For an extensive discussion of this emotional system, see Chapter 16. Here we will focus on specific neuropeptide modulators. Of all emotional systems, probably more neuropeptides have been implicated in the facilitation of fear and anxiety than any other emotional tendency. They include, most prominently, CRH, neuropeptideY (NPY), CCK, alpha-melanocyte stimulating hormone/adrenocorticotropic hormone (a-MSH/ ACTH), diazepam-binding inhibitor (DBI), but also several others, and thus several neuropeptide systems have been considered as primary molecular targets in the treatment of anxiety (Kent et al., 2002).
Corticotropin-releasing hormone antagonisms is everyone's greatest hope for the immediate future. This peptide is thought to serve as the prime coordinator of physiological as well as behavioral stress responses. CRH-related peptides and CRH receptor subtypes are relatively widely distributed in the brain and can serve as targets for drug development for various purposes (Sarnyai et al., 2001). Noradrenergic projections of the locus coeruleus can mediate the role of CRH in general central nervous system stress response (Harro and Oreland, 2001), and the fear response to CRH may be more specifically associated with the central amygdala, which receives noradrenergic projections largely from other noradrenergic nuclei (Sarnyai et al., 2001).
The CRH antagonists are silent in many anxiety tests but are anxiolytic when animals are being stressed (Holsboer, 2001a,b). This suggests that CRH is released upon demand, supporting the general idea that neuropeptides are released only in case of increased neural activation (Hokfelt et al., 2000). This should facilitate their use as prophylactic compounds with limited side effects. One potential problem on the horizon is that there are two types of CRH receptors in the brain that may have opposing effects. Fortunately, each is preferentially activated by different molecules, the first by CRH and the second by urocortins (Reul and Holsboer, 2002). However, in avian models, both of these peptides dramatically facilitate separation distress vocalizations (Panksepp and Bekkedal, 1997).
Another thorny issue lies in the fact that CRH release is clearly a normal home-ostatic mechanism (Dunn and Berridge, 1990) and is activated by stimuli that are stressful in a bodily sense but do not provoke unpleasant emotions. CRH obviously exerts many adaptive effects, and blocking the system may exacerbate certain bodily problems—for instance, inflammation responses, such as those accompanying irritable bowel syndrome, that are normally suppressed by circulating cortisol (Monnikes et al., 2001). There may also be undesirable psychobiological side effects of CRH antagonists—for instance, CRH-deficient mice consume twice as much ethanol as wild-type mice (Olive et al., 2003). Thus, CRH may be important in counteracting drugs of abuse and may be potentially helpful for the treatment of compulsive drug use. Of course, the affectively negative side effects may limit the use of such agents.
There may be something critically different in CRH-mediated neurotransmission in eustress and in emotional disorders. One relevant view is Nemeroff's stress-diathesis theory: Evidence mainly from preclinical studies suggests that stress early in life results in persistent central CRH hyperactivity and increased stress reactivity in adulthood. Genetic disposition coupled with early stress in critical phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing depression and anxiety upon further stress exposure (Heim and Nemeroff, 1999). Thus, CRH antagonists deserve to be evaluated in specific anxiety disorders ranging from generalized anxiety disorder (GAD) to PTSD (See Chapters 11-13, and 16).
Other prominent peptides in the orchestra of anxiety are to be found among the posttranslational processing of CCK, already introduced in the context of SEEKING urges. Short fragments of CCK, CCK-4 and CCK-5 (pentagastrin) that selectively stimulate CCK2 receptors elicit the full panic attack, patients with the disorder reacting to lower doses (Bourin et al., 1996). Regarding generalized anxiety, there is limited evidence. Animal studies using routine anxiety tests (see Chapter 16) have shown that anxiety-like responses can be induced by CCK, but these effects seem to depend upon environmental context (Harro et al., 1993). The brain regions involved remain to be described, albeit amygdala has been implicated. CCK receptor antagonists have anxiolytic-like properties in some but not all experimental paradigms. These drugs can prevent CCK-induced panic, but it has not yet been possible to demonstrate their clinical efficacy in any anxiety disorder. However, the effects of CCK2 antagonists in animal experiments strongly depend on dose, having an inverted U-shaped dose-response curve (Harro et al., 1993), and thus it is quite possible that the doses and achieved brain levels of the drug have been suboptimal. In addition, one should consider the theoretical possibility that in the variety of neural circuits involved in anxiety disorders, CCK is very selectively involved in the neurobiology of panic disorder, which would make it a PANIC peptide rather than a FEAR peptide.
NeuropeptideY is an evolutionarily highly conserved peptide well known for its major role in feeding. Even though there is no unequivocal evidence of the role of NPY in anxiety from human studies, this peptide has been well described in animal models as an endogenous antianxiety compound (Kask et al., 2002). Studies have demonstrated that NPY administered intracerebroventricularly (icv) or intraamygdala elicits an anxiolytic response probably by stimulating the Y1 receptor subtype (Heilig et al., 1994), and these have more recently been complemented with experiments using nonpeptide antagonists selective for the Y1 receptor subtype, with anxiogenic-like properties (Kask et al., 1996). These studies highlight that endogenous NPY is released in novel or challenging environments to suppress the fear response, possibly being one of the mechanisms balancing the action of CRH release (Kask et al., 2002). Interestingly, while exogenous NPY is anxiolytic in several brain regions (e.g., amygdala, lateral septum, and locus coeruleus), endogenous NPY, as revealed in studies with Y1 receptor antagonists, has so far been found anxiolytic only in the dorsal periaqueductal gray matter, a caudal part of the fear circuit (see Chapter 16).
NeuropeptideY is even better known for its orexigenic effects, which appear to be mediated through at least two receptor subtypes, Y1 and Y5 (Kask et al., 1998). Interestingly, in the quoted study it was found that diazepam eliminated the blocking effect of a Y1 receptor antagonist on NPY-elicited feeding. It is tempting to suggest that Y1 receptor activation is an additional measure in NPY-induced feeding (which involves several receptor subtypes) in part by reducing arousal. Thus NPY and Y1 receptor could be conceptualized as a link with an ancient foraging system, promoting appetite (especially for food high in carbohydrates), facilitating DA-mediated locomotion, and reducing fear of novel places and foods at the same time.
There are other neuropeptide systems that have remained less well characterized due to limited understanding of their biology and a shortage of adequate tools but continue to be suspected as important mediators of some types of anxiety. Diazepam binding inhibitor is a peptide that together with some of its processing products, behaves as an inverse agonist of benzodiazepine receptors and an anxiogenic-like compound. It has been found to be increased in the CSF of patients with severe anxiety (Guidotti, 1991). Although DBI is preferentially concentrated in steroidogenic tissues and cells, where it may serve as a metabolic enhancer in stressful conditions, its messenger ribonucleic acid (mRNA) expression is enhanced in rats by conditioned emotional stimuli but not by restraint stress (Katsura et al., 2002). Alpha-MSH and ACTH, peptides of propiomelanocortin origin, elicit vigorous freezing response or flight when injected intracerebrally, at least in some species (Panksepp and Abbott, 1990; Panksepp and Normansell, 1990). A recent study in which brain-derived neu-rotrophic factor was conditionally knocked-out, demonstrated that mice with increased levels of propiomelanocortin were hyperactive after exposure to stressors and preferred dark compartments more strongly than wild-type controls (Rios et al., 2001). Most recently, a novel nonpeptide melanocortin-4-receptor antagonist was found to attenuate the a-MSH-increased cyclic adenosine monophosphate (cAMP) formation and to possess anxiolytic- and antidepressant-like properties in animal models (Chaki et al., 2003).
In sum, it is unlikely that evolution shaped a single "anxiety peptide" that universally elicits fear. Rather there exist distinct peptide-mediated responses to specific environmental challenges, which can function improperly, for example, by turning on at the wrong time or remaining unbalanced by the failure of endogenous antianxiety mechanisms. How such peptides regulate internal affective states, perhaps in conjunction with cognitive elaborations, should eventually tell us much about the varieties of anxiety (Chapter 16).
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