Peptidergic Neurotransmission

Neuropeptides have garnered increasing attention as critical modulators of CNS function. In general, peptide transmitters are released from neurons when they are stimulated at higher frequencies from those required to facilitate release of traditional neurotransmitters, but they can also be colocalized and coreleased together with other neurotransmitters (Cooper et al. 2001; Nestler et al. 2001). Modulation of the firing rate pattern of neurons and subsequent release of neurotransmitters and peptides in a circumscribed fashion are likely important in the basal functioning of the brain as well as response to specific stimuli. For instance, cannabinoids, an example of a neuropeptide neurotransmitter, do not alter the firing rates of hippocampal neurons but instead change the temporal coordination of those neurons, an effect that correlates with memory deficits in individuals (Soltesz and Staley 2006). Virtually every known mammalian bioactive peptide is synthesized first as a precursor protein in which product peptides are flanked by cleavage sites. Neuropeptides are generally found in large dense-core vesicles, whereas other neurotransmitters, such as the monoamines, are packaged in small synaptic vesicles (approximately 50 nm) and are usually half the size of their peptidergic counterparts (Kandel et al. 2000; Squire et al. 2003).

Space limitations preclude an extensive discussion of the diverse array of neuropeptides known to exist in the mammalian brain. Table 1-2 highlights some of the major neuropeptides that may be of particular psychiatric relevance. In the remainder of this section, the basic aspects of peptidergic transmission are highlighted vis-à-vis an overview of opioidergic neurotransmission.

TABLE 1-2. Selected peptides and their presumed relevance to psychiatric disorders and treatment


Opioid and related peptides

Endorphin Enkephalin Dynorphin Nociceptin

Gut-derived peptides

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