We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.

To investigate the involvement of different types of glutamate receptors in recognition memory, selective antagonists of NMDA and kainate receptors were locally infused into the perirhinal cortex of the rat temporal lobe. Such infusion of a selective kainate receptor antagonist produced an unusual pattern of recognition memory impairment: amnesia after a short (20 min) but not a long (24 h) delay. In contrast, antagonism of perirhinal NMDA glutamate receptors by locally infused AP-5 (2-amino-5-phosphonopentanoic acid) impaired recognition memory after the long but not the short delay. For both drugs, impairment was found when the drug was present during acquisition but not when it was present during retrieval. Experiments in vitro indicate that selective antagonism of NMDA receptors containing NR2A subunits blocks perirhinal long-term potentiation (LTP), whereas antagonism of NMDA receptors containing NR2B subunits blocks long-term depression (LTD). However, recognition memory after a 24 h delay was impaired only when both an NR2A and an NR2B antagonist were infused together, not when either was infused separately. These results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, that this region and no other is necessary for both short-term and long-term familiarity discrimination, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD (although it might be independently supported by components of each type of process with one substituting for the other).

Benzodiazepines, including lorazepam, are widely used in human medicine as anxiolytics or sedatives, and at higher doses can produce amnesia. Here we demonstrate that in rats lorazepam impairs both recognition memory and synaptic plastic processes (long-term depression and long-term potentiation). Both impairments are produced by actions in perirhinal cortex. The findings thus establish a mechanism by means of which benzodiazepines impair recognition memory. The findings also strengthen the hypotheses that the familiarity discrimination component of recognition memory is dependent on reductions in perirhinal neuronal responses when stimuli are repeated and that these response reductions are due to a plastic mechanism also used in long-term depression.

Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE. Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality. Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways.

Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE. Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality. Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways.