Neuropeptides are commonly co-expressed with classical neurotransmitters such as glutamate, GABA, or serotonin within the same neurons (Hökfelt et al., 1978). In contrast to classical neurotransmitters, which are stored in small synaptic vesicles, neuropeptides are packaged in large dense-core vesicles (Hökfelt, 1991; Baraban et al., 1997). Neuropeptides are synthesized as prepropeptides in the neuron's Golgi apparatus and transported as propeptides within vesicles to the nerve terminal, where they are processed into their mature forms by prohormone convertases (e.g., PC2). Classical neurotransmitters, by comparison, are synthesized locally at the nerve terminal by specific enzymes.

Neuropeptides function as co-transmitters. Like classical neurotransmitters, they are released via exocytosis. However, exocytosis of large dense-core vesicles requires higher-frequency stimulation than the release of classical transmitters. Consequently, under physiological conditions only modest amounts of neuropeptides are usually released, whereas under pathological conditions, such as epileptic seizures or inflammation, substantially greater amounts are liberated. Unlike classical neurotransmitters, which primarily act at synaptic sites, neuropeptides typically exert their effects independently, through multiple specific receptors that are predominantly located at extra- or perisynaptic sites via volume transmission.

In contrast to classical neurotransmitters, which are either taken up or resynthesized locally at the nerve terminal, neuropeptides require new protein synthesis and axonal transport to replenish depleted stores following release. This process involves increased transcription of -propeptide mRNA, translation, refilling of large dense-core vesicles and often transport to release sites to ensure peptide availability during recurring neuronal stimulation.

One of the earliest demonstrations of activity-dependent increases in neuropeptide levels was provided by Kato and coworkers, who reported elevated somatostatin (SRIF), but not β-endorphin, levels following kindling (Kato et al., 1983). In the rat kainic acid (KA) model of temporal lobe epilepsy (TLE), increased SRIF levels in the frontal cortex and hippocampus seen 30 days after KA injection were preceded by a transient decrease during acute status epilepticus (SE, 3 h after KA administration). This finding indicates robust peptide release during the acute phase, followed by delayed refilling of large dense-core vesicles, a process requiring several days (Sperk et al., 1986).

Since then, numerous studies have examined the effects of seizures and epilepsy on neuropeptide expression, as well as the role of neuropeptides in seizure modulation. The following sections will first focus on neuropeptides that function as co-transmitters in GABAergic interneurons of the hippocampus and will subsequently address neuropeptides primarily expressed in glutamatergic or other neuronal populations.