PSYCHOTOMIMETIC-INDUCTION OF TISSUE-PLASMINOGEN ACTIVATOR MESSENGER-RNA IN CORTICOSTRIATAL NEURONS IN RAT-BRAIN

We have studied in the rat the effects of acute subcutaneous injection of psychotomimetics including methamphetamine (MAP), cocaine and phen cyclidine (PCP) on the expression of a brain plasticity-related molecu le, tissue plasminogen activator (tPA) mRNA, using non-radioactive in situ hybridization histochemistry. In addition to the constitutive exp ression of tPA mRNA in cerebellar Purkinje cells, ventricular ependyma l cells and meningeal blood vessel-associated cells, MAP (1-4 mg/kg), cocaine (30 mg/kg) and PCP (1.25-5 mg/kg) caused a transient and dose- dependent induction of the transcript with its peak at 3 h postinjecti on in a group of neurons of the medial and insular prefrontal cortices , and the piriform cortex. Another indirect dopamine agonist nomifensi ne (20-40 mg/kg) mimicked the tPA mRNA induction in the prefrontal cor tical areas. Moreover, MAP induction of tPA mRNA was markedly inhibite d by pretreatment with a D1 (R(+)-SCH23390: thyl-1-phenyl-2,3,4,5-tetr a-hydro-1H-3-benzazepine hydrochloride) or a D2 (haloperidol) dopamine receptor-preferring antagonist. Intramedial striatum, but not intrath alamic, application of a fluorescent tracer, fluorogold, retrogradely labelled the cortical cells expressing tPA mRNA. The present results s uggest that acute injections of the above psychotomimetic drugs may in duce tPA mRNA in a group of the prefrontal cortical neurons that proje ct to the medial striatum. This tPA mRNA expression may be due to the activation of the dopamine neurotransmission. Because it is well docum ented that single or repeated administration of methamphetamine, cocai ne and PCP produces enduring changes in responses to these drugs in hu mans and experimental animals (e.g. behavioural sensitization), the ps ychotomimetic-induction of tPA mRNA could be implicated in an initial step in the plastic rearrangements in the neuronal circuits underlying long-lasting changes in behavioural expression.