PRAZOSIN INHIBITS MK-801-INDUCED HYPERLOCOMOTION AND DOPAMINE RELEASEIN THE NUCLEUS-ACCUMBENS

This study examined the putative inhibitory effect of the alpha(1)-adr enoceptor antagonist prazosin oxy-2-quinazolinyl)-4-(2-furanylcarbonyl )perazine) on changes evoked by the psychotomimetic, non-competitive N MDA receptor antagonist, dihydroxy-5H-dibenzo-(a,d)cyclohepten-5,10-im ine), in locomotor activity and extracellular concentrations of dopami ne and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovan illic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic a cid (5-HIAA) in the nucleus accumbens as assessed by microdialysis in freely moving rats. MK-801 (0.1 and 0.3 mg/kg, s.c.) induced a signifi cant, dose-dependent increase in horizontal locomotor activity but did not affect rearing. Prazosin administration alone (1 mg/kg, s.c.) onl y slightly reduced horizontal activity during an initial 10 min measur ement period, although it consistently reduced rearing. However, pretr eatment with prazosin effectively suppressed the locomotor stimulation caused by either dose of MK-801 throughout the whole observation peri od, i.e. 40 min. Both doses of MK-801 significantly increased extracel lular levels of dopamine in the nucleus accumbens up to approximately 90%. In addition, MK-801 dose dependently increased dopamine metabolit e concentrations in the nucleus accumbens, but 5-HIAA was significantl y increased only by the high dose of MK-801. When given alone, prazosi n did not affect either dopamine, DOPAC, HVA or 5-HIAA levels. However , prazosin pretreatment effectively blocked MK-801-evoked increases in dialysate dopamine concentrations. Consequently, the potent and selec tive alpha(1)-adrenoceptor antagonist prazosin was found to specifical ly suppress MK-801-evoked, but not basal dopamine release in the nucle us accumbens, while effectively blocking MK-801-evoked locomotor stimu lation with only negligible effects on basal locomotor activity. Thus, alpha(1)-adrenoceptor antagonism may act by reducing the sensitivity of the mesolimbic dopamine system to pharmacological or environmental challenge. Since most antipsychotic drugs exhibit both dopamine D-2 re ceptor and alpha(1)-adrenoceptor antagonistic properties, they may all eviate psychosis not only through blockade of postsynaptic dopamine re ceptors, but also presynaptically on the mesolimbic dopamine system, t hrough their alpha(1)-adrenoceptor antagonistic action. This latter ac tion may contribute to reduce evoked dopamine hyperactivity, e.g. in r esponse to stress.