Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: Nonspatial pretraining eliminates spatial learning deficits.

Abstract

A detailed behavioral analysis of water-maze acquisition showed that the JV-methyl-D-aspartate (NMDA) antagonist NPC17742 and the muscarinic antagonist scopolamine caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze in male rats. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under NPC17742 or scopolamine. The results indicated that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA or muscarinic activity may contribute to but do not appear to be essential for spatial learning in the water maze.The previous article reported results of a detailed behavioral analysis of water maze acquisition under D,L-2-amino-5phosphonovalerate (APV), an JV-methyl-D-aspartate (NMDA) receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA excitatory amino acid receptor antagonist (Cain, Saucier, Hall, Hargreaves, & Boon, 1996). The findings confirmed and extended previous observations of sensorimotor disturbances and documented several novel disturbances that occurred consistently in naive rats tested under CNQX or APV. A correlational analysis showed that there was a consistent association between a wide variety of sensorimotor disturbances and poor acquisition scores in both the hidden and visible platform versions of the maze and in nonmaze tasks such as walking along a narrow beam. These findings arc consistent with, but do not prove, the idea that the sensorimotor disturbances caused some or all of the inferred learning deficit, as reflected by conventional measures of water-maze acquisition.A striking finding of the study was that prior familiarity with the requirements of the task by nonspatial pretraining (Davis, Butcher, & Morris, 1992;Morris, 1989) resulted in rapid learning of the task when the rats were later trained under

A Behavioral Analysis of the Spatial Learning Deficit Induced by the NMDA Receptor Antagonist MK-801 (Dizocilpine) in the Rat

“…The results show that the effects of systemically administered MK-801 on spatial learning in the water maze task cannot be dissociated from motor and/or sensory disturbances. This supports the view that NMDA receptors probably contribute to, but seem not to be crucial for, spatial learning (Cain 1998;Cain et al 1996;Saucier et al 1996).…”

“…This approach differs from the frequently used visible platform version in which the animal has to climb onto the platform protruding from the water Cain et al 1997;Saucier et al 1996;Whishaw et al 1995;Whishaw and Jarrad 1996;Whishaw and Tomie 1997). In the present study, retention was always tested The behavioral tests used in these studies discriminate unspecific drug effects from those on learning and memory.…”

“…It is possible that the stress of being in the water may cointerfere with the disruptive effects of MK-801 on behavioral performance that can differ from those described in studies using observation cages (Sandi et al 1997;Wedzony et al 1994). The importance of performing a behavioral analysis during acquisition of the water maze task is clearly illustrated by recent studies using competitive NMDA receptor antagonists; for example, D,L-2-amino-5-phosphonovalerate (APV), NPC17742 and CGS19755 Cain et al 1997;Saucier et al 1996).…”

Conditioned stimulus familiarity determines effects of MK-801 on fear extinction.

“…Perceptual learning, which can refer to a learned change in the salience and discriminability of a stimulus, is a well-documented and widespread consequence of stimulus exposure, and it profoundly alters how a subject learns about the CS during subsequent conditioning (Hall, 1991). These results are consistent with studies from spatial learning (Bannerman et al, 1995;Saucier & Cain, 1995;Saucier et al, 1996), Pavlovian contextual fear conditioning (Sanders & Fanselow, 2003) and one-trial inhibitory avoidance learning (Roesler et al, 1998), showing that the preexposure to the stimuli or actions to be learned about can determine the effects of NMDA receptor antagonism on later learning. In the case of fear extinction, the present results raise the question: What aspect of fearextinction learning do NMDA receptor antagonists normally disrupt?…”

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

“…Agents that block NMDARs cause severe deficits in hippocampal LTP and impair hippocampal-dependent learning, including spatial learning (Morris et al, 1986). However, NMDAR blockers have a number of other physiologic and behavioral effects that confound the interpretation of those studies Saucier et al, 1996). Additionally, although NMDARs block all measurable LTP, they do not block all spatial learning.…”