Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Peptidergic Transmitter Systems

Jeffrey H. Meyer

Peptides refer to short proteins consisting of chains of less than 100 amino acids. There are as many as 250 peptide neurotransmitters in the brain (see Table XVIII-4.1 for a partial list). Some, such as corticotrophin-releasing factor, have been extensively investigated with respect to mood disorders, but most have not.

Peptides may function as neurotransmitters, neuromodulators and neurohormones. Neurotransmitters are synthesized in presynaptic neurons, and are released after depolarization by presynaptic neurons in sufficient amounts to have effects upon postsynaptic neurons. Neurotransmitters have immediate effects upon postsynaptic neurons and are removed by the synaptic cleft. Neuromodulators have longer term effects upon neurons. For example, a neuromodulator may stimulate a receptor coupled to an effector that influences a second messenger, leading to a cascade that changes ongoing cellular functioning. Neurohormones are similar to neuromodulators except that neurohormones are released into blood, cross the blood-brain barrier, and then bind to receptors.

In this chapter, abnormalities of peptidergic transmitter systems in mood disorders are reviewed. Abnormal peptidergic functioning may involve neurotransmitter, neuromodulator and neurohormone effects. There will be some discussion regarding the role of specific peptidergic transmitter systems in clinical treatment.


It is well known that opioid agonist administration can influence mood, and cause analgesia in humans. Given that these behavioural

Table XVIII-4.1A partial list of peptides in the central nervous system
Adrenocorticotrophic hormone
Corticotrophin-releasing hormone
Growth hormone
Nerve growth factor
Neuropeptide Y
Substance P
Vasoactive intestinal peptide

states are dysregulated during depressive episodes, there has been some interest in measuring abnormalities of opioid receptors during mood disorders.

The major classes of opioid receptors are delta (δ), kappa (κ), and mu (μ). Two reports have found an increase in µ. opioid receptor density in multiple brain regions of suicide victims (Gabilondo et al., 1995; Gross-Isseroff et al., 1990). The earlier study sampled depressed patients. In the later study, the diagnosis was not always known; however, among those in which the diagnosis was known, most had depression. These reports are consistent with preliminary, in vivo, imaging investigations. There is one published abstract reporting an increase in µ opioid receptor binding potential in an [11C] carfentanil positron emission tomography study of depression (Zubieta et al., 1995). The binding potential is proportional to receptor density and affinity (Meyer and Ichise, 2001; Mintun et al., 1984).

Increased µ opioid receptor density should enhance the effects of endogenous opioids and it may seem counterintuitive that increased µ opioid receptor density is observed in depressive episodes. It is possible that these findings may be secondary to lower endogenous opioids or other abnormalities that affect the regulation of this receptor (Law and Loh, 1999).


Cholecystokinin is a family of short-chain peptides which bind to CCK receptors. CCK receptors are categorized into CCKA and CCKB receptors. CCK is of interest in mood disorders because anxiety symptoms often occur comorbidly with depressive episodes, and peptides that have CCKB receptor agonist properties provoke panic attacks (Bradwejn and Koszycki, 1994; Rehfeld, 2000). A second reason for the interest in CCK in mood disorders is that CCK can modulate the release of dopamine in the nucleus accumbens and influence reward behaviours in animal models (Vaccarino, 1994).

Studies sampling CCK in cerebrospinal fluid tend to find no differences between depressed and healthy subjects (Gemer and Yamada, 1982; Gjerris and Rafaelsen, 1984; Gjerris et al., 1984; Rafaelsen and Gjerris, 1985). One study associated state anxiety level with several CCK peptides in a large sample of depressed patients (Lofberg et al., 1998). It has been reported that CCK receptors are increased in frontal cortex of young suicide victims (Harro et al., 1992). The most common diagnosis of a suicide victim is a major depressive episode and major depressive disorder (Barraclough et al., 1974; Robins et al., 1959) so it may be that this abnormality occurs during depressive episodes. Post-mortem investigations of CCK have found no changes in entorhinal cortex concentrations in depressed subjects (Perry et al., 1981) and no changes in several cortex and limbic regions in suicide victims (Kleinman et al., 1985).


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