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-methyl-10,11-dihydroxy-5H-dibenzo(a,b)cyclohepten-5,10-imine), and the competitive NMDA receptor antagonist CGP 39551 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) on extracellular dopamine concentrations were analyzed in the shell and core subdivisions of the nucleus accumbens (NAC), associated with limbic and motor functions, respectively. Extracellular dopamine concentrations were assessed utilizing differential normal pulse voltammetry in chloral hydrate anesthetized, pargyline pretreated rats. Intravenous administration of PCP (0.5 mg/kg) or MK-801 (0.1 mg/kg) both significantly elevated extracellular dopamine levels in the NAC shell but not in the core. However, administration of relatively low doses of the competitive NMDA receptor antagonist CGP 39551 (2.5 mg/kg) failed to affect dopamine output in either region. However, when a higher dose (10 mg/kg) was administered a significant elevation in dopamine output was obtained in the shell compared to the core. Our data demonstrate that non-competitive NMDA receptor antagonists evoke an accumbal dopamine output that is selective to limbic cortical related NAC regions. This profile is shared also by competitive NMDA receptor antagonists 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 may be essentially attributable to the relative degree of NMDA receptor antagonism achieved by the drugs. This experimental model may afford a biochemical means to assess the psychotomimetic liability of NMDA receptor antagonists, a side effect that may reduce their usefulness as neuroprotective agents.
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
M M
MM
Marcus
J M
JM
Mathé
G G
GG
Nomikos
T H
TH
Svensson
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C064540:CGP 39551; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D010622:Phencyclidine; D004298:Dopamine