- Email: [email protected]
CRF2 Receptor Agonists and Nicotine Withdrawal
C H A P T E R
27 CRF2 Receptor Agonists and Nicotine Withdrawal Zsolt Bagosi Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary
Abbreviations ACTH AVP CFLP mice CNS CRF CRF1 CRF2 CRF-BP HPA axis icv ip SNS Ucn1 Ucn2 Ucn3
adrenocorticotropic hormone arginine vasopressin Carworth Farm Lane-Petter mice central nervous system corticotropin-releasing factor corticotropin-releasing factor receptor type 1 corticotropin-releasing factor receptor type 2 corticotropin-releasing factor-binding protein hypothalamic-pituitary-adrenal axis intracerebroventricularly intraperitoneally sympathetic nervous system urocortin 1 urocortin 2 urocortin 3
Corticotropin-releasing factor (CRF) and the urocortins are members of the mammalian CRF family of peptides, having similar biochemical structures but different anatomical distributions, physiological functions, and pharmacological profiles (Fekete & Zorrilla, 2007; Suda, Kageyama, Sakihara, & Nigawara, 2004). CRF is a 41-amino acid mammalian neuropeptide that shows 54% similarity with its fish homolog urotensin and 48% with its frog homolog sauvagine (Vale, Spiess, Rivier, & Rivier, 1981). CRF is synthesized in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala from where it regulates the neuroendocrine, autonomic, and behavioral responses to stress (Bale, Lee, & Vale, 2002; Bale & Vale, 2004). The neuroendocrine response is represented by the activation of the hypothalamic-pituitary-adrenal (HPA) axis and mediated by paraventricular CRF that, along with the synergistic arginine vasopressin (AVP), stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary and the subsequent release of
Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00027-7
glucocorticoids from the adrenal cortex (Bale et al., 2002; Bale & Vale, 2004). The autonomic response is represented by the activation of the sympathetic nervous system (SNS) and mediated by amygdalar CRF that stimulates the release of catecholamines from the locus coeruleus that, in turn, stimulates the release of catecholamines from the adrenal medulla (Bale et al., 2002; Bale & Vale, 2004). Thus, CRF acts not only as a hypothalamic neurohormone but also as an extrahypothalamic neurotransmitter that modulates the behavioral responses to stress, manifested by increased locomotor activity, decreased food and water intake, etc. (Bale et al., 2002; Bale & Vale, 2004). Urocortin 1 (Ucn1) is a 40-amino acid neuropeptide that shares 63% similarity with the fish urotensin and 45% with the human CRF, from which the name urocortin was derived (Vaughan et al., 1995). Ucn1 is synthesized predominantly in the Edinger-Westphal nucleus and the lateral superior olive that project caudally to the spinal cord and the lateral septum (Reul & Holsboer, 2002). Despite of the oculomotor, pupillary, and auditory functions attributed to these brain regions, Ucn1 rather modulates the neuroendocrine and behavioral responses to stress, being a less potent activator of locomotion and a more potent suppressor of food and water ingestion, when compared to CRF (Skelton, Owens, & Nemeroff, 2000). The actions of CRF and Ucn1 are mediated by two distinct G-protein-coupled receptors, CRF1 and CRF2 (Chang, Pearse II, O’Connell, & Rosenfeld, 1993; Lovenberg et al., 1995), and inhibited by CRF-binding protein (CRF-BP) (Behan, Cepoi, et al., 1996; Behan, De Souza, et al., 1996). CRF acts preferentially through CRF1, binding with 15-fold higher affinity to CRF1 than to CRF2, whereas Ucn1 acts equipotently through both CRF receptors, binding with sevenfold higher affinity
213
Copyright © 2019 Elsevier Inc. All rights reserved.
214
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
to CRF1 than CRF itself (Reul & Holsboer, 2002). In the central nervous system (CNS), CRF1 is distributed abundantly in the cerebral cortex, the cerebellum, the amygdala, and the anterior pituitary (Dautzenberg & Hauger, 2002; Van Pett et al., 2000). Urocortin 2 (Ucn2), also known as stresscopin-related peptide in humans, is a 38-amino acid neuropeptide that presents 34% identity with CRF (Reyes et al., 2001). Ucn2 expression was shown in the paraventricular, the supraoptic, and the arcuate nuclei of the hypothalamus and the locus coeruleus and brain regions involved in neuroendocrine control, food intake, water intake, and autonomic control, but Ucn2 projections are unknown yet. Ucn2 was demonstrated to have mild locomotor suppressive and delayed anxiolytic-like effects (Valdez et al., 2002). Urocortin 3 (Ucn3), also known as stresscopin in humans, is another 38-amino acid neuropeptide that exhibits 36% identity with CRF (Lewis et al., 2001). Ucn3 expression was found in the perifornical area of the hypothalamus, the medial nucleus of the amygdala, and the bed nucleus of the stria terminalis, which are adjacent or project to the paraventricular nucleus of the hypothalamus and the lateral septum, brain regions involved in stress coping (Reul & Holsboer, 2002). When compared to Ucn2, Ucn3 was demonstrated to have more acute locomotor suppressive and anxiolytic-like effects (Valdez, Zorrilla, Rivier, Vale, & Koob, 2003). The actions of Ucn2 and Ucn3 are mediated exclusively by CRF2, both having more than 1000-fold higher affinity for CRF2 than for CRF1 (Reul & Holsboer, 2002). Therefore, they are considered selective agonists of CRF2 (Hsu & Hsueh, 2001). CRF2 is limited centrally to the subcortical regions of the brain: the lateral septum, the hypothalamus, the amygdala, and the hippocampus (Dautzenberg & Hauger, 2002; Van Pett et al., 2000). Central administration of CRF and Ucn1 induces activation of the HPA axis reflected by the elevation of the plasma corticosterone concentration and anxiety- and depression-like behavior in mice and rats (Bagosi et al., 2014; Spina et al., 1996, 2002; Tanaka & Telegdy, 2008). In contrast, central administration of Ucn2 and Ucn3 produces anxiolytic and antidepressant actions in rodents (Inoue et al., 2003; Tanaka & Telegdy, 2008; Valdez et al., 2002, 2003). It was hereby hypothesized that in physiological conditions, CRF would initiate the responses to stress activating CRF1 in the anterior pituitary, whereas the urocortins would terminate these responses activating CRF2 in the paraventricular nucleus of the hypothalamus (Bale et al., 2002; Bale & Vale, 2004). Overwhelming stress may induce a pathological stimulation of CRF/CRF1 system in the cerebral cortex and the amygdala over the urocortin/CRF2 system in the lateral septum and the hippocampus that may result in hyperactivity of the HPA axis, anxiety, and depression (Bale et al., 2002; Bale & Vale, 2004). However, the physiological role
of urocortin/CRF2 system in the regulation HPA axis is still under debate, since studies in mice and rats led to contradictory results (Bagosi et al., 2013; Jamieson, Li, Kukura, Vaughan, & Vale, 2006; Maruyama, Makino, Noguchi, Nishioka, & Hashimoto, 2007; Pelleymounter, Joppa, Ling, & Foster, 2004). Nevertheless, a recent hypothesis questions such dualistic and complementary actions of CRF1 and CRF2 and suggests that stress would recruit CRF systems in a brain region and neuron population-specific manner as conditions dictate ( Janssen & Kozicz, 2013). Besides the regulation of the stress responses, CRF and the urocortins have been implicated in nicotine addiction (Bruijnzeel & Gold, 2005; Sarnyai, Shaham, & Heinrichs, 2001). Inspired by the original hypothesis according to which CRF1 and CRF2 exert (mainly) antagonistic effects in the CNS, our recent study aimed to investigate whether the activation of CRF2 by central administration of Ucn2 and Ucn3 would attenuate the anxiety- and the depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice (Bagosi et al., 2016). In this purpose, 72 male CFLP mice were exposed to intraperitoneal treatment with nicotine or saline solution for 7 days, 4 times/day, and then to 1 day of withdrawal. A single intracerebroventricular injection with Ucn2, Ucn3, or saline solution was performed at 12 h or at 24 h following the the last intraperitoneal treatment. After 30 min, the mice were evaluated in an elevated plus-maze test (see “Key Facts of the Elevated Plus-Maze Test”) and a forced swim test (see “Key Facts of the Forced Swim Test”) for signs of anxiety and depression, respectively. States of anxiety and depression are usually associated with the hyperactivity of the HPA axis; hence, after 5 min, the plasma corticosterone concentration was also determined by a chemofluorescent assay (see “Key Facts of the Chemofluorescent Assay”). Half of the mice were tested on the 8th day (12 h after the last intraperitoneal treatment) and half of them on the 9th day (24 h after the last intraperitoneal treatment) (Bagosi et al., 2016). On the 8th day, nicotine-treated mice presented signs of anxiolysis and depression and no significant elevation of the plasma corticosterone concentration (Bagosi et al., 2016). Actually, in the elevated plus-maze test, the time spent in the open arms increased significantly after nicotine treatment, and this parameter increased even more after urocortin treatment, but the number of entries into the open arms and the total number of entries did not change considerably in nicotine-treated mice, compared to the saline-treated ones (Fig. 27.1). In parallel, in the forced swim test, the time spent with climbing and swimming decreased remarkably after nicotine treatment, and these parameters decreased even more after urocortin treatment, but the time spent immobile did not change considerably in nicotine-treated mice, compared to the
215
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
30
≠
20 10 0
24 h
12 h
(A)
Percentage (%)
50 40 30
## ≠
20
# # ≠
10 0 12 h
(B) 25 Number
20 15 10 5 0
(C)
12 h
FIG. 27.1 The effects of Ucn2 and Ucn3 in mice exposed to chronic nicotine treatment and acute nicotine withdrawal and investigated in an elevated plus-maze test. (A) Number of entries into the open arms/total number of entries, (B) time spent in the open arms/total time, and (C) total number of entries. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
saline-treated ones (Fig. 27.2). Most of the behavioral changes described after 12 h of nicotine withdrawal were nonsignificant and accompanied with a slight but nonsignificant elevation of the plasma corticosterone concentration that was reduced significantly after urocortin treatment (Fig. 27.3). On the 9th day, nicotine-treated mice exhibited signs of anxiety and depression and a significant increase of the plasma corticosterone concentration (Bagosi et al., 2016). Accordingly, in the elevated plus-maze test, the number of entries into the open arms and the time spent in the open arms decreased significantly, while the total number of entries did not change significantly in nicotine-treated mice, compared to the saline-treated ones; after treating these mice with urocortins, the first two parameters were increased or normalized (Fig. 27.1). In addition, in the forced swim test, the time spent with climbing and swimming decreased
Time (1 unit = 5 s)
40
25 ##
20 15 ≠
10 5 0 12 h
24 h
(A) 25 Time (1 unit = 5 s)
Percentage (%)
# #
20 15
# #
10 5
≠
0
(B)
12 h
50 Time (1 unit = 5 s)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
50
24 h
≠
40
# #
35 20 10 0 12 h
(C)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
FIG. 27.2 The effects of Ucn2 and Ucn3 in mice exposed to chronic nicotine treatment and acute nicotine withdrawal and investigated in a forced swim test. (A) Climbing activity, (B) swimming activity, and (C) immobility. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
Plasma corticosterone concentration Concentration (μg/100mL)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
50 40
≠
30 20
## # #
10 0 12 h
FIG. 27.3
24 h
Saline ip + Saline icv (12) Saline ip + Ucn2 icv (12) Saline ip + Ucn3 icv (12) Nicotine ip + Saline icv (12) Nicotine ip + Ucn2 icv (12) Nicotine ip + Ucn3 icv (12)
The effects of Ucn2 and Ucn3 on the plasma corticosterone concentration determined by a chemofluorescent assay in mice exposed to chronic nicotine treatment and acute nicotine withdrawal. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
216
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
significantly, while the time spent immobile increased significantly in nicotine-treated mice, compared to the saline-treated ones; after treating these mice with urocortins, all these parameters were returned to normal (Fig. 27.2). The behavioral response described after 24 h of nicotine withdrawal was associated with a significant neuroendocrine response, both of which were reversed completely after urocortin treatment (Fig. 27.3). Previous studies have already suggested that CRF and CRF-like peptides contribute to the acute, chronic, and withdrawal actions of nicotine, based on three observations (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). First, acute administration of nicotine evokes a dosedependent activation of the HPA axis that is reflected by the accumulation of salivary cortisol in humans and plasma corticosterone in mice and rats and seems to be initiated by hypothalamic CRF (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). Despite of the rapid desensitization of this effect that may occur even after a single intake and the tolerance that may develop after repeated intake, chronic administration of nicotine often leads to elevation of the glucocorticoid concentration (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). Second, acute nicotine withdrawal provokes a group of symptoms in both humans and rodents that resembles stress responses and seems to be mediated by extrahypothalamic CRF (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). This nicotine withdrawal syndrome is composed of a somatic (physical) and an affective (emotional) component that appear in few hours and disappear in few days or weeks after cessation of chronic administration of nicotine (Kenny & Markou, 2001; Markou, 2008; Wonnacott, Sidhpura, & Balfour, 2005). The somatic symptoms in humans include bradycardia, gastrointestinal discomfort, and increased appetite; in rodents, they correspond to abdominal constrictions, facial fasciculations, eyeblinks, ptosis and gasps, escape attempts, foot licks, genital grooming shakes, scratches, and yawns (Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). The affective symptoms in humans incorporate craving, anxiety, depression, dysphoria, irritability, and difficulty concentrating; in rodents, they correlate with anhedonia (a diminished interest or pleasure to rewarding stimuli) and conditioned place aversion (an aversive motivational state that becomes associated with environmental cues) (Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). Third, exposure to stress during protracted nicotine withdrawal increases the vulnerability to relapse to smoking in humans and nicotine self-administration in rodents (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). The negative affective state that emerges during acute withdrawal may persist during protracted withdrawal, and its avoidance plays an essential role in this relapse and thereby in the maintenance of nicotine addiction
(Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). Moreover, recent studies have suggested that the affective and the somatic components of nicotine withdrawal syndrome are mediated by CRF1 and CRF2, respectively (Bruijnzeel, 2012; Bruijnzeel et al., 2012; Bruijnzeel & Gold, 2005; Bruijnzeel, Prado, & Isaac, 2009; Bruijnzeel, Zislis, Wilson, & Gold, 2007; George et al., 2007; Kamdi, Nakhate, Dandekar, Kokare, & Subhedar, 2009; Marcinkiewcz et al., 2009). Several studies reported that the administration of selective CRF1 antagonists prevents the dysphoria and the reward deficit observed during nicotine withdrawal (Bruijnzeel et al., 2012; Marcinkiewcz et al., 2009). Another study referred that the administration of nonselective CRF2 agonists, such as CRF and Ucn1, prevents the hyperphagia and the weight gain assessed during nicotine withdrawal (Kamdi et al., 2009). However, our study was the first to demonstrate that intracerebroventricular administration of Ucn2 and Ucn3 ameliorates the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal, suggesting that the selective CRF2 agonists can be potential candidates in the therapy of nicotine withdrawal (Bagosi et al., 2016). For a better understanding of the physiological and pharmacological actions, future studies should perform the infusion of these peptides in specific brain regions, such as the paraventricular nucleus of the hypothalamus and the lateral septum, where CRF2 is colocalized with Ucn2 neurons and axonal projections of Ucn3 neurons (Reul & Holsboer, 2002; Van Pett et al., 2000).
MINI-DICTIONARY OF TERMS Acute nicotine withdrawal Sudden cessation of nicotine following repeated exposure; in rodents, it can be spontaneous or precipitated by the administration of a nicotinic acetylcholine or an opioid receptor antagonist and may last between 2 and 3 h and 2–3 days following the cessation of nicotine. Anxiety A pathological condition characterized by the presence of excessive worry about a variety of topics, events, or activities; in rodents, it can be investigated in open-field exploration test, elevated plus-maze test, light-dark exploration test, social interaction test, etc. CFLP mice An outbred strain of mice, which are commonly used in genetic, toxicological, and pharmacological research; the term CFLP comes from Carworth Farms and Lane-Petter companies. Chronic nicotine administration Repeated exposure to nicotine; in rodents, it can be performed by water drinking; vapor inhalation; osmotic minipumps; and intravenous, subcutaneous, or intraperitoneal injection that may last from 7 to 270 days. Corticotropin-releasing factor (CRF) Also known as corticotropinreleasing hormone. Not only a hypothalamic neurohormone but also an extrahypothalamic neurotransmitter that mediates the neuroendocrine, autonomic, and behavioral responses to stress. Depression A pathological condition characterized by depressed mood and diminished pleasure or interest in daily activities; in rodents, it can be investigated in forced swim test, tail-suspension test, anhedonia test, conditioned place preference test, etc.
MINI-DICTIONARY OF TERMS
Hypothalamic-pituitary-adrenal (HPA) axis A neuroendocrine system that is represented by the release of CRF from the paraventricular nucleus of the hypothalamus that, along with the synergistic AVP, stimulates the release of ACTH from the anterior pituitary and the subsequent release of glucocorticoids from the adrenal cortex. Urocortins (Ucn1, Ucn2, and Ucn3) CRF-like neuropeptides that have similar amino acid structure but different pharmacological profiles compared to CRF.
Key Facts of the Elevated Plus-Maze Test • The elevated plus-maze test is a method validated by Pellow, Chopin, File, and Briley (1985) to investigate the anxiety-like behavior and the efficacy of anxiolytic drugs in rodents. • The apparatus consists of a plus-shaped wooden platform elevated at 40 cm from the floor, made up by four opposing arms of 30 cm x 5 cm. Two of the opposing arms are enclosed by 15 cm-high side and end walls (closed arms), whereas the other two arms have no walls (open arms). • Each mouse is placed in the central area (5 cm x 5 cm) of the maze, facing one of the open arms, and their behavior is assessed by an observer sitting at 1 m distance from the center of the plus maze. • For 5 min period, the following parameters are recorded: (a) the ratio between the number of entries into the open arms and the total number of entries, (b) the ratio between the time spent in the open arms and the total time, and (c) the total number of entries (an entry into an arm is defined as the entry of all four feet of the animal into that arm). • The principle of the test is that open arms are more fear-provoking, and the ratio of the time spent in open versus closed arms or the ratio of the entries into open versus closed arms reflects the relative safety of closed arms as compared with the relative danger of open arms. The above points list the key facts of the elevated plus-maze test used to evaluate anxiety-like signs in rodents. Key Facts of the Forced Swim Test • The forced swim test is a method invented by Porsolt, Bertin, and Jalfre (1977) to investigate the depressionlike behavior and the antidepressant properties of drugs in rodents. • The apparatus consists of a plexiglass cylinder of 40 cm height and 12 cm diameter containing 1.5 L of water maintained at 25 1°C temperature that is positioned on a table. • Each mouse is dropped individually into the water, and their behavior is assessed by an observer sitting at 1 m distance from the table.
217
• For 5 min period, the following parameters are recorded and expressed in time units (1 time unit ¼ 5 s): (a) the climbing activity (the time that mice spent with climbing the walls, in their attempt to escape the cylinder), (b) the swimming activity (the time that mice spent with swimming in the water, in their attempt to remain at the surface), and (c) the immobility (the time that mice spent in an upright position on the surface with its front paws together). • The principle of the test is that in such a situation, from which they cannot escape, animals rapidly became immobile, floating in an upright position and making only small movements to keep their heads above water. In parallel, their attempt to escape the cylinder by climbing or swimming may decrease or cease eventually. The above points list the key facts of the forced swim test used to investigate depression-like signs in rodents. Key Facts of the Chemofluorescent Assay • The chemofluorescent assay is a method described by Zenker and Bernstein (1958) and modified by Purves and Sirett (1965), used to determine the plasma corticosterone concentration. • The assay is based on the principle that the hydrophobic corticosterone can be extracted from the plasma of rodents with methylene chloride and determined with a fluorescent mixture of sulfuric acid and ethyl alcohol. • The chemical substances used are heparin, distilled water, corticosterone standards, methylene chloride, sulfuric acid, and ethyl alcohol. • The apparatus used is a Hitachi 204-A fluorescent spectrophotometer set at 456 nm extinction and 515 emission wavelengths. • The plasma corticosterone concentration is calculated from the values of the standards and expressed in μg/ 100 mL. The above points list the key facts of the chemofluorescent assay used to determine plasma corticosterone concentration. Summary Points • Corticotropin-releasing factor (CRF) and the urocortins (Ucn1, Ucn2, and Ucn3) belong to the mammalian CRF family of peptides. • CRF and Ucn1 bind to both CRF receptors (CRF1 and CRF2), whereas Ucn2 and Ucn3 bind selectively to CRF2. • Besides the regulation of the stress responses, CRF and the urocortins have been implicated in nicotine addiction.
218
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
• Ucn2 and Ucn3 ameliorate the anxiety- and the depression-like state developed during chronic nicotine treatment and consequent acute withdrawal. • Therefore, selective CRF2 agonists can be potential candidates in the therapy of nicotine withdrawal.
References Bagosi, Z., Csabafi, K., Palotai, M., Jaszberenyi, M., Foldesi, I., Gardi, J., et al. (2013). The interaction of urocortin II and urocortin III with amygdalar and hypothalamic cotricotropin-releasing factor (CRF)– reflections on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuropeptides, 47(5), 333–338. Bagosi, Z., Csabafi, K., Palotai, M., Jaszberenyi, M., Foldesi, I., Gardi, J., et al. (2014). The effect of urocortin I on the hypothalamic ACTH secretagogues and its impact on the hypothalamic-pituitary-adrenal axis. Neuropeptides, 48(1), 15–20. Bagosi, Z., Palotai, M., Simon, B., Bokor, P., Buzas, A., Balango, B., et al. (2016). Selective CRF2 receptor agonists ameliorate the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice. Brain Research, 1652, 21–29. Bale, T. L., Lee, K. F., & Vale, W. W. (2002). The role of corticotropinreleasing factor receptors in stress and anxiety. Integrative and Comparative Biology, 42(3), 552–555. Bale, T. L., & Vale, W. W. (2004). CRF and CRF receptors: role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology, 44, 525–557. Behan, D. P., Cepoi, D., Fischer, W. H., Park, M., Sutton, S., Lowry, P. J., et al. (1996). Characterization of a sheep brain corticotropin releasing factor binding protein. Brain Research, 709(2), 265–274. Behan, D. P., De Souza, E. B., Potter, E., Sawchenko, P., Lowry, P. J., & Vale, W. W. (1996). Modulatory actions of corticotropin-releasing factor-binding protein. Annals of the New York Academy of Sciences, 780, 81–95. Bruijnzeel, A. W. (2012). Tobacco addiction and the dysregulation of brain stress systems. Neuroscience and Biobehavioral Reviews, 36(5), 1418–1441. Bruijnzeel, A. W., Ford, J., Rogers, J. A., Scheick, S., Ji, Y., Bishnoi, M., et al. (2012). Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats. Pharmacology, Biochemistry, and Behavior, 101(1), 62–68. Bruijnzeel, A. W., & Gold, M. S. (2005). The role of corticotropinreleasing factor-like peptides in cannabis, nicotine, and alcohol dependence. Brain Research. Brain Research Reviews. 49(3), 505–528. Bruijnzeel, A. W., Prado, M., & Isaac, S. (2009). Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse. Biological Psychiatry, 66(2), 110–117. Bruijnzeel, A. W., Zislis, G., Wilson, C., & Gold, M. S. (2007). Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology, 32(4), 955–963. Chang, C. P., Pearse, R. V., II, O’Connell, S., & Rosenfeld, M. G. (1993). Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron, 11(6), 1187–1195. Dautzenberg, F. M., & Hauger, R. L. (2002). The CRF peptide family and their receptors: yet more partners discovered. Trends in Pharmacological Sciences, 23(2), 71–77. Fekete, E. M., & Zorrilla, E. P. (2007). Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Frontiers in Neuroendocrinology, 28(1), 1–27.
George, O., Ghozland, S., Azar, M. R., Cottone, P., Zorrilla, E. P., Parsons, L. H., et al. (2007). CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proceedings of the National Academy of Sciences of the United States of America, 104(43), 17198–17203. Hsu, S. Y., & Hsueh, A. J. (2001). Human stresscopin and stresscopinrelated peptide are selective ligands for the type 2 corticotropinreleasing hormone receptor. Nature Medicine, 7(5), 605–611. Inoue, K., Valdez, G. R., Reyes, T. M., Reinhardt, L. E., Tabarin, A., Rivier, J., et al. (2003). Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat. The Journal of Pharmacology and Experimental Therapeutics, 305(1), 385–393. Jamieson, P. M., Li, C., Kukura, C., Vaughan, J., & Vale, W. (2006). Urocortin 3 modulates the neuroendocrine stress response and is regulated in rat amygdala and hypothalamus by stress and glucocorticoids. Endocrinology, 147(10), 4578–4588. Janssen, D., & Kozicz, T. (2013). Is it really a matter of simple dualism? Corticotropin-releasing factor receptors in body and mental health. Front Endocrinol (Lausanne), 4, 28. Kamdi, S. P., Nakhate, K. T., Dandekar, M. P., Kokare, D. M., & Subhedar, N. K. (2009). Participation of corticotropin-releasing factor type 2 receptors in the acute, chronic and withdrawal actions of nicotine associated with feeding behavior in rats. Appetite, 53(3), 354–362. Kenny, P. J., & Markou, A. (2001). Neurobiology of the nicotine withdrawal syndrome. Pharmacology, Biochemistry, and Behavior, 70(4), 531–549. Lewis, K., Li, C., Perrin, M. H., Blount, A., Kunitake, K., Donaldson, C., et al. (2001). Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proceedings of the National Academy of Sciences of the United States of America, 98(13), 7570–7575. Lovenberg, T. W., Liaw, C. W., Grigoriadis, D. E., Clevenger, W., Chalmers, D. T., De Souza, E. B., et al. (1995). Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 92(3), 836–840. Marcinkiewcz, C. A., Prado, M. M., Isaac, S. K., Marshall, A., Rylkova, D., & Bruijnzeel, A. W. (2009). Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology, 34(7), 1743–1752. Markou, A. (2008). Review. Neurobiology of nicotine dependence. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 363(1507), 3159–3168. Maruyama, H., Makino, S., Noguchi, T., Nishioka, T., & Hashimoto, K. (2007). Central type 2 corticotropin-releasing hormone receptor mediates hypothalamic-pituitary-adrenocortical axis activation in the rat. Neuroendocrinology, 86(1), 1–16. Pelleymounter, M. A., Joppa, M., Ling, N., & Foster, A. C. (2004). Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III. Peptides, 25(4), 659–666. Pellow, S., Chopin, P., File, S. E., & Briley, M. (1985). Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods, 14(3), 149–167. Porsolt, R. D., Bertin, A., & Jalfre, M. (1977). Behavioral despair in mice: a primary screening test for antidepressants. Archives Internationales de Pharmacodynamie et de Therapie, 229(2), 327–336. Purves, H. D., & Sirett, N. E. (1965). Assay of corticotrophin in dexamethasone-treated rats. Endocrinology, 77(2), 366–374. Reul, J. M., & Holsboer, F. (2002). Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Current Opinion in Pharmacology, 2(1), 23–33. Reyes, T. M., Lewis, K., Perrin, M. H., Kunitake, K. S., Vaughan, J., Arias, C. A., et al. (2001). Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is
REFERENCES
selectively bound by type 2 CRF receptors. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2843–2848. Sarnyai, Z., Shaham, Y., & Heinrichs, S. C. (2001). The role of corticotropin-releasing factor in drug addiction. Pharmacological Reviews, 53(2), 209–243. Skelton, K. H., Owens, M. J., & Nemeroff, C. B. (2000). The neurobiology of urocortin. Regulatory Peptides, 93(1–3), 85–92. Spina, M. G., Merlo-Pich, E., Akwa, Y., Balducci, C., Basso, A. M., Zorrilla, E. P., et al. (2002). Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat. Psychopharmacology, 160(2), 113–121. Spina, M., Merlo-Pich, E., Chan, R. K., Basso, A. M., Rivier, J., Vale, W., et al. (1996). Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science, 273(5281), 1561–1564. Suda, T., Kageyama, K., Sakihara, S., & Nigawara, T. (2004). Physiological roles of urocortins, human homologues of fish urotensin I, and their receptors. Peptides, 25(10), 1689–1701. Tanaka, M., & Telegdy, G. (2008). Antidepressant-like effects of the CRF family peptides, urocortin 1, urocortin 2 and urocortin 3 in a modified forced swimming test in mice. Brain Research Bulletin, 75(5), 509–512. Valdez, G. R., Inoue, K., Koob, G. F., Rivier, J., Vale, W., & Zorrilla, E. P. (2002). Human urocortin II: mild locomotor suppressive and
219
delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide. Brain Research, 943(1), 142–150. Valdez, G. R., Zorrilla, E. P., Rivier, J., Vale, W. W., & Koob, G. F. (2003). Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. Brain Research, 980(2), 206–212. Vale, W., Spiess, J., Rivier, C., & Rivier, J. (1981). Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 213(4514), 1394–1397. Van Pett, K., Viau, V., Bittencourt, J. C., Chan, R. K., Li, H. Y., Arias, C., et al. (2000). Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. The Journal of Comparative Neurology, 428(2), 191–212. Vaughan, J., Donaldson, C., Bittencourt, J., Perrin, M. H., Lewis, K., Sutton, S., et al. (1995). Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature, 378(6554), 287–292. Wonnacott, S., Sidhpura, N., & Balfour, D. J. (2005). Nicotine: from molecular mechanisms to behaviour. Current Opinion in Pharmacology, 5(1), 53–59. Zenker, N., & Bernstein, D. E. (1958). The estimation of small amounts of corticosterone in rat plasma. The Journal of Biological Chemistry, 231 (2), 695–701.
27 CRF2 Receptor Agonists and Nicotine Withdrawal Zsolt Bagosi Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary
Abbreviations ACTH AVP CFLP mice CNS CRF CRF1 CRF2 CRF-BP HPA axis icv ip SNS Ucn1 Ucn2 Ucn3
adrenocorticotropic hormone arginine vasopressin Carworth Farm Lane-Petter mice central nervous system corticotropin-releasing factor corticotropin-releasing factor receptor type 1 corticotropin-releasing factor receptor type 2 corticotropin-releasing factor-binding protein hypothalamic-pituitary-adrenal axis intracerebroventricularly intraperitoneally sympathetic nervous system urocortin 1 urocortin 2 urocortin 3
Corticotropin-releasing factor (CRF) and the urocortins are members of the mammalian CRF family of peptides, having similar biochemical structures but different anatomical distributions, physiological functions, and pharmacological profiles (Fekete & Zorrilla, 2007; Suda, Kageyama, Sakihara, & Nigawara, 2004). CRF is a 41-amino acid mammalian neuropeptide that shows 54% similarity with its fish homolog urotensin and 48% with its frog homolog sauvagine (Vale, Spiess, Rivier, & Rivier, 1981). CRF is synthesized in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala from where it regulates the neuroendocrine, autonomic, and behavioral responses to stress (Bale, Lee, & Vale, 2002; Bale & Vale, 2004). The neuroendocrine response is represented by the activation of the hypothalamic-pituitary-adrenal (HPA) axis and mediated by paraventricular CRF that, along with the synergistic arginine vasopressin (AVP), stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary and the subsequent release of
Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00027-7
glucocorticoids from the adrenal cortex (Bale et al., 2002; Bale & Vale, 2004). The autonomic response is represented by the activation of the sympathetic nervous system (SNS) and mediated by amygdalar CRF that stimulates the release of catecholamines from the locus coeruleus that, in turn, stimulates the release of catecholamines from the adrenal medulla (Bale et al., 2002; Bale & Vale, 2004). Thus, CRF acts not only as a hypothalamic neurohormone but also as an extrahypothalamic neurotransmitter that modulates the behavioral responses to stress, manifested by increased locomotor activity, decreased food and water intake, etc. (Bale et al., 2002; Bale & Vale, 2004). Urocortin 1 (Ucn1) is a 40-amino acid neuropeptide that shares 63% similarity with the fish urotensin and 45% with the human CRF, from which the name urocortin was derived (Vaughan et al., 1995). Ucn1 is synthesized predominantly in the Edinger-Westphal nucleus and the lateral superior olive that project caudally to the spinal cord and the lateral septum (Reul & Holsboer, 2002). Despite of the oculomotor, pupillary, and auditory functions attributed to these brain regions, Ucn1 rather modulates the neuroendocrine and behavioral responses to stress, being a less potent activator of locomotion and a more potent suppressor of food and water ingestion, when compared to CRF (Skelton, Owens, & Nemeroff, 2000). The actions of CRF and Ucn1 are mediated by two distinct G-protein-coupled receptors, CRF1 and CRF2 (Chang, Pearse II, O’Connell, & Rosenfeld, 1993; Lovenberg et al., 1995), and inhibited by CRF-binding protein (CRF-BP) (Behan, Cepoi, et al., 1996; Behan, De Souza, et al., 1996). CRF acts preferentially through CRF1, binding with 15-fold higher affinity to CRF1 than to CRF2, whereas Ucn1 acts equipotently through both CRF receptors, binding with sevenfold higher affinity
213
Copyright © 2019 Elsevier Inc. All rights reserved.
214
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
to CRF1 than CRF itself (Reul & Holsboer, 2002). In the central nervous system (CNS), CRF1 is distributed abundantly in the cerebral cortex, the cerebellum, the amygdala, and the anterior pituitary (Dautzenberg & Hauger, 2002; Van Pett et al., 2000). Urocortin 2 (Ucn2), also known as stresscopin-related peptide in humans, is a 38-amino acid neuropeptide that presents 34% identity with CRF (Reyes et al., 2001). Ucn2 expression was shown in the paraventricular, the supraoptic, and the arcuate nuclei of the hypothalamus and the locus coeruleus and brain regions involved in neuroendocrine control, food intake, water intake, and autonomic control, but Ucn2 projections are unknown yet. Ucn2 was demonstrated to have mild locomotor suppressive and delayed anxiolytic-like effects (Valdez et al., 2002). Urocortin 3 (Ucn3), also known as stresscopin in humans, is another 38-amino acid neuropeptide that exhibits 36% identity with CRF (Lewis et al., 2001). Ucn3 expression was found in the perifornical area of the hypothalamus, the medial nucleus of the amygdala, and the bed nucleus of the stria terminalis, which are adjacent or project to the paraventricular nucleus of the hypothalamus and the lateral septum, brain regions involved in stress coping (Reul & Holsboer, 2002). When compared to Ucn2, Ucn3 was demonstrated to have more acute locomotor suppressive and anxiolytic-like effects (Valdez, Zorrilla, Rivier, Vale, & Koob, 2003). The actions of Ucn2 and Ucn3 are mediated exclusively by CRF2, both having more than 1000-fold higher affinity for CRF2 than for CRF1 (Reul & Holsboer, 2002). Therefore, they are considered selective agonists of CRF2 (Hsu & Hsueh, 2001). CRF2 is limited centrally to the subcortical regions of the brain: the lateral septum, the hypothalamus, the amygdala, and the hippocampus (Dautzenberg & Hauger, 2002; Van Pett et al., 2000). Central administration of CRF and Ucn1 induces activation of the HPA axis reflected by the elevation of the plasma corticosterone concentration and anxiety- and depression-like behavior in mice and rats (Bagosi et al., 2014; Spina et al., 1996, 2002; Tanaka & Telegdy, 2008). In contrast, central administration of Ucn2 and Ucn3 produces anxiolytic and antidepressant actions in rodents (Inoue et al., 2003; Tanaka & Telegdy, 2008; Valdez et al., 2002, 2003). It was hereby hypothesized that in physiological conditions, CRF would initiate the responses to stress activating CRF1 in the anterior pituitary, whereas the urocortins would terminate these responses activating CRF2 in the paraventricular nucleus of the hypothalamus (Bale et al., 2002; Bale & Vale, 2004). Overwhelming stress may induce a pathological stimulation of CRF/CRF1 system in the cerebral cortex and the amygdala over the urocortin/CRF2 system in the lateral septum and the hippocampus that may result in hyperactivity of the HPA axis, anxiety, and depression (Bale et al., 2002; Bale & Vale, 2004). However, the physiological role
of urocortin/CRF2 system in the regulation HPA axis is still under debate, since studies in mice and rats led to contradictory results (Bagosi et al., 2013; Jamieson, Li, Kukura, Vaughan, & Vale, 2006; Maruyama, Makino, Noguchi, Nishioka, & Hashimoto, 2007; Pelleymounter, Joppa, Ling, & Foster, 2004). Nevertheless, a recent hypothesis questions such dualistic and complementary actions of CRF1 and CRF2 and suggests that stress would recruit CRF systems in a brain region and neuron population-specific manner as conditions dictate ( Janssen & Kozicz, 2013). Besides the regulation of the stress responses, CRF and the urocortins have been implicated in nicotine addiction (Bruijnzeel & Gold, 2005; Sarnyai, Shaham, & Heinrichs, 2001). Inspired by the original hypothesis according to which CRF1 and CRF2 exert (mainly) antagonistic effects in the CNS, our recent study aimed to investigate whether the activation of CRF2 by central administration of Ucn2 and Ucn3 would attenuate the anxiety- and the depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice (Bagosi et al., 2016). In this purpose, 72 male CFLP mice were exposed to intraperitoneal treatment with nicotine or saline solution for 7 days, 4 times/day, and then to 1 day of withdrawal. A single intracerebroventricular injection with Ucn2, Ucn3, or saline solution was performed at 12 h or at 24 h following the the last intraperitoneal treatment. After 30 min, the mice were evaluated in an elevated plus-maze test (see “Key Facts of the Elevated Plus-Maze Test”) and a forced swim test (see “Key Facts of the Forced Swim Test”) for signs of anxiety and depression, respectively. States of anxiety and depression are usually associated with the hyperactivity of the HPA axis; hence, after 5 min, the plasma corticosterone concentration was also determined by a chemofluorescent assay (see “Key Facts of the Chemofluorescent Assay”). Half of the mice were tested on the 8th day (12 h after the last intraperitoneal treatment) and half of them on the 9th day (24 h after the last intraperitoneal treatment) (Bagosi et al., 2016). On the 8th day, nicotine-treated mice presented signs of anxiolysis and depression and no significant elevation of the plasma corticosterone concentration (Bagosi et al., 2016). Actually, in the elevated plus-maze test, the time spent in the open arms increased significantly after nicotine treatment, and this parameter increased even more after urocortin treatment, but the number of entries into the open arms and the total number of entries did not change considerably in nicotine-treated mice, compared to the saline-treated ones (Fig. 27.1). In parallel, in the forced swim test, the time spent with climbing and swimming decreased remarkably after nicotine treatment, and these parameters decreased even more after urocortin treatment, but the time spent immobile did not change considerably in nicotine-treated mice, compared to the
215
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
30
≠
20 10 0
24 h
12 h
(A)
Percentage (%)
50 40 30
## ≠
20
# # ≠
10 0 12 h
(B) 25 Number
20 15 10 5 0
(C)
12 h
FIG. 27.1 The effects of Ucn2 and Ucn3 in mice exposed to chronic nicotine treatment and acute nicotine withdrawal and investigated in an elevated plus-maze test. (A) Number of entries into the open arms/total number of entries, (B) time spent in the open arms/total time, and (C) total number of entries. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
saline-treated ones (Fig. 27.2). Most of the behavioral changes described after 12 h of nicotine withdrawal were nonsignificant and accompanied with a slight but nonsignificant elevation of the plasma corticosterone concentration that was reduced significantly after urocortin treatment (Fig. 27.3). On the 9th day, nicotine-treated mice exhibited signs of anxiety and depression and a significant increase of the plasma corticosterone concentration (Bagosi et al., 2016). Accordingly, in the elevated plus-maze test, the number of entries into the open arms and the time spent in the open arms decreased significantly, while the total number of entries did not change significantly in nicotine-treated mice, compared to the saline-treated ones; after treating these mice with urocortins, the first two parameters were increased or normalized (Fig. 27.1). In addition, in the forced swim test, the time spent with climbing and swimming decreased
Time (1 unit = 5 s)
40
25 ##
20 15 ≠
10 5 0 12 h
24 h
(A) 25 Time (1 unit = 5 s)
Percentage (%)
# #
20 15
# #
10 5
≠
0
(B)
12 h
50 Time (1 unit = 5 s)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
50
24 h
≠
40
# #
35 20 10 0 12 h
(C)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
FIG. 27.2 The effects of Ucn2 and Ucn3 in mice exposed to chronic nicotine treatment and acute nicotine withdrawal and investigated in a forced swim test. (A) Climbing activity, (B) swimming activity, and (C) immobility. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
Plasma corticosterone concentration Concentration (μg/100mL)
24 h
Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6) Saline ip + Saline icv (6) Saline ip + Ucn2 icv (6) Saline ip + Ucn3 icv (6) Nicotine ip + Saline icv (6) Nicotine ip + Ucn2 icv (6) Nicotine ip + Ucn3 icv (6)
50 40
≠
30 20
## # #
10 0 12 h
FIG. 27.3
24 h
Saline ip + Saline icv (12) Saline ip + Ucn2 icv (12) Saline ip + Ucn3 icv (12) Nicotine ip + Saline icv (12) Nicotine ip + Ucn2 icv (12) Nicotine ip + Ucn3 icv (12)
The effects of Ucn2 and Ucn3 on the plasma corticosterone concentration determined by a chemofluorescent assay in mice exposed to chronic nicotine treatment and acute nicotine withdrawal. Values are presented as means SEM; statistically significant difference was accepted for P < .05 and indicated with 6¼ for nicotine ip + saline icv vs saline ip + saline icv and with # for nicotine ip + Ucn2 or Ucn3 icv vs nicotine ip + saline icv. Abbreviations: icv, intracerebroventricularly; ip, intraperitoneally; Ucn2, urocortin 2; Ucn3, urocortin 3. Adapted from Bagosi et al. (2016), with permission from Elsevier.
216
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
significantly, while the time spent immobile increased significantly in nicotine-treated mice, compared to the saline-treated ones; after treating these mice with urocortins, all these parameters were returned to normal (Fig. 27.2). The behavioral response described after 24 h of nicotine withdrawal was associated with a significant neuroendocrine response, both of which were reversed completely after urocortin treatment (Fig. 27.3). Previous studies have already suggested that CRF and CRF-like peptides contribute to the acute, chronic, and withdrawal actions of nicotine, based on three observations (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). First, acute administration of nicotine evokes a dosedependent activation of the HPA axis that is reflected by the accumulation of salivary cortisol in humans and plasma corticosterone in mice and rats and seems to be initiated by hypothalamic CRF (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). Despite of the rapid desensitization of this effect that may occur even after a single intake and the tolerance that may develop after repeated intake, chronic administration of nicotine often leads to elevation of the glucocorticoid concentration (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). Second, acute nicotine withdrawal provokes a group of symptoms in both humans and rodents that resembles stress responses and seems to be mediated by extrahypothalamic CRF (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). This nicotine withdrawal syndrome is composed of a somatic (physical) and an affective (emotional) component that appear in few hours and disappear in few days or weeks after cessation of chronic administration of nicotine (Kenny & Markou, 2001; Markou, 2008; Wonnacott, Sidhpura, & Balfour, 2005). The somatic symptoms in humans include bradycardia, gastrointestinal discomfort, and increased appetite; in rodents, they correspond to abdominal constrictions, facial fasciculations, eyeblinks, ptosis and gasps, escape attempts, foot licks, genital grooming shakes, scratches, and yawns (Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). The affective symptoms in humans incorporate craving, anxiety, depression, dysphoria, irritability, and difficulty concentrating; in rodents, they correlate with anhedonia (a diminished interest or pleasure to rewarding stimuli) and conditioned place aversion (an aversive motivational state that becomes associated with environmental cues) (Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). Third, exposure to stress during protracted nicotine withdrawal increases the vulnerability to relapse to smoking in humans and nicotine self-administration in rodents (Bruijnzeel & Gold, 2005; Sarnyai et al., 2001). The negative affective state that emerges during acute withdrawal may persist during protracted withdrawal, and its avoidance plays an essential role in this relapse and thereby in the maintenance of nicotine addiction
(Kenny & Markou, 2001; Markou, 2008; Wonnacott et al., 2005). Moreover, recent studies have suggested that the affective and the somatic components of nicotine withdrawal syndrome are mediated by CRF1 and CRF2, respectively (Bruijnzeel, 2012; Bruijnzeel et al., 2012; Bruijnzeel & Gold, 2005; Bruijnzeel, Prado, & Isaac, 2009; Bruijnzeel, Zislis, Wilson, & Gold, 2007; George et al., 2007; Kamdi, Nakhate, Dandekar, Kokare, & Subhedar, 2009; Marcinkiewcz et al., 2009). Several studies reported that the administration of selective CRF1 antagonists prevents the dysphoria and the reward deficit observed during nicotine withdrawal (Bruijnzeel et al., 2012; Marcinkiewcz et al., 2009). Another study referred that the administration of nonselective CRF2 agonists, such as CRF and Ucn1, prevents the hyperphagia and the weight gain assessed during nicotine withdrawal (Kamdi et al., 2009). However, our study was the first to demonstrate that intracerebroventricular administration of Ucn2 and Ucn3 ameliorates the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal, suggesting that the selective CRF2 agonists can be potential candidates in the therapy of nicotine withdrawal (Bagosi et al., 2016). For a better understanding of the physiological and pharmacological actions, future studies should perform the infusion of these peptides in specific brain regions, such as the paraventricular nucleus of the hypothalamus and the lateral septum, where CRF2 is colocalized with Ucn2 neurons and axonal projections of Ucn3 neurons (Reul & Holsboer, 2002; Van Pett et al., 2000).
MINI-DICTIONARY OF TERMS Acute nicotine withdrawal Sudden cessation of nicotine following repeated exposure; in rodents, it can be spontaneous or precipitated by the administration of a nicotinic acetylcholine or an opioid receptor antagonist and may last between 2 and 3 h and 2–3 days following the cessation of nicotine. Anxiety A pathological condition characterized by the presence of excessive worry about a variety of topics, events, or activities; in rodents, it can be investigated in open-field exploration test, elevated plus-maze test, light-dark exploration test, social interaction test, etc. CFLP mice An outbred strain of mice, which are commonly used in genetic, toxicological, and pharmacological research; the term CFLP comes from Carworth Farms and Lane-Petter companies. Chronic nicotine administration Repeated exposure to nicotine; in rodents, it can be performed by water drinking; vapor inhalation; osmotic minipumps; and intravenous, subcutaneous, or intraperitoneal injection that may last from 7 to 270 days. Corticotropin-releasing factor (CRF) Also known as corticotropinreleasing hormone. Not only a hypothalamic neurohormone but also an extrahypothalamic neurotransmitter that mediates the neuroendocrine, autonomic, and behavioral responses to stress. Depression A pathological condition characterized by depressed mood and diminished pleasure or interest in daily activities; in rodents, it can be investigated in forced swim test, tail-suspension test, anhedonia test, conditioned place preference test, etc.
MINI-DICTIONARY OF TERMS
Hypothalamic-pituitary-adrenal (HPA) axis A neuroendocrine system that is represented by the release of CRF from the paraventricular nucleus of the hypothalamus that, along with the synergistic AVP, stimulates the release of ACTH from the anterior pituitary and the subsequent release of glucocorticoids from the adrenal cortex. Urocortins (Ucn1, Ucn2, and Ucn3) CRF-like neuropeptides that have similar amino acid structure but different pharmacological profiles compared to CRF.
Key Facts of the Elevated Plus-Maze Test • The elevated plus-maze test is a method validated by Pellow, Chopin, File, and Briley (1985) to investigate the anxiety-like behavior and the efficacy of anxiolytic drugs in rodents. • The apparatus consists of a plus-shaped wooden platform elevated at 40 cm from the floor, made up by four opposing arms of 30 cm x 5 cm. Two of the opposing arms are enclosed by 15 cm-high side and end walls (closed arms), whereas the other two arms have no walls (open arms). • Each mouse is placed in the central area (5 cm x 5 cm) of the maze, facing one of the open arms, and their behavior is assessed by an observer sitting at 1 m distance from the center of the plus maze. • For 5 min period, the following parameters are recorded: (a) the ratio between the number of entries into the open arms and the total number of entries, (b) the ratio between the time spent in the open arms and the total time, and (c) the total number of entries (an entry into an arm is defined as the entry of all four feet of the animal into that arm). • The principle of the test is that open arms are more fear-provoking, and the ratio of the time spent in open versus closed arms or the ratio of the entries into open versus closed arms reflects the relative safety of closed arms as compared with the relative danger of open arms. The above points list the key facts of the elevated plus-maze test used to evaluate anxiety-like signs in rodents. Key Facts of the Forced Swim Test • The forced swim test is a method invented by Porsolt, Bertin, and Jalfre (1977) to investigate the depressionlike behavior and the antidepressant properties of drugs in rodents. • The apparatus consists of a plexiglass cylinder of 40 cm height and 12 cm diameter containing 1.5 L of water maintained at 25 1°C temperature that is positioned on a table. • Each mouse is dropped individually into the water, and their behavior is assessed by an observer sitting at 1 m distance from the table.
217
• For 5 min period, the following parameters are recorded and expressed in time units (1 time unit ¼ 5 s): (a) the climbing activity (the time that mice spent with climbing the walls, in their attempt to escape the cylinder), (b) the swimming activity (the time that mice spent with swimming in the water, in their attempt to remain at the surface), and (c) the immobility (the time that mice spent in an upright position on the surface with its front paws together). • The principle of the test is that in such a situation, from which they cannot escape, animals rapidly became immobile, floating in an upright position and making only small movements to keep their heads above water. In parallel, their attempt to escape the cylinder by climbing or swimming may decrease or cease eventually. The above points list the key facts of the forced swim test used to investigate depression-like signs in rodents. Key Facts of the Chemofluorescent Assay • The chemofluorescent assay is a method described by Zenker and Bernstein (1958) and modified by Purves and Sirett (1965), used to determine the plasma corticosterone concentration. • The assay is based on the principle that the hydrophobic corticosterone can be extracted from the plasma of rodents with methylene chloride and determined with a fluorescent mixture of sulfuric acid and ethyl alcohol. • The chemical substances used are heparin, distilled water, corticosterone standards, methylene chloride, sulfuric acid, and ethyl alcohol. • The apparatus used is a Hitachi 204-A fluorescent spectrophotometer set at 456 nm extinction and 515 emission wavelengths. • The plasma corticosterone concentration is calculated from the values of the standards and expressed in μg/ 100 mL. The above points list the key facts of the chemofluorescent assay used to determine plasma corticosterone concentration. Summary Points • Corticotropin-releasing factor (CRF) and the urocortins (Ucn1, Ucn2, and Ucn3) belong to the mammalian CRF family of peptides. • CRF and Ucn1 bind to both CRF receptors (CRF1 and CRF2), whereas Ucn2 and Ucn3 bind selectively to CRF2. • Besides the regulation of the stress responses, CRF and the urocortins have been implicated in nicotine addiction.
218
27. CRF2 RECEPTOR AGONISTS AND NICOTINE WITHDRAWAL
• Ucn2 and Ucn3 ameliorate the anxiety- and the depression-like state developed during chronic nicotine treatment and consequent acute withdrawal. • Therefore, selective CRF2 agonists can be potential candidates in the therapy of nicotine withdrawal.
References Bagosi, Z., Csabafi, K., Palotai, M., Jaszberenyi, M., Foldesi, I., Gardi, J., et al. (2013). The interaction of urocortin II and urocortin III with amygdalar and hypothalamic cotricotropin-releasing factor (CRF)– reflections on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuropeptides, 47(5), 333–338. Bagosi, Z., Csabafi, K., Palotai, M., Jaszberenyi, M., Foldesi, I., Gardi, J., et al. (2014). The effect of urocortin I on the hypothalamic ACTH secretagogues and its impact on the hypothalamic-pituitary-adrenal axis. Neuropeptides, 48(1), 15–20. Bagosi, Z., Palotai, M., Simon, B., Bokor, P., Buzas, A., Balango, B., et al. (2016). Selective CRF2 receptor agonists ameliorate the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice. Brain Research, 1652, 21–29. Bale, T. L., Lee, K. F., & Vale, W. W. (2002). The role of corticotropinreleasing factor receptors in stress and anxiety. Integrative and Comparative Biology, 42(3), 552–555. Bale, T. L., & Vale, W. W. (2004). CRF and CRF receptors: role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology, 44, 525–557. Behan, D. P., Cepoi, D., Fischer, W. H., Park, M., Sutton, S., Lowry, P. J., et al. (1996). Characterization of a sheep brain corticotropin releasing factor binding protein. Brain Research, 709(2), 265–274. Behan, D. P., De Souza, E. B., Potter, E., Sawchenko, P., Lowry, P. J., & Vale, W. W. (1996). Modulatory actions of corticotropin-releasing factor-binding protein. Annals of the New York Academy of Sciences, 780, 81–95. Bruijnzeel, A. W. (2012). Tobacco addiction and the dysregulation of brain stress systems. Neuroscience and Biobehavioral Reviews, 36(5), 1418–1441. Bruijnzeel, A. W., Ford, J., Rogers, J. A., Scheick, S., Ji, Y., Bishnoi, M., et al. (2012). Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats. Pharmacology, Biochemistry, and Behavior, 101(1), 62–68. Bruijnzeel, A. W., & Gold, M. S. (2005). The role of corticotropinreleasing factor-like peptides in cannabis, nicotine, and alcohol dependence. Brain Research. Brain Research Reviews. 49(3), 505–528. Bruijnzeel, A. W., Prado, M., & Isaac, S. (2009). Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse. Biological Psychiatry, 66(2), 110–117. Bruijnzeel, A. W., Zislis, G., Wilson, C., & Gold, M. S. (2007). Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology, 32(4), 955–963. Chang, C. P., Pearse, R. V., II, O’Connell, S., & Rosenfeld, M. G. (1993). Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron, 11(6), 1187–1195. Dautzenberg, F. M., & Hauger, R. L. (2002). The CRF peptide family and their receptors: yet more partners discovered. Trends in Pharmacological Sciences, 23(2), 71–77. Fekete, E. M., & Zorrilla, E. P. (2007). Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Frontiers in Neuroendocrinology, 28(1), 1–27.
George, O., Ghozland, S., Azar, M. R., Cottone, P., Zorrilla, E. P., Parsons, L. H., et al. (2007). CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proceedings of the National Academy of Sciences of the United States of America, 104(43), 17198–17203. Hsu, S. Y., & Hsueh, A. J. (2001). Human stresscopin and stresscopinrelated peptide are selective ligands for the type 2 corticotropinreleasing hormone receptor. Nature Medicine, 7(5), 605–611. Inoue, K., Valdez, G. R., Reyes, T. M., Reinhardt, L. E., Tabarin, A., Rivier, J., et al. (2003). Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat. The Journal of Pharmacology and Experimental Therapeutics, 305(1), 385–393. Jamieson, P. M., Li, C., Kukura, C., Vaughan, J., & Vale, W. (2006). Urocortin 3 modulates the neuroendocrine stress response and is regulated in rat amygdala and hypothalamus by stress and glucocorticoids. Endocrinology, 147(10), 4578–4588. Janssen, D., & Kozicz, T. (2013). Is it really a matter of simple dualism? Corticotropin-releasing factor receptors in body and mental health. Front Endocrinol (Lausanne), 4, 28. Kamdi, S. P., Nakhate, K. T., Dandekar, M. P., Kokare, D. M., & Subhedar, N. K. (2009). Participation of corticotropin-releasing factor type 2 receptors in the acute, chronic and withdrawal actions of nicotine associated with feeding behavior in rats. Appetite, 53(3), 354–362. Kenny, P. J., & Markou, A. (2001). Neurobiology of the nicotine withdrawal syndrome. Pharmacology, Biochemistry, and Behavior, 70(4), 531–549. Lewis, K., Li, C., Perrin, M. H., Blount, A., Kunitake, K., Donaldson, C., et al. (2001). Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proceedings of the National Academy of Sciences of the United States of America, 98(13), 7570–7575. Lovenberg, T. W., Liaw, C. W., Grigoriadis, D. E., Clevenger, W., Chalmers, D. T., De Souza, E. B., et al. (1995). Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 92(3), 836–840. Marcinkiewcz, C. A., Prado, M. M., Isaac, S. K., Marshall, A., Rylkova, D., & Bruijnzeel, A. W. (2009). Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology, 34(7), 1743–1752. Markou, A. (2008). Review. Neurobiology of nicotine dependence. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 363(1507), 3159–3168. Maruyama, H., Makino, S., Noguchi, T., Nishioka, T., & Hashimoto, K. (2007). Central type 2 corticotropin-releasing hormone receptor mediates hypothalamic-pituitary-adrenocortical axis activation in the rat. Neuroendocrinology, 86(1), 1–16. Pelleymounter, M. A., Joppa, M., Ling, N., & Foster, A. C. (2004). Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III. Peptides, 25(4), 659–666. Pellow, S., Chopin, P., File, S. E., & Briley, M. (1985). Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods, 14(3), 149–167. Porsolt, R. D., Bertin, A., & Jalfre, M. (1977). Behavioral despair in mice: a primary screening test for antidepressants. Archives Internationales de Pharmacodynamie et de Therapie, 229(2), 327–336. Purves, H. D., & Sirett, N. E. (1965). Assay of corticotrophin in dexamethasone-treated rats. Endocrinology, 77(2), 366–374. Reul, J. M., & Holsboer, F. (2002). Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Current Opinion in Pharmacology, 2(1), 23–33. Reyes, T. M., Lewis, K., Perrin, M. H., Kunitake, K. S., Vaughan, J., Arias, C. A., et al. (2001). Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is
REFERENCES
selectively bound by type 2 CRF receptors. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2843–2848. Sarnyai, Z., Shaham, Y., & Heinrichs, S. C. (2001). The role of corticotropin-releasing factor in drug addiction. Pharmacological Reviews, 53(2), 209–243. Skelton, K. H., Owens, M. J., & Nemeroff, C. B. (2000). The neurobiology of urocortin. Regulatory Peptides, 93(1–3), 85–92. Spina, M. G., Merlo-Pich, E., Akwa, Y., Balducci, C., Basso, A. M., Zorrilla, E. P., et al. (2002). Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat. Psychopharmacology, 160(2), 113–121. Spina, M., Merlo-Pich, E., Chan, R. K., Basso, A. M., Rivier, J., Vale, W., et al. (1996). Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science, 273(5281), 1561–1564. Suda, T., Kageyama, K., Sakihara, S., & Nigawara, T. (2004). Physiological roles of urocortins, human homologues of fish urotensin I, and their receptors. Peptides, 25(10), 1689–1701. Tanaka, M., & Telegdy, G. (2008). Antidepressant-like effects of the CRF family peptides, urocortin 1, urocortin 2 and urocortin 3 in a modified forced swimming test in mice. Brain Research Bulletin, 75(5), 509–512. Valdez, G. R., Inoue, K., Koob, G. F., Rivier, J., Vale, W., & Zorrilla, E. P. (2002). Human urocortin II: mild locomotor suppressive and
219
delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide. Brain Research, 943(1), 142–150. Valdez, G. R., Zorrilla, E. P., Rivier, J., Vale, W. W., & Koob, G. F. (2003). Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. Brain Research, 980(2), 206–212. Vale, W., Spiess, J., Rivier, C., & Rivier, J. (1981). Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 213(4514), 1394–1397. Van Pett, K., Viau, V., Bittencourt, J. C., Chan, R. K., Li, H. Y., Arias, C., et al. (2000). Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. The Journal of Comparative Neurology, 428(2), 191–212. Vaughan, J., Donaldson, C., Bittencourt, J., Perrin, M. H., Lewis, K., Sutton, S., et al. (1995). Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature, 378(6554), 287–292. Wonnacott, S., Sidhpura, N., & Balfour, D. J. (2005). Nicotine: from molecular mechanisms to behaviour. Current Opinion in Pharmacology, 5(1), 53–59. Zenker, N., & Bernstein, D. E. (1958). The estimation of small amounts of corticosterone in rat plasma. The Journal of Biological Chemistry, 231 (2), 695–701.