Nerve cells have two distinct properties that distinguish them from all other types of cells in the body. First, they conduct bioelectrical signals for relatively long distances without any loss of signal strength. Second, they possess specific, intracellular connections with other cells and with tissues that they innervate such as muscles and glands. These connections determine the type of information a neuron can receive and also the nature of the responses it can yield.
It is not within the scope of this text to give a detailed account of the anatomical structure of the central nervous system; this has been very adequately covered in a number of excellent textbooks, some of which are listed in the Appendix. However, to understand the physiological mechanisms which form the basis of psychopharmacology, a brief outline of the subject will be given.
Essentially all nerve cells have one or more projections termed dendrites whose primary function is to receive information from other cells in their vicinity and pass this information on to the cell body. Following the analysis of this information by the nerve cell, bioelectrical changes occur in the nerve membrane that result in the information being passed to the nerve terminal situated at the end of the axon. The change in membrane permeability at the nerve terminal then triggers the release of the neurotransmitter.
There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it.
The structure of the nerve cell and nerve terminal is shown in Figure 1.6. Although different neurotransmitters can be produced at different synapses within the brain, the individual neuron seems capable of releasing only one major neurotransmitter from its axonal terminal, for example noradrenaline or acetylcholine. This view was originally postulated by Sir Henry Dale in 1935 and was subsequently called Dale's Law, not incidentally by Dale himself! It is now known that, in addition to such ''classical transmitters'', peptides and/or prostaglandins may also be co-released, and Dale's Law has been modified in the light of such evidence. The nature of the physiological response to any transmitter will depend on the function of the target receptor upon which it acts. For example, acetylcholine released from a motor neuron will stimulate the nicotinic receptor on a muscle end-plate and cause muscle contraction. When the same neurotransmitter is released from the vagus nerve innervating the heart, however, it acts on muscarinic receptors and slows the heart.
Recently it has become apparent that neurotransmitters can also be released from dendrites as well as axons. For example, in dendrites found on the cells of the substantia nigra dopamine may be released which then diffuses over considerable distances to act on receptors situated on the axons and dendrites of GABAergic and dopaminergic neurons in other regions of the basal ganglia. Another means of communication between nerve cells involves dendrodendritic contacts, where the dendrites from one cell communicate directly with those of an adjacent cell. In the olfactory bulb, for example, such synapses appear to utilize GABA as the main transmitter. Thus any neuron responding to inputs that may converge from several sources may inhibit, activate or otherwise modulate the cells to which it projects and, because many axons are branched, the target cells may be widely separated and varied in function. In this way, one neuron may project to an inhibitory or excitatory cell which may then excite, inhibit or otherwise modulate the activity of the original cell. As most neurons are interlinked in an intricate network the complexity of such transmitter interactions becomes phenomenal! In brief, neurons can be conceived as complex gates which integrate the data they receive and, via their specific collection of transmitters and modulators, have a large repertoire of effects which they impose upon their target cells.
Neuronal plasticity is an essential component of neuronal adaptability and there is increasing evidence that this is primarily a biochemical rather than a morphological process. The neuron is not a fixed entity in terms of the quantity of transmitter it releases, and transmitters which are co-localized in a nerve terminal may be differentially secreted under different conditions. This, together with the repeated firing of some neurons that appear to have ''leaky'' membranes, may underlie the rhythmicity of neuronal activity within the brain.
Plasticity is also evident at the level of the neurotransmitter receptors. These are fluid structures that can be internalized into the membrane so that their density, and affinity for a transmitter, on the outer surface of the nerve membrane may change according to functional need.
Perhaps it is not surprising to find that our knowledge of how the brain works and where defects that lead to abnormal behaviour can arise is so deficient. The approach to understanding the biochemical basis of psychiatric disease is largely based on the assumption that the brain is chemically homogeneous, which is improbable! Nevertheless, there has been some success in recent years in probing the changes that may be causally related to schizophrenia, depression and anxiety. It should be apparent to anyone interested in the neurosciences that the brain is more than a sophisticated computer that follows a complicated programme, and any dogmatic approach to unravelling the complexities of this dynamic, plastic collection of organs which we call "brain" is doomed to failure.
In CONCLUSION, it can be seen that the adaptability of the organism to external and internal environmental changes is largely dependent on the functional flexibility of the cellular structure of the different brain areas. It is too often assumed that the brain is structurally homogeneous and that, like the heart or liver, once a drug penetrates the blood-brain barrier, it has access to most central compartments. Clearly this is not the case and the pharmacokinetic properties of a psychotropic drug (lipophilicity, molecular size, etc.), as well as the relative blood perfusion rate of a specific brain region which will depend on the metabolic activity at the time of day the drug is administered, could profoundly affect its concentration in a part of the brain. In support of this view, it is known that following its parenteral administration, the concentration of chlorpromazine in the left hemisphere is higher than in the right hemisphere, which presumably reflects the increased functional activity of the left hemisphere. Hopefully this chapter will provide a basis for understanding the physical substrate upon which psychotropic drugs act to produce their effects on the brain.
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