The past several decades have witnessed a veritable explosion of knowledge about the central nervous system (CNS), and in no area has this been as impressive as in peptide neurobiology. Numerous peptide neurotransmitter candidates have been identified and characterized, their CNS distributions mapped, and their genes cloned. The tenet one neuron-one transmitter erroneously attributed to Dale has been convincingly refuted with numerous demonstrations of neurons containing multiple peptides or combinations of peptide and nonpeptide neurotransmitters. Additionally, since the early 1980s there has been an embarrassment of riches in the form of knowledge about neurotransmitter receptor diversity, diversity of receptor-effector coupling, and neurotransmitter transporters. These discoveries have not yet been fully integrated into what is known about normal or aberrant CNS function, although dysfunction at virtually any level could conceivably lead to neuropsychiatric deficits.
[...] Attempts to verify peptide turnover may be made if the mRNA concentration, peptide concentration, receptor up- regulation or down-regulation, and degradative activity are known. Although methods to achieve each of these goals are now available, they have not generally been applied in combination to the same tissue sample. Whereas the differences between neuropeptides and the classic monoamine and amino-acid neurotransmitters are often striking, their CNS effects are similar in that they primarily excite or inhibit discrete neurons upon direct application. [...]
[...] In the hypothalamus most of the SRIF-containing neurons that project to the median eminence have been shown to emanate from cell bodies mainly in the rostral periventricular nucleus, with some in the paraventricular nucleus and none in the arcuate nucleus. Thus, the other hypothalamic regions (arcuate, suprachiasmatic, ventromedial) containing SRIF neurons probably do not project to the median eminence and may perform a regulatory or feedback function on neurons containing other hypothalamic releasing factors, such as GRF, CRF, TRH, or their afferents. [...]
[...] Related peptides are often contained in the same prohormone sequence, as is the case for neurotensin and neuromedin N. Those peptides are separated by a single pair of dibasic residues on their common mRNA and yet have distinctly different distribution patterns in the brain. Other tissues may also exhibit processing that is different from that of the brain, as is seen for neuromedin N in the mouse ileum. Multiple active peptide copies can also be contained in the prohormone structure as is noted with TRH, which has five complete copies in the mammalian 285 amino acid prohormone. [...]
[...] TRH colocalization with another peptide, substance and a classic transmitter, serotonin, has been described in a population of neurons on the median raphe nucleus and spinal cord. Corticotropin-releasing factor has been reported to be colocalized with three other neuropeptides (vasopressin, oxytocin, and neurotensin) in some neurons of the hypothalamic paraventricular nucleus in both rats and humans. Somatostatin has been found in g-aminobutyric acid (GABA) neurons of the thalamus of cats and the cortex of rats, and with neuropeptide Y in the striatum, hippocampus, and cortex. [...]
[...] Because CRF injection into the locus ceruleus elicits fearful or anxious behavior, one could postulate that stress activates the CRF neurons terminating in the locus ceruleus noradrenergic neurons and that the increased CRF content in the locus represents an increased release of the CRF in this region onto the noradrenergic cell bodies. One can further postulate that the resulting increased noradrenergic signal, and perhaps other inputs to the paraventricular nucleus of the hypothalamus, mediates the stress-induced increased release of CRF from the median eminence, which is detected as decreased CRF concentrations. [...]
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