Neuropeptides In Psychiatric Disorders

Similarly to the classic neurotransmitters, mounting evidence is available about changes in neuropeptide expression and processing in several psychiatric disorders. Neuropep-tides are present in brain tissue as well as in cerebrospinal fluid (CSF). Although the neurotransmitter function of neuropeptides is associated with their synthesis in situ in brain and anatomical distribution via neuropeptidergic fiber systems, their abundant presence in the CSF may be primarily due to simple drainage into the CSF, and may serve as a useful indirect marker of neuropeptide function and metabolism. Alternatively, neuropeptides functioning as neurohormones may be actively delivered into the CSF from central or peripheral sources and employ the pathways of CSF circulation as avenues of transport (Burbach, 1982). CSF levels of neuropeptides may help establish global functional states in the nervous system (e.g., affective states), and they may achieve this by orchestrating activities in many other neurochemical systems (Rothman et al., 2002). Thus CSF peptide titers may have an active regulatory role in relation to central nervous system (CNS) functions and behaviors, such as pain and anxiety symptoms, as well as a function of therapeutic doses of psychoactive drugs (Post et al., 1982).

So far neuropeptide studies in many psychiatric conditions have produced some variable results. A major possible problem is heterogeneity in subject populations, as well as various technical obstacles in obtaining comparable samples, especially of postmortem material. Regarding the CSF studies, the use of neuropeptide titers for studying in vivo alterations in central neuronal activities is enhanced by a knowledge of CSF physiology and pathology. Degradation of CSF constituents during collection, storage, and analysis may introduce errors in quantification (Wood, 1980). Ventriculospinal concentration gradients, circadian rhythms, physical activity, stress, medications, concomitant illness, obstructed CSF circulation, age, and sex alter the baseline neurochemical composition of CSF. For example, many studies on CRH levels in the CSF may be biased because of insufficient control for stress caused by sampling (Mitchell, 1998).

Among the better explored connections is the role of CRH in stress-related disorders, including depression (Holsboer, 2001a,b; Harro and Oreland, 2001; De Souza and Grigoriadis, 2002). Levels of CRH in the CSF have been found to be higher and CRH receptor densities lower in some populations of depressed patients, and the number of CRH-expressing neurons in the hypothalamic paraventricular nucleus is higher. Recurrence of depression can be fairly well predicted on the basis of enhanced cortisol response to CRH after dexamethasone-induced feedback inhibition of anterior pituitary (Reul and Holsboer, 2002). Several nonpeptide antagonists of the CRH1 receptor subtype have recently been developed. There is preliminary evidence that such drugs may be efficient against anxiety and depression (Zobel et al., 2000).

While CRH is used by several neuronal populations in the CNS and peripheral nervous system, a recent discovery of orexins (also called hypocretins) has provided an example of a highly localized neuropeptide system that is unequivocally associated with at least one disorder of the CNS. Orexins are expressed in neurons of dorsolateral hypothalamus and regulate arousal states and feeding but also appear to be causally related to the sleep disorder narcolepsy (Sutcliffe and de Lecea, 2002). In humans, narcolepsy is caused by the loss of orexin neurons probably because of an autoimmune attack or by mutation of the orexin-2 receptor (Willie et al., 2001). Studies of this novel neuropeptide family have greatly enhanced our understanding of the biochemistry, physiology, and anatomy of switching between waking and sleeping, which in turn provides clues as to how better therapies may be developed to facilitate optimal arousal states. The excessive daytime sleepiness of narcoleptics is currently treated with DA-potentiating psychostimulants, but evidence that orexins can stimulate the DA neurons in the ventral tegmental area (Korotkova et al., 2003) suggests that orexin facilitators (e.g., receptor agonists) may promote arousal with a wider safety margin.

Following the idea that neurotensin may be strongly related to the pathogene-sis of schizophrenia (see below), the density of neurotensin receptors was studied in the intermediate and caudal entorhinal cortex and hippocampal formation of subjects with schizophrenia or affective disorder and in control subjects (Hamid et al., 2002). Not only schizophrenic but also affective disorder subjects had decreased neurotensin receptor density in the entorhinal cortex. These findings highlight regional changes in neurotensin receptor binding levels in the mesial temporal lobe in psychopathol-ogy. However, since there was no clear diagnostic specificity for these changes, being evident to varying degrees in both schizophrenia and affective disorders, neurotensin may be related to some functional brain mechanism these diagnostic groups have in common.

In some instances, an absence of a major change in a neuropeptide in the presence of other neurotransmitter changes could also be a pathogenic mechanism, as suggested for galanin, a neuropeptide with multiple inhibitory actions on the circuitries of learning and memory. In Alzheimer's disease, levels of many neurotransmitters decrease, but the expression of galanin progressively increases (Counts et al., 2001). In these conditions, galanin may inhibit the activity of remaining cholinergic neurons and thus worsen the compensatory abilities of the declining brain. Recent studies that demonstrate that galanin overexpressing transgenic mice have reduced numbers of cholinergic neurons and performance deficits in memory tests (Steiner et al., 2001) suggest that galanin may be even more closely linked to the primary pathological process. Furthermore, the ability of galanin to increase the autoinhibition of the locus coeruleus (Hokfelt et al.,

1999) has been proposed as one pathogenetic contributory factor to the development of depression (Harro and Oreland, 2001). In both instances, galanin receptor antagonists could be anticipated to be reasonable treatment options.

As already noted, nonpeptide antagonists of the NK1 receptor have been added to the list of potential drugs to treat depression. In subjects with major depressive disorder there is decreased binding to NK1 receptors across all layers of rostral orbitofrontal cortex (Brodmann's area 47) (Stockmeier et al., 2002). The pathophysiology of depression and the reported therapeutic benefit of NK1 receptor antagonists may thus involve NK1 receptors in prefrontal cortex. The ability of NK2 antagonists to show anxiolytic-like properties in ethological tests, while being inactive in classic measures sensitive to ben-zodiazepines (see Chapter 16), has spurred interest in investigation of these compounds in anxiety disorders involving unavoidable traumatic stress, particularly posttraumatic stress disorder (PTSD) (Kent et al., 2002).

In conclusion, many changes in neuropeptides can be found in psychiatric disorders. However, it is not clear whether these are most fruitfully interpreted as pertinent to specific diagnostic entities or rather to distinct psychobiological domains (i.e., psychological endophenotypes) that contribute to different disorders (van Praag,

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