Neurotransmitters and neuropeptides

The number of putative neurotransmitters has been dramatically increased during the last decade. In addition to the classical monoamine neurotransmitters (acetylcholine and catecholamines) and a few amino acids, at least 30 neuropeptides have been discovered: all these compounds can act as chemical messengers in the mammalian nervous system. Immunohistochemistry has allowed the precise localisation of these neurotrarismitters and neuropeptides and thus contributed to the understanding of how certain regions of the brain work. This expanding knowledge of the relationship between structure and function has been accompanied by the realisation that certain neurological and psychiatric disorders are caused by an imbalance (overproduction or deficit) of these substances. It is for this reason that the distribution of neurotransmitters and neuropeptides is of considerable importance not only to neurobiologists, but also to histopathologists. Neurochemical analyses of post-mortem brains are affected by various factors including sampling, precision of dissection, age, sex, medication, the agonal state of the patient and post-mortem delay.

Of the monoamines, acetylcholine is found in the motor nuclei of the cranial nerves and in the motor neurons of the spinal cord; in these locations it serves as the chemical messenger for neuromuscular transmission. Acetylcholine is also present in the intrinsic pathways within the central nervous system, and cholinergic neurons project in a diffuse ascending system from the medial septal nuclei to the hippocampus and from the nucleus basalis of Meynert to the cerebral cortex.³⁹ The basal ganglia are rich in this monoamine and the enzymes related to its metabolism: choline acetyltransferase and acetylcholinesterase, the synthesising and catabolising enzyme respectively. Large cholinergic neurons have been recently demonstrated by histochemistry in the human striatum, but only the isolation, purification and immunohistochemical localisation of choline acetyltransferase have made a more comprehensive mapping of cholinergic pathways possible.

There are three catecholamines in the central nervous system: noradrenaline, adrenaline (epinephrine) and dopamine. The noradrenergic svstem is localised in the brainstem nuclei, the largest of which is the locus ceruleus, the pigmented column of cells in the rostral part of the pontine tegmentum: axons originating from these cells establish extensive connections with the cerebral cortex and hippocampus. The hypothalamus is also rich in noradrenergic fibres.

The adrenergic system, in contrast, is more restricted: cells in the pons and medulla project to other brainstem structures or to the hypothalamus.

The major dopaminergic pathway originates in the pars compacta of the substantia nigra and ascends to the striatum: devastation of this system is the underlying cause of Parkinson's disease.'² In addition to this nigrostriatal pathway, there is also a mesocortical and mesolimbic dopaminergic system: cells in the ventral tegmentum of the midbrain project to the cerebral cortex and to the limbic areas respectively.

The raphe nuclei form a long, ill-defined chain in the midline of the brainstem; their nerve cells give rise to the serotoninergic system which contains 5-hydroxytryptamine (serotonin) and projects to various sites in the forebrain including the hypothalamus, basal ganglia and medial forebrain bundle, and descends to the anterior and posterior horns of the spinal cord.

Gamma-aminobutyric acid (GABA), glutamate and glycine are amino acid neurotransmitters. GABA is the principal inhibitory neurotransmitter in the vertebrate nervous system and one-third of all nerve terminals in the rat brain appears to be GABAergic.³⁶ Moreover, neurophysiology, auto-radiography and irrrrnunohistochemistry have all demonstrated that inhibitory synapses of the cerebellum utilise GABA and that the major efferent pathways of the Purkinje cells are also GABAergic. GABA is also found in the spinal cord, although glycine is the maior inhibitory neurotransmitter at this site. Glycine Occurs in the small inhibitory interneurons of the grey matter and acts upon the large motor neurons of the anterior horn. An increasing body of evidencc suggests that glutamate is the universal putativc excitatory neurotransmitter in the central nervous system. The possibility that some excitatorv synapses use aspartate instead of glutamate cannot be excluded: the properties of these amino acids are too similar to allow a clear-cut separation. In the hippocampus, the major afferent pathways and the local interneurons use glutamate, as do the granule cells, the principal excitatory intern eurons in the cerebellum.

The last decade has witnessed the discovery of a variety of neuropeptides which may act as neurotransmitters or neuromodulators. The increasing list of these small peptides includes circulating hormones, pituitary peptides, opioid peptides, intestinal hormones, hypothalamic releasing factors and a group of miscellaneous peptides. Some of these compounds have been known to be the products of the endocrine or the neuroendocrine system, whilst other peptides, like the endorphins and enkephalins, have been more recently discovered. The neuropeptides may represent a different mode of intercellular communication from the fast and point-to-point action of amino acids such as GABA and glutamate: they have a slower time course, less precise spatial connections and a wider range of chemical messengers.

There are now more than 30 regulatory peptides and it is likely that more will be discovered. Recent developments in neurotransmitter research have confirmed the view that neurons of the central nervous system are secretory cells and that the products of this activity represent the chemical signals of interneuronal communication.

It has been recognised that some of the neurotransmitters and neuropeptides are abnormally distributed in a variety of neurological and psychiatric disorders, including extra-pyramidal abnormalities, Alzheimer's disease, epilepsy, schizophrenia and anxiety.