Drug neurotransmitter receptors

The aim of this chapter is to consider the structure, distribution and functional properties of neurotransmitter receptors in the brain in general and discuss the principles of how the action of drugs at these receptors can be studied. (See relevant Chapters for detail of individual NT receptors.)... 

These approaches to receptor identification and classification were, of course, pioneered by studies with peripheral systems and isolated tissues. They are more difficult to apply to the CNS, especially in in vivo experiments, where responses depend on a complex set of interacting systems and the actual drug concentration at the receptors of interest is rarely known. However, the development of in vitro preparations (acute brain slices, organotypic brain slice cultures, tissue-cultured neurons and acutely dissociated neuronal and glial cell preparations) has allowed more quantitative pharmacological techniques to be applied to the action of drugs at neurotransmitter receptors while the development of new recording methods such as patch-clamp... 

Neurotransmitter receptors have evolved as one of the key components in the ability of the central nervous system to coordinate the behaviour of the whole animal, to process and respond to sensory input, and to adapt to change in the environment. These same receptors are therefore ideal targets for drug action because of their central role in the activity of the nervous system. A rational approach to the development of new therapeutic strategies involving the action of drugs at receptors in the nervous system is based on knowledge of receptor structure, distribution and function. 

Kuhar, M.J. Locolization of drug and neurotransmitter receptors in brain by light microscopic autoradiography. In Iverson, L.L. Iverson, S.D. and Snyder, S.H., eds. Handbook of Psvcho-pharmacoloav. 15. New York Plenum Publishing Corp., 1982. pp. 299-320. 

Other drugs, like GHB and Rohypnol , can interact directly with the neurotransmitter receptors to either enhance or block the effects of the brain s own neurotransmitters. Still other drugs can alter the metabolic breakdown or clearance of certain neurotransmitters after they are released from the synaptic terminal, thereby altering how long the neurotransmitter affects the activity of other nearby neurons. 

In contrast to the ionotropic receptors, the metabotropic receptors are monomeric in structure and unique in that they show no structural similarity to the other G-protein-coupled neurotransmitter receptors. They are located both pre- and postsynaptically and there is experimental evidence that they are involved in synpatic modulation and excitotoxicity, functions which are also shared with the NMDA receptors. To date, no drugs have been developed for therapeutic use which are based on the modulation of these receptors. 

In SUMMARY, irrespective of the specificity of the antidepressants following their acute administration, it can be speculated that a common feature of all these drugs is to correct the abnormality in neurotransmitter receptor function. Such an effect of chronic antidepressant treatment may parallel the time of onset of the therapeutic response and contribute to the receptor sensitivity hypothesis of depression and the common mode of action of antidepressants. 

In CONCLUSION it appears that the chemically and pharmacologically diverse drugs that act as antidepressants have two properties in common. Firstly, they demonstrate approximately equal clinical efficacy and require several weeks administration to produce an optimal therapeutic effect. Secondly, they all modulate a number of different t)rpes of mainly postsynaptic neurotransmitter receptors in animals and in depressed... 

Bennett, J. P. Jr, Yamamura, H. L Neurotransmitter, hormone, or drug receptor binding methods, in Neurotransmitter Receptor Binding, ed. Yamamura, H. L, Enna, S. J., Kuhar, M. J., Raven Press, New York, 1985, pp 61-89. 

Sekine, Y., Rikihisa, T, Ogata, H., Echizen, H., and Arakawa, Y. (1999) Correlations between in vitro activity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions. Eur J Clin Pharmacol 55 583— 587. 

---