Abstract
A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks.
Highlights
It has been extensively demonstrated that the cholinergic and glutamatergic systems are involved in cognitive processes, and some lines of evidence suggest an interaction between muscarinic and N-methyl-d-aspartate receptors (NMDARs) in the regulation of learning and memory [1], which has mainly been assessed in the hippocampus
Subjects were only included if their injector tips were located bilaterally within the prelimbic cortex (PLC) within the area delimited by the anterior cingulate and infralimbic cortices and in which no tissue damage resulting from the rate or volume of the infusions was detected (Fig. 1A)
The current research shows that potentiating NMDAR function in the PLC by DCS may attenuate mnemonic deficits induced by muscarinic receptor antagonism in two olfactory learning paradigms, a stimulus-reward task and a relational memory task [38,50,51], which share some underlying structures, such as the PLC, but not others, such as the hippocampus [28,33,34]
Summary
It has been extensively demonstrated that the cholinergic and glutamatergic systems are involved in cognitive processes, and some lines of evidence suggest an interaction between muscarinic and N-methyl-d-aspartate receptors (NMDARs) in the regulation of learning and memory [1], which has mainly been assessed in the hippocampus. Systemic concomitant administration of ineffective doses of muscarinic and NMDAR antagonists produced amnesic effects in several tasks, such as spatial mazes [4,5], contextual fear conditioning [1], inhibitory avoidance [6,7] and a visual recognition memory task [8]. As for intracerebral studies, early research suggested that the hippocampus may be involved in the muscarinic/NMDA interaction as reversal, with DCS, of SCOPinduced deficits in spatial working memory was found when both drugs were injected into the hippocampus [22,23]. A recent report showed that injections of NMDA into the medial septum, a main hippocampal afferent, reduced SCOP-induced amnesia in inhibitory avoidance [24]
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