Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia.
BACKGROUND
Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to "model" aspects of schizophrenia in preclinical studies.


OBJECTIVE
To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition.


RESULTS
An initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801.


CONCLUSIONS
Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.
Gilmour
Gary
G
Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU206PH, England, UK. gilmour_gary@lilly.com
Pioli
Elsa Y
EY
Dix
Sophie L
SL
Smith
Janice W
JW
Conway
Michael W
MW
Jones
Wendy T
WT
Loomis
Sally
S
Mason
Rebecca
R
Shahabi
Shahram
S
Tricklebank
Mark D
MD
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate