Effects of competitive and non-competitive NMDA receptor antagonists on dopamine output in the shell and core subdivisions of the nucleus accumbens

The effects of acute intravenous administration of the non-competitive NMDA receptor antagonists, phencyclidine (PCP), dizocilpine (MK-801; (+)-5-meth yl-10,11-dihydroxy-5H-dibenzo(a,b)cyclohepten-5,10-imine), and the competit ive NMDA receptor antagonist CGP 39551 (DL-(E)-2-amino-4-methyl-5-phosphono -3-pentanoic acid) on extracellular dopamine concentrations were analyzed i n the shell and core subdivisions of the nucleus accumbens (NAC), associate d with limbic and motor functions, respectively. Extracellular dopamine con centrations were assessed utilizing differential normal pulse voltammetry i n chloral hydrate anesthetized, pargyline pretreated rats. Intravenous administration of PCP (0.5 mg/kg) or MK-801 (0.1 mg/kg) both si gnificantly elevated extracellular dopamine levels in-the NAC shell but not in the core. However, administration of relatively low doses of the compet itive NMDA receptor antagonist CGP 39551 (2.5 mg/kg) failed to affect dopam ine output in either region. However, when a higher dose (10 mg/kg) was adm inistered a significant elevation in dopamine output was obtained in the sh ell compared to the core. Our data demonstrate that non-competitive NMDA receptor antagonists evoke a n accumbal dopamine output that is selective to limbic cortical related NAC regions. This profile is shared also by competitive NMDA receptor antagoni sts when given in high, but not low doses. Our results are compatible with the reported elicitation of PCP-like behavioral effects by competitive NMDA receptor antagonists when administered in relatively high doses. Moreover, these findings suggest that differences in the regional accumbal dopamine output between competitive and non-competitive NMDA receptor antagonists ma y be essentially attributable to the relative degree of NMDA receptor antag onism achieved by the drugs. This experimental model may afford a biochemic al means to assess the psychotomimetic liability of NMDA receptor antagonis ts, a side effect that may reduce their usefulness as neuroprotective agent s. (C) 2001 Elsevier Science Ltd. All rights reserved.