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In addition to the classical low molecular weight transmitters described above such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, an increasing number of peptides ranging in size from three up to forty or more aminoacids, have been identified in neurons. During the last 15 years a large number of investigators using biochemical, immunohistochemical and pharmacological techniques have demonstrated the neurotransmitter and\or neuromodulatory role of a great number of these peptides (for review see Hokfelt 1991). The majority of peptides have been found to coexist with classical, small molecular weight transmitters both in the central and in the peripheral nervous system. In the intrinsic population of the cerebral cortex peptides were found to coexist with the inhibitory amino acid GABA

(Hendry et al 1984).

When classical transmitters and neuropeptides coexist the two types of messenger molecules may have different subcellular storage sites. It has recently been documented in the CNS (Verhage et al 1991), as had previously been shown for the PNS (for review see Hokfelt et al 1991) that two kinds of vesicles are found in the nerve terminals; the small, clear synaptic vesicles found near the active zone which contain exclusively the classical transmitter and the large, dense core vesicles located at ectopic sites which contain peptide plus classical transmitter.

Thus, peptides can be released only when the large, dense core vesicles are activated. There is recent evidence from different systems in the CNS (Bean and Roth 1991; Iverfeldt et al 1989) that individual action potentials firing at low frequency will not release peptides and that activation of large vesicles requires bursting or high frequency activity.

Furthermore, it has been shown in nerve terminals from quinea pig hippocampus (Verhage et al 1991) that neuropeptide release is triggered by small elevations in Ca++ concentrations in the bulk cytoplasm, whereas secretion of the classical transmitter requires higher Ca++ elevation, as produced in the vicinity of Ca++ channels. Thus, it is obvious that neuropeptides and classical transmitters may be differentially released.

A number of essential differences concerning the two coexisting messenger systems have to be kept in mind: Peptide production takes place in the endoplasmic reticulum mostly in the cell-body, with subsequent axonal transport to the nerve terminal, whilst classical transmitters are produced both in the nerve terminals and in the cell-body. One consequence of this asymmetric distribution of biosynthetic activities is that it is possible to rapidly deplete the nerve terminal with respect to neuropeptides, while the classical transmitter levels are only slightly if at all lowered.

It is also noteworthy that tissue stores of classical transmitters are often 50-1000 times higher than those of peptide neurotransmitters (review by Bartfal et al 1988) when these stores are measured at the . nerve terminal

level. Thus the nerve terminal is equipped for more frequent use of the classical transmitter in comparison to the peptide.

The nature of the postsynaptic effect that neuropeptides induce when released from nerve terminals is quite different from that of classical transmitters (see review by Hokfelt 1991): while classical transmitters induce a rapid and short lasting response, peptides evoke responses of longer duration. There is even some evidence that peptides are not released at active zones into the synaptic cleft, but are released extrajuncionally (Thureson-Klein and Klein 1990) and may diffuse over some distance from the point of release.

Along with their potent role as neurotransmitters, peptides have been shown to act as neuromodulators in a number of systems (Kow 1988 for review). As such, they alter the response of a particular substrate to a given transmitter. The latter may or may not be the classical transmitter they coexist with in the nerve terminal. In the visual cortex where SOM and GABA are known to coexist (Hendry et al 1984) and although SOM can modulate the responses of cortical neurons to visual stimulation (review by Sillito 1985), results failed to show any modulatory effects of SOM on GABA actions. The same was shown to be true for another population of visual cortical neurons which colocalize GABA with CCK (Sillito 1985 for review). On the contrary, iontophoretic application of VIP even in low doses is capable of enhancing the inhibitory responses of somatosensory cortical neurons to iontophoretically applied GABA (Sessler et al 1991).

Concomitant application of VIP and NE produces additive or more than additive potentiation of GABA inhibition.

Peptide neuromodulation is characterized by remarkable specificity with respect to the transmitter effect that is being modulated, the substrate and the region where the modulation is taking place (Kow and Pfaff 1988 for review). However, a degree of convergence of modulatory influences from different peptides has been observed, since there are a number of cases where several peptides modulate a given neuronal response. In the cerebral cortex for example, the excitatory responses of cortical neurons to ACh have been found to be attenuated by SP, CCK and VIP

(Lamour et al 1983).

There is increasing evidence supporting a trophic role of peptides in a number of developmental processes (Hokfelt 1991 for review). Thus, VIP was shown to increase survival of spinal cord neurons in culture (Brenneman and Eiden 1986), to stimulate the growth of human keratocytes

(Haegerstrand et al 1989) and influence bone mineralization (Hohmann et al 1986).

Finally, a number of these peptides may serve other biological roles in the brain as, for example, VIP induces glycogenolysis in cortical slices via stimulation of cAMP (Magisteti 1981) and thus, regulates the energy metabolism in cortical cells. Additionally, VIP has been established as a strong vasodialatory agent (Edvinsson 1985) .