mental disorders.

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