The Enduring Legacy of 250 Years of Pharmacology in Edinburgh.

In 1768, 250 years ago, the University of Edinburgh appointed Francis Home to the first chair of materia medica, the accumulated knowledge of materials used in healing. Francis Home and his colleagues were determined to improve the quality of medical training in Edinburgh by introducing a final examination and compiling a catalog of medicines validated by the Royal College of Physicians of Edinburgh. The catalog, known as the Edinburgh Pharmacopoeia, was a great success, partly due to the orderly nature of its contents, its routine editing to eliminate worthless entries, and the introduction of new treatments whose preparation was precisely documented. In a relatively short time, the worth of the Edinburgh Pharmacopoeia was recognized throughout Europe, America, and the British Empire. Today, the British and European Pharmacopoeias are catalogs of publicly available, legally enforceable standards for active pharmaceutical ingredients and finished dosage forms of pharmaceutical products and medical devices. Home and the many luminaries who succeeded him would surely take pleasure and pride in the fact that the mantra of today's medicines regulators worldwide is little different from that of these early visionaries: "To take better advantage of the best possible science in the service of the public health and our health-care systems" ( 1 , p. 492).

The odour span task: a novel paradigm for assessing working memory in mice.

Impoverished odour recognition and memory are amongst the earliest symptoms observed in mild cognitive impairment, Alzheimer's disease and schizophrenia, and have been advocated as early disease bio-markers. Although transgenic animals modelling disease pathologies continually emerge, there remains a paucity of tasks to examine olfactory working memory in mice. The present studies describe a mouse odour span task, which assesses the ability to remember increasing numbers of odours. Since caspase-3 is highly expressed throughout the olfactory system, we postulated that mice over-expressing this apoptogenic protein would exhibit impaired performance in the odour span task. Mice over-expressing human caspase-3 (Tg) exhibited age-independent deficits in olfactory working memory (6-18 months) compared with wild-type littermates, requiring longer for task acquisition and exhibiting impaired asymptotic performance, with reduced span lengths, lower accuracy and increased error rates. These impairments appeared to be selective for working memory, as Tg mice had no deficits in odour discriminatory ability or in locomotor measures. Importantly, nicotine, which improves working memory span in man, reversed the deficits exhibited by Tg mice. In conclusion, the mouse odour span task can detect subtle changes in olfactory working memory induced by genetic manipulation and drug administration and therefore should be applied to animal models of neurological disease.

Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice.

alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level. Furthermore, alpha7-nAChR KO mice were significantly impaired in the odour span task when compared to WT mice, in a pattern consistent with impaired attention. These behavioural deficits were associated with the loss of alpha7-nAChRs, as alpha4beta2-nAChR density was unaltered in these mice. Thus these studies intimate that the attentional impairment in alpha7-nAChR transgenic mice maybe core to other deficits in cognition.

Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor.

In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of alpha7 nAChR knockout (KO) mice in the 5-CSR task. alpha7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as alpha7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the alpha7 nAChR may be involved in mediating these effects of nicotine.

Motor neurons and the sense of place.

Seventy years ago George Romanes began to document the anatomical organization of the spinal motor system, uncovering a multilayered topographic plan that links the clustering and settling position of motor neurons to the spatial arrangement and biomechanical features of limb muscles. To this day, these findings have provided a structural foundation for analysis of the neural control of movement and serve as a guide for studies to explore mechanisms that direct the wiring of spinal motor circuits. In this brief essay we outline the core of Romanes's findings and place them in the context of recent studies that begin to provide insight into molecular programs that assign motor pool position and to resolve how motor neuron position shapes circuit assembly. Romanes's findings reveal how and why neuronal positioning contributes to sensory-motor connectivity and may have relevance to circuit organization in other regions of the central nervous system.

Walter Laing Macdonald Perry KT OBE, Barron Perry of Walton, 21 June 1921 - 17 July 2003.

Lord Perry of Walton died suddenly on 17 July 2003, at the age of 82 years. Walter Laing Macdonald Perry was a native of Dundee, educated at Morgan Academy Dundee, Ayr Academy, Dundee High School and St Andrews University (MB ChB, MD and DSc), winning the Rutherford Silver Medal for his MD thesis and the Sykes Gold Medal for his DSc thesis. After Casaulty Officer and House Surgeon posts in 1943-44, he served as a Medical Officer in the Colonial Medical Service in Nigeria in 1944-46, then briefly as a Medical Officer in the RAF, 1946-47, before embarking on a scientific career on the staff of the Medical Research COuncil at the National Institute for Medical Research from 1947 to 1958, serving as Director of the Department of Biological Standards from 1952 to 1958. Professionally, he achieved MRCP (ED) in 1963 and was elected FRCPE in 1967, FRCP in 1978, FRSE in 1960 and FRS in 1985. In 1958 he came to Edinburgh as Professor of Pharmacology, holding the Chair from 1958 to 1968. During this time he also served as Dean of the Faculty of Medicine (1965-67) and Vice-Principal of the University (1967-68) before leaving to become the inaugural Vice-Chancellor of the Open University in 1968, a post he held until 1980. During this period at the Open University he developed a second distinguish career as a university administrator and a promotor and facilitator of open and distance learning, in which fields he later performed extensive work on behalf of the United Nations. A third career, in politics and public life, began with his ennoblement to a life peerage in 1979, taking the title of Walton in the County of Buckinghamshire, the initial base of the Open University. Latterly Walter sat as a Liberal Democrat, having twice been Social Democratic Party deputy leader in the Lords in the 1980s. He took an active role in the Lords' Select Committee on Science and Technology and held interests in and spoke on many areas of public policy, including fisheries policy. Recognition of his distinguished careers came with a succession of honours; OBE in 1957, Knight Bachelor in 1974 and Baron in 1979; 10 honorary degrees from UK, North American, College London; the Wellcome Gold Medal in 1993 and Inaugural Royal Medal of the Royal Society of Edinburgh in 2000. He was Chairman, President or member of numerous commercial, educational, public interest and scientific bodies. Lord Perry's publications included sole or part authorship of approximately 90 books, research papers and abstracts. Shining through of Walter Perry's careers are strengths of commitment and sheer hard work, rigorous analysis of scientific, educational and organizational problems, experimentation and pursuit of clear objectives. Against scepticism, elitism and ill-informed criticism he drove through the establishment of the Open University. It is today respected internationally, is by some orders of magnitude our largest university in terms of student enrollment and is demonstrably successful outcome from an experiment initiated 40 years ago. It represents a fine monument to Walter Perry.

The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei.

The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are implicated in the photic entrainment of circadian rhythms in the suprachiasmatic nuclei (SCN). We now report that mice carrying a null mutation of the VPAC(2) receptor for VIP and PACAP (Vipr2(-/-)) are incapable of sustaining normal circadian rhythms of rest/activity behavior. These mice also fail to exhibit circadian expression of the core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene arginine vasopressin (AVP) in the SCN. Moreover, the mutants fail to show acute induction of mPer1 and mPer2 by nocturnal illumination. This study highlights the role of intercellular neuropeptidergic signaling in maintenance of circadian function within the SCN.