Gastos e Inversiones

Since the isolation, cloning, and characterization of CRH by Vale et al. (1981), many studies have emerged that consistently show that CRH plays a key role not only in the neurohumoral adaptation to stress, but also in the co- ordination of behavioral responses (A. J. Dunn and Berridge 1990; Holsboer et al. 1992; Owens and Nemeroff 1991). Specifically, the groups led by Koob and by Nemeroff showed that CRH is critically involved in producing symp- toms that are prevalent in depression, such as increased anxiety, anorexia, and decreased sexual activity (Butler et al. 1990; Heinrichs et al. 1992; Swerdlow et al. 1989). In addition, vegetative signs and sleep EEG alterations typical for stress and depression are likely to be mediated by CRH (Ehlers et al. 1986; Holsboer et al. 1988).

Recently, these studies were enhanced by studies using antisense probes directed against the messenger ribonucleic acid of CRH (CRH mRNA), which resulted in anxiolytic effects similar to those observed with CRH an- tagonists (Skutella et al. 1994). Also recently, a transgenic mouse was gener- ated that overexpressed CRH and showed increases in anxiety-related behavior as assessed by the elevated plus-maze experiment (Stenzel-Poore et al. 1994). The possibility that this anxiogenic effect of CRH overexpression was not mediated primarily by CRH, but rather by developmental compensa- tion of the transgene, had been ruled out by the effect of _α-helical CRH-(9-41), which is a CRH antagonist that was able to reduce anxiety-re- lated behavior in these mice.

A new dimension was introduced into the CRH hyperdrive hypothesis when the groups of both Vale and de Souza showed the presence of two dif- ferent CRH receptors with a distinct pharmacology and tissue localization (Lovenberg et al. 1995; Perrin et al. 1993). In addition to these two recep- tors, CRH1and CRH2, a CRH-binding protein (CRH-BP) has been identified

and found to be present in abundance in the brain, mainly in the neocortex, the dentate gyrus, the olfactory bulb, the amygdala complex (excluding the medial nucleus), the raphe nucleus, and the reticular formation. Localization at the pituitary is limited to corticotropic cells. This distribution pattern strongly suggests that CRH-BP contributes to neuroendocrine and behavioral functions (E. Potter et al. 1992). Both the anatomical distribution and the pharmacology of CRH receptors in the brain point to distinct functional properties. Analysis of CRH1 and CRH2 receptor mRNA expression in the

rat brain showed that CRH₁receptors are abundant in neocortical, cerebel- lar, and sensory systems as well as at pituitary corticotrophs. In contrast, the

distribution of CRH₂receptors appears to be more specific, with higher con- centrations at subcortical structures, including the lateral septum and various hypothalamic nuclei. It is noteworthy that both receptors are expressed in the hypothalamus and hippocampus.

In a preliminary attempt to sort out which of these two receptors might mediate anxiogenic effects of CRH, we conducted a number of behavioral studies in rats pretreated with intracerebroventricularly administered anti- sense probes targeted against either the CRH1 or the CRH2 receptor

(Liebsch et al. 1995). As illustrated in Figure 2–2, only an antisense-gener- ated “knock-down” against CRH1 receptors, not CRH2, was able to reduce

anxiety-related behavior in rats. Based on this finding, we concluded that the CRH1receptor is a prime candidate for pharmaceutical interventions to de-

crease disorders related to stress, particularly anxiety, that may ultimately

Figure 2–2. Intracerebral infusion of antisense oligonucleotides (AS-ODN) that were targeted to the cloned CRH1and CRH2receptor mRNA prevent transla- tion into the receptor protein. Only a “knock-down” of the CRH1receptor, but not of the CRH2receptor, reduces anxiety-related behavior in rats that were exposed to the elevated plus-maze test after central corticotropin-releasing hormone (CRH) administration. *P < .05, **P < .01.

Source. Adapted from Liebsch G, Landgraf R, Gerstberger R, et al: “Chronic Infu- sion of a CRH1Receptor Antisense Oligodeoxynucleotide Into the Central Nucleus of the Amygdala Reduced Anxiety-Related Behavior in Socially Defeated Rats.”

Regulatory Peptides 59:229–239, 1995. Copyright 1995, Elsevier Science – NL.

result in the development of a mood disorder.

CRH probably does not act alone. According to clinical neuro- endocrinology, vasopressin is a prime candidate for the synergy of CRH ef- fects at pituitary CRH1receptors, and it also has behavioral effects that are

compatible with a role in depression. Chronic psychosocial stress enhances vasopressin expression and increases the number of hypothalamic neurons coexpressing CRH and vasopressin. Infusion of an antisense oligodeoxy- nucleotide, which corresponds to the mRNA of vasopressin type I receptor, into the septum led to reduced anxiety-related behavior that parallels de- creases in vasopressin receptor binding (Landgraf et al. 1995).

Yet another peptide candidate possibly involved in mood disorder–related behaviors has been identified only recently by the laboratory of Vale. These researchers characterized a member of the CRH family that has sequence identity of 64% with urotensin I (mainly occurring in the suckerfish) and of 45% with human CRH, and they named it urocortin (Vaughan et al. 1995). This peptide is of interest, as it is 10-fold more potent than CRH in accumu- lating cyclic adenosine monophosphate (cAMP) in cells transfected tran- siently with CRH₂receptors. This is consistent with the view that urocortin is the preferred mammalian ligand for the CRH2 receptor, particularly the

CRH_2βsplice variant. However, urocortin also acts powerfully at CHR₁re- ceptors, as evidenced by its 7-fold higher potential to induce secretion of ACTH from pituitary cells. Urocortin appears to be much more potent than CRH in suppressing feeding behavior, as shown by abolishment of food con- sumption in fasting rats, whereas, in contrast to CRH, urocortin has no anxiogenic effects (Koog and Spina, personal communication, cited in Vaughan et al. 1995). Finally, urocortin binds strongly to CRH-BP, which un- derscores how intricately these neuropeptide systems are intertwined (Fig- ure 2–3).