New Hypotheses to Guide Future Antidepressant Drug Development

Ketamine and the next generation of antidepressants with a rapid onset of action

1. The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF(1)) and 2 (CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF(1) receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors. 2. Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. 3. Nonselective CRF(1)/CRF(2) antagonists and selective CRF(1) antagonists inhibit exogenous (central or peripheral) CRF- and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF(2) antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals. 4. These findings implicate CRF(1) receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF(1)-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.

Recently characterized selective agonists and developed antagonists for the corticotropin releasing factor (CRF) receptors are new tools to investigate stress-related functional changes. The influence of mammalian CRF and related peptides injected intracerebroventricularly (i.c.v.) on gastric and colonic motility, and the CRF receptor subtypes involved and their role in colonic response to stress were studied in conscious mice. The CRF(1)/CRF(2) agonists rat urocortin 1 (rUcn 1) and rat/human CRF (r/h CRF), the preferential CRF(1) agonist ovine CRF (oCRF), and the CRF(2) agonist mouse (m) Ucn 2, injected i.c.v. inhibited gastric emptying and stimulated distal colonic motor function (bead transit and defecation) while oCRF(9-33)OH (devoid of CRF receptor affinity) showed neither effects. mUcn 2 injected peripherally had no colonic effect. The selective CRF(2) antagonist astressin(2)-B (i.c.v.), at a 20 : 1 antagonist: agonist ratio, blocked i.c.v. r/hCRF and rUcn 1 induced inhibition of gastric transit and reduced that of mUcn 2, while the CRF(1) antagonist NBI-35965 had no effect. By contrast, the colonic motor stimulation induced by i.c.v. r/hCRF and rUcn 1 and 1h restraint stress were antagonized only by NBI-35965 while stimulation induced by mUcn 2 was equally blocked by both antagonists. None of the CRF antagonists injected i.c.v. alone influenced gut transit. These data establish in mice that brain CRF(1) receptors mediate the stimulation of colonic transit induced by central CRF, urocortins (1 and 2) and restraint stress, while CRF(2) receptors mediate the inhibitory actions of these peptides on gastric transit.

Studies towards the next generation of antidepressants. Part 4: Derivatives of 4-(5-fluoro-1 H-indol-3-yl)cyclohexylamine with affinity for the serotonin transporter and the 5-HT 1A receptor

Assessment of serum level of corticotropin-releasing factor in primary nocturnal enuresis

Inhibition of serotonin outflow by nociceptin/orphaninFQ in dorsal raphe nucleus slices from normal and stressed rats: Role of corticotropin releasing factor

It is well established that corticotropin-releasing factor (CRF), a peptide comprised of 41 amino acids, is the major physiological regulator of the pituitary-adrenal axis by virtue of its role as the hypothalamic hypophysiotropic hormone that modulates the secretion of adrenocorticotropin (ACTH) from the anterior pituitary gland. In addition to its neuroendocrine role, CRF appears to function as a neurotransmitter or neuromodulator in extrahypothalamic brain areas. The peptide and its receptors are distributed throughout the central nervous system (CNS), and CRF is released by depolarizing concentrations of potassium in a calcium-dependent manner. After direct CNS administration, CRF produces a number of behavioral and physiological effects that are reminiscent of both an organism's response to stress and to the symptoms of patients with major depression. These include: diminished food consumption, decreased sexual behavior, disturbed sleep, alterations in locomotor activity and sympathetic nervous system activation. Alterations in regional brain CRF concentration in rats were observed after acute and chronic stress, i.e. decreased hypothalamic and increased locus coeruleus CRF concentrations. To test the hypothesis that CRF is hypersecreted in patients with major depression, the concentration of CRF in cerebrospinal fluid (CSF) in drug-free depressed patients and age- and sex-matched controles was measured in two studies. The depressed patients exhibited a clear group-related increase in CSF CRF concentrations. To further test this hypothesis that CRF is chronically hypersecreted in depressed patients, the number and affinity of CRF receptors in frontal cortex was measured in a group of suicides and age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressive disorders are endemic as they affect around 16% of the population at some point over the lifespan, and they result in personal suffering, increased risk of suicide and notable socio-economic burden. The core symptoms include low mood, low self-esteem, and a general loss of interest. Because the neurobiological mechanisms of depressive disorders remain poorly understood, and current treatments are only effective in approximately two-thirds of patients, there is intensive ongoing research on the molecular and neural mechanisms underlying depression and its therapies, to determine the factors of risk or resilience to depression and to identify new therapeutic targets.

The behavioural and electrophysiological effects of CRF in rat frontal cortex

Corticotropin-releasing factor (CRF) plays a prominent role in mood disorders like anxiety and depression. Upon experimentally-induced neuropathy, it is up-regulated in limbic structures such as the amygdala. This review discusses the literature on the role of CRF in pain processing and highlights the amygdala as key center in pain control. Not only has CRF analgesic effects following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). We here postulate a central mechanism for pain control with the amygdala as critical brain component in turning the sensation of pain on and off. Upon painful stimuli, CRFR1 in the amygdala is activated by CRF and induces hyperalgesia. The activated CRFR1 is then internalized (pain initiation) to trigger the translocation of the cytoplasmic CRFR2 to the plasma membrane. This CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, such as urocortins, which leads to analgesia (pain termination). Redistribution of the CRF receptors to their initial locations and activity states completes the on-off switching. We propose that in neuropathic pain, this mechanism is dysregulated, which leads to a state of permanent hyperalgesia, and we present an integrative (patho)physiological model for the way disturbed CRF receptor signaling in the amygdala could initiate neuropathic pain.

Corticotropin-releasing factor (CRF) plays an integral role in mediating stress responses and anxiety. However, little is known regarding the role of CRF in ethanol consumption, a behavior often associated with stress and anxiety in humans. The present study sought to determine the role of CRF in ethanol consumption, locomotor sensitivity and reward by examining these behaviors in C57BL/6J x 129S mice with a targeted disruption in the gene encoding the CRF prohormone. Male wild-type and CRF-deficient mice were given concurrent access to ethanol and water in both limited and unlimited-access two-bottle choice paradigms. Taste reactivity (saccharin or quinine vs water) was examined in a similar manner under continuous-access conditions. Blood ethanol levels and clearance were measured following limited ethanol access as well as a 4-g/kg i.p. injection of ethanol. Locomotor stimulant effects of ethanol were measured in an open-field testing chamber, and the rewarding effects of ethanol were examined using the conditioned place preference paradigm. CRF-deficient mice displayed normal body weight, total fluid intake, taste reactivity and blood ethanol clearance, but consumed approximately twice as much ethanol as wild types in both continuous- and limited-access paradigms. CRF-deficient mice failed to demonstrate a locomotor stimulant effect following acute administration of ethanol (2 g/kg i.p.), and also failed to demonstrate a conditioned place preference to ethanol at 2 g/kg i.p., but did display such a preference at 3 g/kg i.p. CRF deficiency may lead to excessive ethanol consumption by reducing sensitivity to the locomotor stimulant and rewarding effects of ethanol.

Since the discovery and structural elucidation of corticotropin-releasing factor (CRF) synthetic ovine and human CRF have become useful tools for the diagnosis of pituitary and adrenocortical disorders. The stimulation of release of adrenocorticotropic hormone (ACTH) after a dose of 100 micrograms CRF allows differentiation of the various causes of secondary adrenal insufficiency. In patients with specific autoimmune corticotroph disorders or general inflammatory or tumorous destruction of the anterior pituitary there is no rise of ACTH after intravenous administration of CRF. In contrast, patients with secondary adrenal failure due to suprasellar lesions show a rise of ACTH from a low or unmeasurable basal level without an accompanying cortisol response, demonstrating the integrity of the corticotroph and the atrophy of the cRF neuron and the adrenocortical cell. Similar observations are made in patients with secondary adrenal failure resulting from long-term glucocorticoid treatment. This demonstrates that the main reason for adrenal insufficiency after glucocorticoid treatment is the persisting suppression of the activity of CRF neurons. In patients with adrenocortical hyperfunction (Cushing's syndrome) the CRF stimulation test differentiates unequivocally between autonomous adrenal hypercortisolism and ACTH-dependent bilateral adrenal hyperplasia. However, the differential diagnosis between eutopic pituitary (Cushing's disease) and paraneoplastic ACTH secretion (ectopic ACTH syndrome) is difficult. Recent results show that catheterization of the sinus petrous inferior and measurement of ACTH in central and peripheral blood before and after CRF injection allows this differential diagnosis to be made with confidence. The usefulness of measuring CRF plasma levels is not established. The only exception to this is in cases of ectopic CRF syndrome, which is a rare cause of Cushing's syndrome.

Gastrin-releasing peptide (GRP) exerts several functions within the hypothalamus and may be involved in the regulation of pituitary hormone secretion. The purpose of this study was to investigate the central effect of GRP on hypothalamic-pituitary-adrenal axis activity in the male rat. Intracerebroventricular (i.c.v.) but not intravenous administration of GRP (1, 10, 100 ng/rat) increased plasma ACTH and corticosterone concentrations in a dose-dependent manner. The highest dose (100 ng/rat) of GRP increased plasma ACTH and corticosterone 4- and 14-fold, respectively. This increase peaked at 30–60 min after i.c.v. injection, decreased gradually and returned to baseline levels 240 min after GRP administration. The i.c.v. administration of (Leu¹³-ψ-CH₂NH-Leu¹⁴) bombesin, a competitive and specific GRP receptor antagonist, had no effect on ACTH and corticosterone secretion; however, a dose of 1 µg/rat completely blocked the increase of both hormones induced by GRP (10 ng). By using α-helical (9–41) corticotropin-releasing factor (CRF), a competitive antagonist of CRF, the role of CRF on GRP-induced ACTH and corticosterone secretion was also explored. α-Helical (9–41) CRF (10 µg/rat) blocked the increase in ACTH and corticosterone secretion induced by GRP (10 ng). The results obtained in this study suggest that GRP increases the secretion of ACTH and corticosterone in the plasma by acting centrally on GRP receptors, and that endogenous GRP receptor ligands do not tonically regulate ACTH and corticosterone secretion. Furthermore, the hypothalamus-pituitary-adrenal-activating effects induced by GRP appear to be mediated, at least in part, by CRF.

1. The respiratory effects of corticotrophin-releasing factor (CRF) and the CRF antagonists alpha-helical CRF 9-41 (alpha hCRF) and [DPhe 12, Nle 21-38] rCRF (12-41) (DPhe CRF) have been studied in unanaesthetized fetal lambs of 125-140 days gestation. 2. CRF when given as a 10 micrograms bolus followed by a 5 micrograms h-1 infusion into a lateral cerebral ventricle caused prolonged continuous fetal breathing movements which were stimulated in both amplitude and frequency but which did not persist during hypoxia. 3. Lower doses of CRF (20 ng bolus followed by 10 ng h-1) increased the amplitude but not the frequency of fetal breathing movements which did not become continuous. 4. At higher doses (20 micrograms bolus followed by 10-15 micrograms h-1) CRF induced cerebral convulsions which were also associated with fetal breathing movements of increased amplitude and frequency. 5. The CRF antagonists alpha hCRF and DPhe CRF both inhibited fetal breathing movements and induced a prolonged apnoea which was resistant to the stimulatory effects of 5-6% hypercapnia. 6. We conclude that CRF stimulates breathing movements in the fetal lamb. The finding that administration of the CRF antagonists alone cause apnoea suggests that CRF may have a tonic role in the regulation of fetal breathing movements.

Adult male rats were used to determine whether high circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) were capable of releasing ACTH independently of endogenous corticotropin-releasing factor (CRF). On one hand, CRF antibodies or a potent CRF antagonist significantly decreased, but did not totally abolish the ACTH response to the intravenous (i.v.) injection of recombinant rat IL-6. These results suggest that this cytokine might act either directly on the pituitary, or can release ACTH through mechanisms that do not involve CRF. On the other hand, the CRF antagonist or antibodies significantly (but not totally) blocked ACTH secretion due to the i.v. injection of endotoxin (LPS) while enhancing the ability of this immune stimulus to increase serum IL-6 concentrations. These results indicate that during endotoxemia, even very elevated circulating IL-6 concentrations were not able to release large amounts of ACTH in the absence of CRF drive. These data also illustrate the ability of a CRF antagonist or CRF antibodies to significantly augment IL-6 secretion, which indicates an inhibitory influence of the endogenous peptide in the paradigm we used. As comparable findings were obtained in adrenal-intact and adrenalectomized rats, they suggest that endogenous CRF is involved in the IL-6 response to LPS independently of circulating corticosteroids or other adrenal factors.