One clinical pharmacologist acquired an interest in her field after studying calcium channels in the heart and cardiovascular system at the Pfizer Central Research in Switzerland. Her research on cardiac arrythmias helped her decide to continue on a doctoral course in pharmacology, which can be funded by student fellowships provided by the UK government. She acquired a grant from the British Pharmacological society and was able to work on the regulation of potassium channels in the heart.
The Assn. of the British Pharmaceutical Industry (ABPI) is composed of pharmaceutical companies that fund pharmaceutical and pharmacological research in the UK. It has created a demand for pharmacologists trained in information technology, data handling, animal handling and communication skills apart from their role in drug development. Many positions are available in drug companies, and the ABPI is also involved in promoting interest in pharmacology as a career.
When a typical glutamate-containing neurone fires, an action potential is propagated down the branching axon through more than a thousand varicosities. At each of these release sites the probability that a synaptic vesicle will be exocytosed into the synaptic cleft is individually controller] by means of presynaptic receptors: autoreceptors responding by positive or negative feedback to previously released transmitter, or heteroreceptors under the influence of other neurotransmitters or modulators. The simplest system in which to investigate presynaptic modulation is the isolated nerve terminal or synaptosome; studies with this preparation have revealed a complex interplay of signal-transduction pathways.
The activation of peripheral nociceptors is the subject of intense scrutiny, because of its significance in pain regulation. Genetic approaches, including homology cloning, difference cloning and transgenic manipulation of mice are providing useful insights into nociceptor function. Recent work suggests that transcriptional regulators (for example, islet-I), which are expressed relatively selectively in sensory neurones, play a crucial role in defining cellular phenotype. Difference cloning has identified genes which encode both ligand-gated and voltage-gated ion channels expressed by small- diameter sensory neurones. The role of inflammatory mediators such as NGF in regulating nociceptor function has been clarified in mis-expression and deletion studies. An understanding of the mechanisms that regulate gene expression in nociceptors should provide new ways to manipulate nociceptor sensitivity, with potential significance for pain therapy.
Polysialic acid (PSA), a homopolymer attached to the neural cell adhesion molecule (NCAM), serves as a modulator of cell interactions, Polysialic acid exhibits a highly regulated expression pattern. During embryonic development its abundant expression is closely correlated with axon pathfinding and targeting, and with certain aspects of muscle formation. Its level also can be altered by synaptic activity. During neonatal development and in the adult brain, PSA expression is more restricted, being primarily associated with regions capable of morphological or physiological plasticity. The ability to perturb PSA in vivo by a specific glycosidase and by the creation of NCAM-deficient mice has led to extensive analysis of its biological function. These studies suggest that the primary role of PSA is to promote changes in cell interactions and thereby facilitate plasticity in the structure and function of the nervous system.
Corticotrophin-releasing factor (CRF) acts within both the brain and the periphery to coordinate the overall response of the body to stress. The involvement of the CRF systems in a variety of both CNS and peripheral disease states has stimulated great interest in this peptide as a potential site of therapeutic intervention. The recent cloning of multiple CRF receptor subtypes has precipitated a new era in CRF research that has allowed precise molecular, pharmacological and anatomical examination of mammalian CRF receptors. In this article, Derek Chalmers and colleagues highlight the major differences between the two classes of CRF receptors, CRF and CRF , and a functionally related CRF-binding protein, and discuss the relevance of these sites to the ongoing development of CRF-based therapeutics.
Fetal nigral grafts have been demonstrated to survive, secrete dopamine, form synaptic connections with host neurons, and reverse behavioral disturbances in experimental models of parkinsonism. These findings suggest that fetal nigral grafting may be a useful therapy for patients with Parkinson's disease (PD). Recent preliminary clinical trials of transplantation in PD have shown increased striatal fluorodopa uptake (measured using positron emission tomography) and clinical benefit in some patients. An autopsy study of one patient who had received fetal nigral transplants demonstrated robust graft survival and striatal reinnervation, with no evidence of host-derived sprouting or immune rejection. The development of a successful clinical transplantation program depends on a careful consideration of the transplantation variables and the related long-term risks and benefits to the patients.
A model of basal ganglia functioning proposed a few years ago suggests that increased and decreased activity in basal ganglia output to the thalamus underlies akinesia, as seen in Parkinson's disease, and dyskinetic movements as seen in Huntington's disease or after treatment with L-dopa and neuroleptics, respectively. Although the basic features of this model have stood the test of time, patterns of electrophysiological activity and changes in indices of GABA-dependent transmission in the external pallidum lead to a reconsideration of the mechanisms responsible for these changes in output activity.
In addition to their well-established roles as neurotransmitters and neuromodulators, growing evidence suggests that nucleotides and nucleosides might also act as trophic factors in both the central and peripheral nervous systems. Specific extracellular receptor subtypes for these compounds are expressed on neurons, glial and endothelial cells, where they mediate strikingly different effects. These range from induction of cell differentiation and apoptosis, mitogenesis and morphogenetic changes, to stimulation of synthesis or release, or both, of cytokines and neurotrophic factors, both under physiological and pathological conditions. Nucleotides and nucleosides might be involved in the regulation of development and plasticity of the nervous system, and in the pathophysiology of neurodegenerative disorders. Receptors for nucleotides and nucleosides could represent a novel target for the development of therapeutic strategies to treat incurable diseases of the nervous system, including trauma- and ischemia-associated neurodegeneration, demyelinating and aging-associated cognitive disorders.