Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition

Abstract

Behavioural pharmacology is an interdisciplinary field at the intersection of several research areas that ultimately lead to the development of drugs for clinical use and build understanding of how brain functions enable cognition and behaviour. In this article, the development of behavioural pharmacology in the UK is briefly surveyed, and the current status and success of the field is highlighted by the progress in our understanding of learning and memory that has resulted from discoveries in glutamate receptor pharmacology allied to theoretical and methodological advances in behavioural neuroscience. We describe the original breakthrough in terms of the role of NMDA receptors in hippocampal-mediated spatial learning and long-term potentiation, and review recent advances that demonstrate the involvement of glutamate receptor in working memory, recognition memory, stimulus-response learning and memory, and higher cognitive functions. We also discuss the unique functions of NMDA receptors and the fundamental role of AMPA receptors in processes that are common to some of these forms of memory, including encoding, consolidation and retrieval.

Figure 1

Stages of memory processing inferred from the results of neuropharmacological experiments. Depicted are two trials of any standard learning paradigm: (a) acquisition training and (b) retention testing. Pharmacological interventions before acquisition can potentially affect a range of sensory, perceptual, attentional, motivational and motor performance factors, in addition to learning and memory processes. To rule out the nonspecific factors that affect learning and memory per se, it is usually necessary to compare the effects on performance that is previously established (e.g. after a single trial of training as in the retention test). A lack of effect on retention indicates a specific effect on learning or memory-related processes such as encoding or memory consolidation. A lack of effect on initial training in acquisition accompanied by an effect on retention usually indicates a specific effect on memory consolidation or retrieval. The post-trial manipulations administered after the acquisition trial (e.g. in the home cage) cannot affect simple performance factors during the acquistion trial but do affect the hypothetical processes of memory consolidation. The time-limited nature of consolidation means that post-trial treatments soon after the first trial will affect memory consolidation, indicated by performance in the retention test, typically 1–7 days later. However, ineffective post-trial treatments at later time-points than immediate post-trial indicate the temporally limited nature of the consolidation process and rule out proactive effects of post-trial treatments themselves on the retention test. Working memory is an active process of memory that is usually engaged soon after perceptual processing to encode memory traces into passive storage. However, memories that are re-activated by memory cues also place retrieval memory traces into an active form in working memory for the guidance of behaviour (see for further details).

Figure 2

Results from a study on the effects of drugs on glutamate receptors following infusion of the drugs into the rat perirhinal cortex . The study by Winters and Bussey examined, for the first time, the effects of glutamate receptor manipulations on visual-recognition memory (memory for a familiar object) in experimental animals, following administration of the drugs at pre-acquisition, post-training trial or pre-retention test stages. This enabled identification of the nature of the involvement of glutamate receptors in the different phases of memory according to the logic described in Figure 1. Substances were infused directly into the rat perirhinal cortex via implanted cannulae because this region has been implicated in visual-recognition memory processes (see main text for further details). (a) NMDA receptor blockade in the perirhinal cortex following administration of AP5 impairs long-term but not short-term object recognition memory. (b) AMPA receptor blockade and NMDA receptor blockade in the perirhinal cortex following CNQX and AP5 administration, respectively, disrupts consolidation of object-recognition memory for up to 40 min post-trial. (c) AMPA receptor blockade but not NMDA receptor blockade in the perirhinal cortex disrupts retrieval in object-recognition memory during the retention test. ©2005 by the Society for Neuroscience .