TY - JOUR
T1 - Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists
AU - Grant, Kathleen A.
AU - Colombo, Giancarlo
AU - Grant, Julia
AU - Rogawski, Michael A.
N1 - Funding Information:
We thank Drs A. Thurkauf, W. Danysz and B.R. de Costa, and NIDA Research Technology Branch and Astra Arcus USA for generous gifts of drugs; Dr David Reboussin for advice on the statistical analyses; and Dr Michael A. Nader for his constructive suggestions concerning the preparation of the manuscript. These studies were supported in part by PHS grant AA09346.
PY - 1996/12
Y1 - 1996/12
N2 - The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im ine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.
AB - The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-im ine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.
KW - N-methyl-D-aspartate antagonist
KW - N-methyl-D-aspartate receptor
KW - dizocilpine (MK-801)
KW - drug discrimination
KW - glutamate receptor
KW - ketamine
KW - phencyclidine
KW - rat
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U2 - 10.1016/S0028-3908(96)00147-5
DO - 10.1016/S0028-3908(96)00147-5
M3 - Article
C2 - 9076750
AN - SCOPUS:0030483729
SN - 0028-3908
VL - 35
SP - 1709
EP - 1719
JO - Neuropharmacology
JF - Neuropharmacology
IS - 12
ER -