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Neuropeptides and amphibian prey-catching behavior
Comparative Biochemistry and Physiology Part B 132 (2002) 151–162
Review
Neuropeptides and amphibian prey-catching behavior夞 James A. Carr*, Cary L. Brown, Roshi Mansouri, Srividhya Venkatesan Department of Biological Sciences, Texas Tech University, Box 4-3131, Lubbock, TX 79409, USA Received 27 January 2001; received in revised form 15 May 2001; accepted 24 May 2001
Abstract In mammals, a number of hypothalamic neuropeptides have been implicated in stress-induced feeding disorders. Recent studies in anurans suggest that stress-related neuropeptides may act on elemental aspects of visuomotor control to regulate feeding. Corticotropin-releasing hormone (CRH) and a-melanocyte-stimulating hormone, potent anorexic peptides in mammals, inhibit visually-guided prey-catching in toads. Neuropeptide Y (NPY), an orexic peptide in mammals, may be an important neuromodulator in inhibitory pre-tectal–tectal pathways involved in distinguishing predator and prey. Melanocortin, NPY and CRH neurons project onto key visuomotor structures within the amphibian brain, suggesting physiological roles in the modulation of prey-catching. Thus, neuropeptides involved in feeding behavior in mammals influence the efficacy of a visual stimulus in releasing prey-catching behavior. These neuropeptides may play an important role in how frogs and toads gather and process visual information, particularly during stress. 䊚 2002 Elsevier Science Inc. All rights reserved. Keywords: Amphibian; Melanocortin; Melanocortin receptor; Corticotropin-releasing hormone; Neuropeptide Y; Optic tectum; Thalamus; Feeding; Stress; Anti-predator
1. Introduction Anuran prey-catching behavior has been used extensively to study the neuronal decision making events that underlie the visual identification of a prey-item. When a toad or frog is presented with a moving visual stimulus of the appropriate size and configuration, it responds immediately with a series of quantifiable behaviors that include orienting towards the prey, approaching, and snapping (Ewert, 1980). This behavior is exquisitely sensi夞 This paper was submitted as part of the proceedings of the 20th Conference of European Comparative Endocrinologists, organized under the auspices of the European Society of Comparative Endocrinology, held in Faro, Portugal, 5–9 September 2000. *Corresponding author. Tel.: q1-806-742-2724; Fax: q1806-742-2963. E-mail address: [email protected] (J.A. Carr).
tive to the size and shape of the prey-item. Changing a small rectangular prey-dummy from a horizontal (longitudinal axis parallel to movement directionsworm) to a vertical orientation (longitudinal axis perpendicular to movement directionsanti-worm) releases cryptic posturing (avoidance behavior) in which the animal crouches to the ground and remains motionless (Ewert, 1980). Although the motor commands driving preycatching behavior reside solely within the central nervous system (CNS), the ability of appropriate sensory stimuli to release these behaviors depends upon the homeostatic and endocrine status of the organism. For example, during the breeding season, prey-catching and avoidance behaviors are both suppressed in favor of allowing the animal to approach large objects, such as a potential mate, a visual stimulus that would otherwise release avoid-
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ance behavior (Ewert, 1980). Satiety can also influence the efficacy with visual stimuli release prey-catching behavior. Overfeeding or the infusion of the stomach with glucose reduces all facets (orienting, approaching, and snapping) of preycatching behavior in Bufo bufo (Laming and Cairns, 1998). Toads emerging from a simulated winter hibernation and fed meal worms ad libitum will increase their food intake steadily for 4 weeks after emergence, whereupon they stop eating even if food continues to be made available ad libitum (Guha et al., 1980). These studies suggest that motivation has an important impact on the ability of the visuomotor system to discriminate and respond to otherwise optimal prey configurations. In many animals, exposure to an intensely acute or chronic stressor inhibits feeding behavior through complex mechanisms that almost certainly involve hypothalamic neuropeptides but are otherwise poorly understood. The anuran prey-catching model offers promise for investigating how neuropeptides affect feeding behavior in a relatively simple model. The goal of this review was to summarize existing knowledge of neuropeptides and prey-catching behavior within the context of what is known about stress and feeding behavior in mammals. 2. Experimental analysis of prey-catching behavior There are several features of amphibian preycatching behavior that are amendable to experimental analysis. First, prey-catching behavior can be used to assess the effects of a test substance on the drive to follow a prey-item. This is measured by determining the frequency of prey-oriented behaviors in response to an optimal releasing stimulus. As mentioned previously, prey-catching itself is composed of several independent ballistic movements (orient, approach, snap) that could theoretically be affected in different ways by a test substance. Studies in sated toads indicate that reduced motivation associated with over-feeding reduces all components of prey catching (Laming and Cairns, 1998). Secondly, prey-catching behavior can be used to assess the effects of a test substance on a simple form of learning, habituation. Habituation occurs after repeated exposure of a toad to a moving prey-item and consists of two independently testable components: acquisition and extinction. Dur-
ing acquisition, there is a gradual decline in the number of prey-oriented turning movements if the stimulus is presented continuously over a period of 1–2 h. The recovery phase (extinction) generally requires a stimulus-free period of 4–8 h after testing. Neuroactive peptides known to improve learning and memory in mammals have the same general effect on acquisition and extinction in toads (Horn et al., 1979; Carpenter and Carr, 1996). The neurophysiological and neuroanatomical basis for habituation of prey-catching behavior has been extensively studied (Ewert and Ingle, ¨ 1971; Finkenstadt and Ewert, 1983; Lara and ¨ and Ewert, 1988; Wang Arbib, 1985; Finkenstadt and Arbib, 1991; Wang and Ewert, 1992) providing a template for addressing how and where neuropeptides may act to influence visual learning. Finally, the toad is an excellent model for investigating electrophysiological correlates of sub-cortical visuomotor processing, especially as they apply to behavior in a freely-moving animal. Ewert and others (reviewed in Ewert, 1997) have successfully used a neurophysiological approach to investigate the sensorimotor coding of tectal neurons. Successfully locating and acquiring a prey item requires that different types of tectal neurons (each responding to different aspects of prey size, shape, and movement) converge on medullary premotor systems to encode distinct response features (snap, turn) of prey-catching. More importantly, techniques are now available for studying how these ‘ bug-detector ’ cells respond to changes in feeding activity and motivational state. 3. Hypothalamic neuropeptides and preycatching The role of the hypothalamus in eating disorders has been known for years based on clinical data from patients with hypothalamic lesions (Celesia et al., 1981) as well as lesioning studies in laboratory rodents (Kalra et al., 1999). Intensive research into the hypothalamic mechanisms mediating leptin action (Zhang et al., 1994) have implicated a number of hypothalamic neuropeptides in the physiological control of feeding behavior. Some of these, including neuropeptide Y (NPY), the melanocortins, and the corticotropinreleasing hormone (CRH) family, have effects on feeding behavior that were well-described prior to the discovery of leptin (Vergoni et al., 1986; Negri et al., 1985; Kalra et al., 1991, reviewed in Inui,
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1999). Others, such as cocaine and amphetamineregulated transcript (CART, Kuhar et al., 2000) and the orexinsyhypocretins (de Lecea et al., 1998; Sakurai et al., 1998) have been discovered more recently (see Lin et al., 2000 for a recent review). The realization that some of these same peptides are important neuroendocrine mediators of the stress response has implicated them in stressinduced feeding disorders. 3.1. The melanocortins The melanocortins include peptides related to corticotropin (ACTH) and a-melanocyte-stimulating hormone (aMSH) that are derived through post-translational processing of pro-opiomelanocortin (POMC). Five melanocortin receptors have been cloned in mammals (see Wikberg et al., 2000, for a recent review). Melanocortin (MC) MC-2 receptors preferentially bind ACTH and are found primarily on adrenal steroidogenic cells (Xia and Wikberg, 1996). The MC-1, MC-3, and MC4 receptors preferentially bind MSH peptides but have different tissue distributions. MC-1 receptors are located principally on melanocytes and mediate the effects of aMSH on melanin synthesis and dispersion. MC-3 and MC-4 receptors both are found within the CNS, although regional patterns of expression are quite different for the two receptor types; MC-3 expression is restricted to the hypothalamus and limbic system (Roselli-Rehfuss et al., 1993) whereas MC-4 is ubiquitously expressed through the brain and spinal cord (Mountjoy et al., 1994). MC-3 receptor expression has also been reported in the placenta, GI tract, and heart. MC-5 receptors are widely expressed in peripheral tissues including adrenal glands, adipose tissue, and exocrine glands (Wikberg et al., 2000). Although it has been known since the 1950s that melanocortins affect learning and memory, it wasn’t until the 1980s that Vergoni et al. (1986) showed an inhibitory effect of ACTH on food intake. The recent discovery that the targeted disruption of the MC-4 receptor causes a form of adult-onset obesity (Huszar et al., 1997) launched a flurry of work into the satiety effects of these peptides. It is now known that neuronal melanocortins play a key role in regulating energy metabolism and feeding behavior in mammals (see Hagan et al., 1999; Inui, 1999; Benoit et al., 2000; Vergoni et al., 2000 for recent reviews). The inhibitory effects of melanocortins on feeding may
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be particularly important during stress. Administration of a selective MC-4 receptor antagonist partially blocks stress-induced reductions in feeding behavior in rats (Vergoni et al., 1999). The first study to demonstrate an effect of melanocortin peptides on toad prey-catching behavior was by Horn et al. (1979), showing that dorsal lymph sac (DLS) administration of ACTH enhanced the acquisition and delayed the extinction of habituation. Subsequent work demonstrated that the inhibitory effects of ACTH are contained within the heptapeptide core sequence of the peptide (Horn and Horn, 1982). While ACTH, aMSH, and ACTH w4–10x were all effective in facilitating acquisition, (Nle4, D-Phe7)a-MSH (NDP-MSH) and des-acetyl a-MSH were not (Carpenter and Carr, 1996). We (Olsen et al., 1999) have more recently shown that aMSH facilitates habituation in a dose-dependent manner with corresponding dose-dependent elevations in plasma aMSH (Olsen et al., 1999). The effects of aMSH are not mediated by adrenal corticosteroids, but are probably mediated centrally, as radiolabeled aMSH can be detected in the third ventricle by microdialysis within minutes after injection (Olsen et al., 1999). The receptor mediating the effects of aMSH on prey-catching behavior has not been identified. In rats, the feeding effects of the melanocortins are mediated by the MC-4 receptor. It would be surprising if the MC-4 receptor is involved in toad prey-catching behavior, however, as NDP-MSH, the most selective ligand for the mammalian MC¨ et al., 1996), has no effect on 4 receptor (Schioth prey-oriented turning (Carpenter and Carr, 1996). The possibility exists that an as-yet unidentified melanocortin receptor mediates these effects and possibly other learning effects of the melanocortins in mammals. For example, our present knowledge of the ligand selectivity for the MC-4 and MC-3 ¨ et al., 1996) does not accomreceptors (Schioth modate the fact that the melanocortin heptapeptide core sequence is as effective as ACTH in certain learning paradigms (see De Wied and Jolles, 1982). Furthermore, substituting L-Phe with its Denantiomer improves aMSH binding to MC-3 and MC-4 receptors, but results in behavioral effects opposite to those observed with the native peptides (De Wied and Jolles, 1982; Kobobun et al., 1983). Although it was initially speculated that D-Phe substitute analogs might antagonize binding to melanocortin receptors, it is clear that NDP-MSH as well as NDP-MSH fragments containing the D-
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Phe7 substitution are agonists at both the MC-1 (melanocyte) and MC-4 receptors (Haskell-Luevano et al., 1997). While virtually all studies suggest that melanocortins reduce food intake, b-endorphin (bE), another peptide cleaved from POMC, seems to have just the opposite effect. Intra-cerebroventricular administration of bE increases food intake in fish (de Pedro et al., 1995), birds (Deviche and Schepers, 1984), and mammals (McKay et al., 1981), and may play a physiological role in stressinduced over-eating (see below) as naloxone reverses stress-induced over-eating in rats (Morley et al., 1983). The effects of bE on prey-catching have not yet been investigated. 3.2. CRH-related peptides CRH has potent inhibitory effects on feeding, as does urocortin, a CRH-related neuropeptide (Spina et al., 1996). A physiological role for CRH is suggested by the fact that a-helical CRH, a selective receptor antagonist, can partially reduce restraint stress-induced reductions in feeding while immunoneutralization of endogenous CRH completely reverses stress-induced anorexia (Shibasaki et al., 1988). In humans, anorexia nervosa is associated with increased levels of CRH in CSF and increased blood cortisol levels (Gold et al., 1986; Hotta et al., 1986). Fig. 1 shows the effect of ovine CRH on preycatching behavior. A single dose of CRH (10 mg) reduced the mean number of prey-oriented turning movements when administered 30 min prior to testing. In these studies, we noticed that all of the CRH-treated animals exhibited maximal pupil dilation, a response known to be mediated by badrenergic receptors in toads (Morris, 1976). To determine if the effects of CRH on prey-catching were mediated by b-adrenergic stimulation, toads were injected DLS with isoproterenol (10 mg) or 0.6% NaCl. Isoproterenol had no effect on preycatching (Fig. 1), suggesting the effects of CRH were not secondary to activation of b-adrenergic receptors. It is also unlikely that the effects of CRH are mediated by adrenal corticosteroids, as the administration of corticosterone (10 mg), at a dose that elevates blood plasma corticosterone to levels (Carpenter and Carr, 1996) observed during stress (Olsen et al., 1999), has no effect on preycatching behavior (Fig. 1).
3.3. NPY In mammals, NPY is a potent stimulator of feeding behavior (Inui, 1999). Electrophysiological evidence in toads suggests that NPY may convey inhibitory signals from the pre-tectum to the tectum. NPY applied directly to the surface of the optic tectum inhibits tectal excitation elicited by stimulation of the optic nerve (Schwippert and Ewert, 1995). These effects are presumably mediated by Y2 receptors, as NPY and NPY 13–36 but not NPY 18–36 inhibit retino-tectal transfer in Bufo marinus (Schwippert et al., 1998). The effects of NPY mimic the pattern of tectal inhibition that occurs after electrical stimulation of the pre-tectum (Schwippert and Ewert, 1995). The effects of NPY on prey-catching behavior are not known. 4. Anatomical considerations 4.1. Prey-catching circuitry The neuroanatomical basis of prey-catching behavior has been the subject of recent reviews (Ewert, 1997; Ewert et al., 1999). Anatomical, electrophysiological and behavioralylesion studies support a retinal–tectumypre-tectum–medullary– spinal cord pathway for responding to prey. At least seven types of tectal neurons that respond to various aspects of prey-configuration and project to medullary motor control areas have been identified (Ewert, 1997). Inhibitory pre-tectal–tectal pathways prevent the spread of electrical excitation in the tectum, in effect sharpening tectal motor output. The ventral telencephalon (striatum) appears to indirectly modulate tectal bug-detector cells by tonically inhibiting the pre-tectum through fibers carried in the lateral forebrain bundle (Ewert et al., 1999). In the intact animal, this allows a cautious approach to the prey-item (Ewert, 1997). Lesioning studies also support a role for the nucleus of the medial longitudinal fasciculus (nMLF) in relaying tectal output to the medulla (Kostyk and Grobstein, 1987; Masino and Grobstein, 1989). The wealth of data on the anatomy of the toad visual system provides a strong foundation for addressing the question of how and where hypothalamic neuropeptidergic systems may influence sub-cortical visuomotor processing.
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Fig. 1. Influence of ovine CRH (A), isoproterenol (B), and corticosterone (C) on prey-catching behavior in the Texas Toad, Bufo speciosus. Toads were injected via the dorsal lymph sac with 10 mgy200 ml of the test substance or vehicle solution 30 min prior to testing. Prey-catching behavior was tested as previous described (Carpenter and Carr, 1996). (A) The effects of a single injection of oCRH on the percentage of animals responding to a prey-item ()5 turnsy5 min) and the total number of prey-oriented turns in the first 5 min of testing. oCRH significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (two-tailed t-test, P-0.05). (B) The effects of a single injection of isoproterenol on the percentage of animals responding to a prey-item and the total number of prey-oriented turning reactions in the first 5 min of testing. Isoproterenol had no effect on either parameter (P)0.05). (C) The effects of a single injection of corticosterone on the percentage of animals responding to a prey-item and the total number of prey-oriented turning reactions in the first 5 min of testing. Corticosterone was dissolved in absolute ethanol and diluted 1:100 in 0.6% NaCl. Vehicle injected toads received the same percentage of ethanol dissolved in 0.6% NaCl. Corticosterone had no effect on either parameter (P)0.05).
4.2. Melanocortins In mammals, aMSH and other peptides derived from POMC are produced by hypothalamic neurons in the arcuate nucleus (Jacobowitz and O’Donohue, 1978; O’Donohue et al., 1979; O’Donohue and Jacobowitz, 1980; Joseph et al., 1985). Comparative neuroanatomical studies suggest the location of these hypothalamic cells is evolutionarily conserved, as all amphibian species studied so far possess an infundibular POMC cell group (Hayes and Loh, 1990; D’Aniello et al., 1994; Kim and Carr, 1997; Tuinhof et al., 1998; Venkatesan and Carr, 2001). In addition, several amphibian species possess an additional POMC cell group in the pre-
optic hypothalamus (Doerr-Schott et al., 1981; Yui, 1983; Benyamina et al., 1986; Vallarino, 1987; Hayes and Loh, 1990; D’Aniello et al., 1994; Tuinhof et al., 1998; Venkatesan and Carr, 2001). Although POMC neurons send isolated fibers to the pre-tectum and tectum (Kim and Carr, 1997), the most striking projection is to the ventral telencephalon, specifically the amphibian homolog of the basal ganglia (nucleus accumbens and striatum) (Benyamina et al., 1986; Kim and Carr, 1997; Tuinhof et al., 1998). The basal ganglia regulate tectal function via both direct and indirect pathways (Marin et al., 1997; Marin et al. 1998). By innervating the basal ganglia, neuronal melanocortins may gain access to multiple modes of
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tectal regulation and thereby influence prey-catching behavior. 4.3. CRH-related peptides CRH belongs to a family of peptides that includes sauvagine, urotensin I and urocortin (Lovejoy and Balment, 1999). Consistent with its action as a hypophysiotropic peptide, CRH-immunoreactivity (ir) is found in hypothalamic neurons, predominately in the anterior pre-optic area and magnocellular nucleus (reviewed in Andersen et al., 1992). CRH- and sauvagine-ir also have been observed in the optic tectum of frogs (Bhargava and Rao, 1993; Gonzalez et al., 1996). Interestingly, CRH- and sauvagine-ir neurons have been identified in the nMLF in the mesencephalic tegmentum. Neurons in the nMLF have been shown to drive spinal motor and interneurons in fish (Bosch et al., 1995; Uematsu and Todo, 1997) and may participate in mediating tecto-spinal information flow during prey-orienting behaviors (Kostyk and Grobstein, 1987). NMLF lesions that spare descending tectospinal tracts produce ipsilateral turning deficits toward a prey-stimulus in frogs (Masino and Grobstein, 1989). Whether CRH- or sauvagine neurons in the nMLF of anurans project to spinal motor neurons remains to be seen, but deserves consideration given the well-documented effects of CRH on locomotor activity in amphibians (Moore et al., 1984; Lowry et al., 1990) and mammals (Dunn and Berridge, 1990). In newts, CRH alters the discharge patterns of medullary neurons involved in locomotor behaviors (Lowry et al., 1996). 4.4. NPY NPY is the most abundant and widely expressed neuropeptide in the mammalian brain (White, 1993). NPY neurons are also widely distributed in a number of hypothalamic and extra-hypothalamic sites in anurans. Hypothalamic NPY neurons are found in the suprachiasmatic nucleus and infundibulum (Andersen et al., 1992). Extra-hypothalamic NPY neurons have been observed in the pallium, pre-tectal thalamus, the optic tectum, torus semicircularis, and mid-brain tegmentum (Danger et al., 1985; Andersen et al., 1992). Of significance is the intense NPY-ir innervation of the retinorecipient layer of the tectum. Lesioning studies indicate that these fibers arise from NPY-immu-
noreactive cells in the pre-tectum (Kozicz and Lazar, 1994). Electrophysiological studies indicate that NPY cells may contribute to pre-tectal inhibition of the tectum, both in anurans (Schwippert and Ewert, 1995) and urodeles (Luksch and Roth, 1996). NPY innervation of the pre-tectum and tectum is also seen in birds (Britto et al., 1989; Boswell et al., 1998) and mammals (Chronwall et al., 1985; Botchkina and Morin 1995; Morin and Blanchard, 1997; Borostyankoi et al., 1999), suggesting that this peptide may have an evolutionarily conserved role in modulating sub-cortical visuomotor processing. 5. Stress and prey-catching behavior Stress affects feeding behavior in all vertebrates in a manner that depends upon both the duration and intensity of the stressor. Generally, exposure to a severe acute or a chronic stressor reduces feeding behavior, ultimately leading to reduced body weight, a condition called stress-induced anorexia. For example, exposure to painful (strong tail pinching) or psychological stressors (repeated immobilization, novel environment) both lead to severe anorexia, even mimicking, in some cases, pain-induced anorexia (Holland et al., 1977) and anorexia nervosa (Donohoe, 1984), respectively, in humans. In contrast, exposure to a mild stressor, such as mild tail-pinch in rats, can actually enhance feeding behavior and cause animals to overeat (Rowland and Antelman, 1976). Stress-induced over eating has also been well-described in humans (Troop and Treasure, 1997). Potentially threatening visual stimuli reduce prey-catching behavior. Toads will ignore an otherwise effective prey-stimulus if simultaneously presented with a visual stimulus that resembles a predator (Ewert, 1980, 1997). Recent work in our laboratory has revealed that acute exposure to unrelated noxious or stressful agents also reduces prey-catching behavior. Acute exposure to ether vapors, which activates the hypothalamo–hypophysial–adrenal axis in toads (Olsen et al., 1999), leads to a dramatic reduction in the percentage of animals responding to a prey-item when tested 1 h after the ether exposure. This stressor also significantly reduced the total number of preyoriented turns observed in the first 5 min of testing (Fig. 2a). To rule out the possibility that the effects of ether were due to a sedative effect, we also examined prey-catching behavior after exposure to
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Fig. 2. Influence of ether exposure (a) and crowding (b) on prey-catching behavior in the Texas Toad, Bufo speciosus. Prey-catching behavior was tested as previous described (Carpenter and Carr, 1996). (a) The effects of a 2-min exposure to ether vapors (Olsen et al., 1999) on the percentage of animals responding to a prey-item ()5 turnsy5 min) and the total number of prey-oriented turns in the first 5 min of testing. Toads were tested after a 1-h recovery from the ether exposure. Exposure to ether vapors significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (two-tailed t-test, P-0.05). (b) The effects of crowding on the percentage of animals responding and the total number of prey-oriented turns in the first 5 min of testing. Test animals were individually identified by placing a loose-fitting colored elastic band around the right leg and then were placed in a white plastic cage (20.5=23.5=45 cm) containing 10 other randomly selected toads. Test animals were removed after 60 min and prey-catching behavior tested immediately. Crowding significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (twotailed t-test, P-0.05).
an unrelated stressor, crowding. As shown in Fig. 2b, exposure to a 60-min crowding stress significantly reduced the percentage of animals responding to a moving prey-item and significantly reduced the number of prey-oriented turns per min. 6. Hypothalamic neuropeptides and stress In rats, stress alters hypothalamic POMC synthesis (Hollt et al., 1986; Baubet et al., 1994; Larsen and Mau, 1994) and brain content of the POMC peptides aMSH (Khorram et al., 1985) and bE (Rossier et al., 1977; Millan et al., 1981). We have examined the effects of various stressors on neuronal POMC systems in Bufo (Kim and
Carr, 1997; Olsen et al., 1999). We initially observed that although brain and plasma aMSH are not altered as a result of habituation, confinement within the prey-catching test arena causes a decrease in the aMSH content of the telencephalon, suggesting enhanced secretion of the peptide by ascending POMC neurons (Kim and Carr, 1997). Exposure to an acute stressor (5 min ether vapors), sufficient to elevate plasma corticosterone levels, also causes a decrease in telencephalic aMSH content (Olsen et al., 1999). Whether alterations in release of aMSH contribute to stressinduced inhibition of prey-catching (see above) remains to be tested. In mammals, exposure to an acute stressor alters the synthesis and release of
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CRH (Koob, 1999) and NPY (Conrad and McEwen, 2000) within the brain. Changes in CRH and NPY content during stress in toads have not been investigated. 7. Satiety or anti-predator peptides? The need to eat is a powerful motivating drive in all animals. In the laboratory, the amount of food recently ingested is, arguably, the major determinant in feeding. In nature, however, toads must assess the trade-off between predation risk and feeding behavior. Predation risk can have a significant impact on foraging and feeding strategies, especially in juvenile toads, as they often feed during the day to maximize growth rate (Lillywhite et al., 1973). Toads have few natural predators because of the toxic material contained within the paratoid glands. Snakes (particularly garter snakes, Thamnophis sp., and hognose snakes, Heterodon platyrhinos and H. nasicus) are the major predators of toads in North America. Elegant behavioral ecology studies have shown that garter snakes use visual cues when hunting toads (Heinen, 1995). It is not surprising then that, when encountered with a snake, toads assume a cryptic posture, crouching close to the ground and remaining still (Heinen, 1994a). This is just one component of cryptic anti-predator behavior. Toads also will choose substrates that are physically complex (Heinen, 1993) and can background adapt (Heinen, 1994b), thereby reducing the likelihood that they will be captured by garter snakes (Heinen, 1993, 1994b). An interesting feature of this anti-predator behavior is that the releasing features are not species specific — toads will perform the same behavior in response to non-predatory snakes (Heinen, 1994a). The cryptic posturing (reducing movement, crouching) observed in the presence of a snake is identical to the behavior elicited by electrical stimulation of the pre-tectum or presentation of an anti-worm stimulus (Ewert, 1980). Considering the strong selection pressure to reduce unnecessary movement in the presence of a predator, the adaptive significance of being able to override prey-catching behavior (tectum-driven) in favor of cryptic behavior (pre-tectum-driven) becomes apparent. What is fascinating about the toad’s visual system is that exposure of a naive toads to seemingly unrelated noxious stimuli such as crowding or ether vapors also inhibits prey-catch-
ing behavior. Thus, when faced with a novel, but potentially threatening stimulus, toads reduce preyoriented movement just as they would when presented with a predator. Moreover, neuropeptides known to be involved in stress-induced inhibition of feeding in mammals also inhibit prey-catching behavior. By facilitating habituation to non-relevant visual stimuli, melanocortins reduce unnecessary movement and may make the animal less conspicuous to a potential predator, as suggested by behavioral ecology studies (Heinen, 1994a, 1995). This is not an unfamiliar role for melanocortins, as these peptides were originally discovered as pituitary intermediate lobe factors that cause skin darkening and background adaptation in frogs. Skin darkening is another form of crypsis that presumably aids in predator avoidance when the animal is on a dark background. Interestingly, toads prefer dark vs. light substrates and move less frequently on a dark background, presumably making them less conspicuous to a potential predator (Heinen, 1994b). It is intriguing to speculate that melanocortins have a primitive role as antipredator peptides. 8. Concluding remarks Making the right behavioral decision at the right time can be a life or death situation, especially when an animal is in a confrontational situation. Visual circuitry in toads has evolved to ensure that prey-catching behavior is inhibited in favor of cryptic behavior when a predator is detected. Ecological studies show that avoidance and escape behaviors reduce the risk of predation. A similar reduction in prey-catching behavior occurs when toads are exposed to non-specific stressors. Two families of hypothalamic neuropeptides, CRH and the melanocortins, rapidly affect prey-catching behavior, but in different ways. CRH affects the drive to follow a moving prey-item while the melanocortins affect habituation. Whether these peptides contribute to stress-induced inhibition of prey-catching is not clear, but can be tested in future studies with the use of selective receptor antagonists. More importantly, future studies should address whether stress andyor CRH actually reduce feeding motivation or promote the emergence of other behaviors (escape, avoidance) that override prey-catching behavior.
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Acknowledgments The work described in this review was supported by grants from the Texas Tech University (TTU) Department of Biological Sciences, TTU Research Enhancement Fund, the Howard Hughes Medical Institute through the Undergraduate Biological Sciences Education Program to TTU (C. Brown) and the Clark’s Scholar’s program (R. Mansouri). References Andersen, A.C., Tonon, M.C., Pelletier, G., Conlon, J.M., Fasolo, A., Vaudry, H., 1992. Neuropeptides in the amphibian brain. Int. Rev. Cytol. 138, 89–210. ` Baubet, V., Fevre-Montange, M., Gay, N., Debilly, G., Bobillier, P., Cespuglio, R., 1994. Effects of an acute immobilization stress upon proopiomelanocortin (POMC) mRNA levels in the mediobasal hypothalamus: a quantitative in situ hybridization study. Brain Res. Mol. Brain Res. 26, 163–168. Benoit, S., Schwartz, M., Baskin, D., Woods, S.C., Seeley, R.J., 2000. CNS melanocortin system involvement in the regulation of food intake. Horm. Behav. 37, 299–305. ´ Benyamina, M., Delbende, C., Jegou, S., et al., 1986. Localization and identification of a-melanocyte-stimulating hormone (a-MSH) in the frog brain. Brain Res. 366, 230–237. Bhargava, S., Rao, P.D., 1993. Distribution of corticotropinreleasing factor immunoreactive neurons in the brain of the tiger frog, Rana tigrina. Neurosci. Lett. 154, 27–30. Boswell, T., Millam, J.R., Li, Q., Dunn, I.C., 1998. Cellular localization of neuropeptide Y mRNA and peptide in the brain of the Japanese quail and domestic chicken. Cell Tissue Res. 293, 31–38. Borostyankoi, Z.A., Gorcs, T.J., Hamori, J., 1999. Immunocytochemical mapping of NPY and VIP neuronal elements in the cat subcortical visual nuclei, with special reference to the pretectum and accessory optic system. Anat. Embryol. 200, 495–508. Bosch, T.J., Maslam, S., Roberts, B.L., 1995. A polyclonal antibody against mammalian FOS can be used as a cytoplasmic neuronal activity marker in a teleost fish. J. Neurosci. Methods 58, 173–179. Botchkina, G.I., Morin, L.P., 1995. Organization of permanent and transient neuropeptide Y-immunoreactive neuron groups and fiber systems in the developing hamster diencephalon. J. Comp. Neurol. 357, 573–602. Britto, L.R., Hamassaki, D.E., Keyser, K.T., Karten, H.J., 1989. Neurotransmitters, receptors, and neuropeptides in the accessory optic system: an immunohistochemical survey in the pigeon (Columba livia). Vis. Neurosci. 3, 463–475. Carpenter, A.M., Carr, J.A., 1996. The effects of melanocortin peptides and corticosterone on habituation in the great plains toad, Bufo cognatus. Horm. Behav. 30, 236–243. Celesia, G.G., Archer, C.R., Chung, H.D., 1981. Hyperphagia and obesity. Relationship to medial hypothalamic lesions. J. Am. Med. Assoc. 246, 151–153. Chronwall, B.M., DiMaggio, D.A., Massari, V.J., Pickel, V.M., Ruggiero, D.A., O’Donohue, T.L., 1985. The anatomy of
159
neuropeptide-Y-containing neurons in rat brain. Neuroscience 15, 1159–1181. Conrad, C.D., McEwen, B.S., 2000. Acute stress increases neuropeptide Y mRNA within the arcuate nucleus and hilus of the dentate gyrus. Brain Res. Mol. Brain Res. 79, 102–109. D’Aniello, B., Imperatore, C., Fiorentino, M., Vallarino, M., Rastogi, R.K., 1994. Immunocytochemical localization of POMC-derived peptides (adrenocorticotropic hormone, amelanocyte-stimulating hormone and b-endorphin) in the pituitary, brain and olfactory epithelium of the frog, Rana esculenta, during development. Cell Tissue Res. 278, 509–516. Danger, J.M., Guy, J., Benyamina, M., et al., 1985. Localization and identification of neuropeptide Y (NPY)-like immunoreactivity in the frog brain. Peptides 6, 1225–1236. de Lecea, L., Kilduff, T.S., Peyron, C., et al., 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327. de Pedro, N., Delgado, M.J., Alonso-Bedate, M., 1995. Central administration of beta-endorphin increases food intake in goldfish: pretreatment with the opioid antagonist naloxone. Regul. Pept. 55, 189–195. Deviche, P., Schepers, G., 1984. Intracerebroventricular injection of ostrich beta-endorphin to satiated pigeons induces hyperphagia but not hyperdipsia. Peptides 5, 691–694. De Wied, D., Jolles, J., 1982. Neuropeptides derived from proopiocortin: behavioral, physiological, and neurochemical effects. Physiol. Rev. 62, 976–1059. Doerr-Schott, J., Dubois, M.P., Lichte, C., 1981. Immunohistochemical localisation of substances reactive to antisera against a- and b-endorphin and met-enkephalin in the brain of Rana temporaria L. Cell Tissue Res. 217, 79–92. Donohoe, T.P., 1984. Stress-induced anorexia: implications for anorexia nervosa. Life Sci. 34, 203–218. Dunn, A.J., Berridge, C.W., 1990. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Brain Res. Rev. 15, 71–100. Ewert, J.P., 1980. Neuroethology. Springer-Verlag, New York. Ewert, J.P., 1997. Neural correlates of key stimulus and releasing mechanism: a case study and two concepts. Trends Neurosci. 20, 332–339. Ewert, J.P., Ingle, D., 1971. Excitatory effects following habituation of prey-catching activity in frogs and toads. J. Comp. Physiol. Psychol. 77, 369–374. Ewert, J.P., Buxbaum-Conradi, H., Glagow, M., Rottgen, A., Schurg-Pfeiffer, E., Schwippert, W.W., 1999. Forebrain and midbrain structures involved in prey-catching behaviour of toads: stimulus-response mediating circuits and their modulating loops. Eur. J. Morphol. 37, 172–176. ¨ T., Ewert, J.P., 1983. Visual pattern discrimination Finkenstadt, through interactions of neural networks: a combined electrical brain stimulation, brain lesion, and extracellular recording study in Salamandra salamandra. J. Comp. Physiol. wAx 153, 99–110. ¨ T., Ewert, J.P., 1988. Stimulus-specific long-term Finkenstadt, habituation of visually guided orienting behavior toward prey in toads: a 14C–2DG study. J. Comp. Physiol. wAx 163, 1–11.
160
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162
Gold, P.W., Gwirtsman, H., Avgerinos, P.C., et al., 1986. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. N. Engl. J. Med. 314, 1335–1342. Gonzalez, G.C., Bountzioukas, S., Gonzalez, E.S., et al., 1996. Hypothalamic and extrahypothalamic sauvagine-like immunoreactivity in the bullfrog (Rana catesbeiana) central nervous system. J. Comp. Neurol. 365, 256–267. Guha, K., Jorgensen, C.B., Larsen, L.O., 1980. Relationship between nutritional state and testes function, together with observations on patterns of feeding, in the toad, Bufo bufo. J. Zool. Lond. 192, 147–155. Hagan, M.M., Rushing, P.A., Schwartz, M.W., et al., 1999. Role of the CNS melanocortin system in the response to overfeeding. J. Neurosci. 19, 2362–2367. Haskell-Luevano, C., Hendrata, S., North, C., et al., 1997. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. Med. Chem. 40, 2133–2139. Hayes, W.P., Loh, Y.P., 1990. Correlated onset and patterning of proopiomelanocortin gene expression in embryonic Xenopus brain and pituitary. Development 110, 747–757. Heinen, J.T., 1993. Substrate choice and predation risk in newly-metamorphosed American toads, Bufo americanus: an experimental analysis. Am. Midl. Natur. 130, 184–192. Heinen, J.T., 1994a. Antipredator behavior of newly metamorphosed American toads (Bufo a. americanus), and mechanisms of hunting by Eastern garter snakes (Thamnophis s. sirtalis). Herpetologica 50, 137–145. Heinen, J.T., 1994b. The significance of color change in newly metamorphosed American toads (Bufo a. americanus). J. Herp. 28, 87–93. Heinen, J.T., 1995. Predator cues and prey-responses: a test using Eastern garter snakes (Thamnophis s. sirtalis) and American toads (Bufo a. americanus). Copeia 1995, 738–741. Holland, J.C., Rowland, J., Plumb, M., 1977. Psychological aspects of anorexia in cancer patients. Cancer Res. 37, 2425–2428. Horn, E., Greiner, B., Horn, I., 1979. The effect of ACTH on habituation of the turning reaction in the toad Bufo bufo L. J. Comp. Physiol. 131, 129–135. Horn, I., Horn, E., 1982. The influence of ACTH fragments on habituation of the prey catching behaviour in the European toad (Bufo bufo L.). Physiol. Behav. 28, 497–500. Hotta, M., Shibasaki, T., Masuda, A., et al., 1986. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. J. Clin. Endocrinol. Metab. 62, 319–324. Hollt, V., Przewlocki, R., Haarman, I., et al., 1986. Stress induced alterations in the levels of mRNA coding for POMC and prolactin in rat pituitary. Neuroendocrinology 43, 277–282. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., et al., 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141. Inui, A., 1999. Feeding and body-weight regulation by hypothalamic neuropeptides-mediation of the actions of leptin. Trends Neurosci. 22, 62–67.
Jacobowitz, D.M., O’Donohue, T.L., 1978. Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc. Natl. Acad. Sci. 75, 6300–6304. Joseph, S.A., Pilcher, W.H., Knigge, K.M., 1985. Anatomy of the corticotropin-releasing factor and opiomelanocortin systems of the brain. Fed. Proc. 44, 100–107. Kalra, S.P., Dube, M.G., Sahu, A., Phelps, C.P., Kalra, P.S., 1991. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. USA 88, 10931–10935. Kalra, S.P., Dube, M.G., Pu, S., Xu, B., Horvath, T.L., Kalra, P.S., 1999. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20, 68–100. Khorram, O., Bedran de Castro, J.C., McCann, S.M., 1985. Stress-induced secretion of alpha-melanocyte-stimulating hormone and its physiological role in modulating the secretion of prolactin and luteinizing hormone in the female rat. Endocrinology 117, 2483–2489. Kim, Y., Carr, J.A., 1997. Alterations in brain and plasma concentrations of alpha-melanocyte-stimulating hormone during habituation of prey catching behavior in toads. Brain Behav. Evol. 49, 149–161. Kobobun, K., O’Donohue, T.L., Handelmann, G.E., Sawyer, T.K., Hruby, V.J., Hadley, M.E., 1983. Behavioral effects of w4-norleucine, 7-D-phenylalaninex-a-melanocyte-stimulating hormone. Peptides 4, 721–724. Koob, G.F., 1999. Corticotropin-releasing factor, norepinephrine, and stress. Biol. Psychiatry 46, 1167–1180. Kozicz, T., Lazar, G., 1994. The origin of tectal NPY immunopositive fibers in the frog. Brain Res. 635, 345–348. Kostyk, S.K., Grobstein, P., 1987. Neuronal organization underlying visually elicited prey orienting in the frog — II. Anatomical studies on the laterality of central projections. Neuroscience 21, 57–82. Kuhar, M.J., Adams, L.D., Hunter, R.G., Vechia, S.D., Smith, Y., 2000. CART peptides. Regul. Pept. 89, 1–6. Laming, P.R., Cairns, C., 1998. Effects of food, glucose, and water ingestion on feeding activity in the toad (Bufo bufo). Behav. Neurosci. 112, 1266–1272. Lara, R., Arbib, M.A., 1985. A model of the neural mechanisms responsible for pattern recognition and stimulus specific habituation in toads. Biol. Cybern. 51, 223–237. Larsen, P.J., Mau, S.E., 1994. Effect of acute stress on the expression of hypothalamic messenger ribonucleic acids encoding the endogenous opioid precursors preproenkephalin A and proopiomelanocortin. Peptides 15, 783–790. Lillywhite, H.B., Licht, P., Chelgren, P., 1973. The role of behavioral thermoregulation in the growth energetics of the toad, Bufo boreas. Ecology 54, 375–383. Lin, X., Volkoff, H., Narnaware, Y., Bernier, N.J., Peyon, P., Peter, R.E., 2000. Brain regulation of feeding behavior and food intake in fish. Comp. Biochem. Physiol. A 126, 415–434. Lovejoy, D.A., Balment, R.J., 1999. Evolution and physiology of the corticotropin-releasing factor (CRF) family of neuropeptides in vertebrates. Gen. Comp. Endocrinol. 115, 1–22. Lowry, C.A., Deviche, P., Moore, F.L., 1990. Effects of corticotropin-releasing factor (CRF) and opiates on amphibian locomotion. Brain Res. 513, 94–100.
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162 Lowry, C.A., Rose, J.D., Moore, F.L., 1996. Corticotropinreleasing factor enhances locomotion and medullary neuronal firing in an amphibian. Horm. Behav. 30, 50–59. Luksch, H., Roth, G., 1996. Pretecto-tectal interactions: effects of lesioning and stimulating the pretectum on field potentials in the optic tectum of salamanders in vitro. Neurosci. Lett. 217, 137–140. McKay, L.D., Kenney, N.J., Edens, N.K., Williams, R.H., Woods, S.C., 1981. Intracerebroventricular beta-endorphin increases food intake of rats. Life Sci. 29, 1429–1434. Marin, O., Gonzalez, A., Smeets, W.J.A.J., 1997. Basal ganglia organization in amphibians: efferent connections of the striatum and the nucleus accumbens. J. Comp. Neurol. 380, 23–50. Marin, O., Smeets, W.J.A.J., Gonzalez, A., 1998. Evolution of the basal ganglia in tetrapods: a new perspective based on recent studies in amphibians. Trends Neurosci. 21, 487–494. Masino, T., Grobstein, P., 1989. The organization of descending tectofugal pathways underlying orienting in the frog, Rana pipiens. II. Evidence for the involvement of a tecto-tegmento-spinal pathway. Exp. Brain. Res. 75, 245–264. Millan, M.J., Przewlocki, R., Jerlicz, M., Gramsch, C., Hollt, V., Herz, A., 1981. Stress-induced release of brain and pituitary beta-endorphin: major role of endorphins in generation of hyperthermia, not analgesia. Brain Res. 208, 325–338. Moore, F.L., Roberts, J., Bevers, J., 1984. Corticotropinreleasing factor (CRF) stimulates locomotor activity in intact and hypophysectomized newts (Amphibia). J. Exp. Zool. 231, 331–333. Morin, L.P., Blanchard, J.H., 1997. Neuropeptide Y and enkephalin immunoreactivity in retinorecipient nuclei of the hamster pretectum and thalamus. Vis. Neurosci. 14, 765–777. Morley, J.E., Levine, A.S., Rowland, N.E., 1983. Stress induced eating. Life Sci. 32, 2169–2182. Morris, J.L., 1976. Motor innervation of the toad iris (Bufo marinus). Am. J. Physiol. 231, 1272–1278. Mountjoy, K.G., Mortrud, M.T., Low, M.J., Simerly, R.B., Cone, R.D., 1994. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308. Negri, L., Noviello, L., Noviello, V., 1985. Effects of sauvagine, urotensin I and CRF on food intake in rats. Peptides Suppl. 3, 53–57. O’Donohue, T.L., Miller, R.L., Jacobowitz, D.M., 1979. Identification, characterization and stereotaxic mapping of intraneuronal alpha-melanocyte stimulating hormone-like immunoreactive peptides in discrete regions of the rat brain. Brain Res. 176, 101–123. O’Donohue, T.L., Jacobowitz, D.M., 1980. Studies of alphaMSH-containing nerves in the brain. Prog. Biochem. Pharmacol. 16, 69–83. Olsen, C.M., Lovering, A.T., Carr, J.A., 1999. a-melanocytestimulating hormone and habituation of prey-catching behavior in the Texas toad, Bufo speciosus. Horm. Behav. 36, 62–69. Roselli-Rehfuss, L., Mountjoy, K.G., Robbins, L.S., et al., 1993. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. USA 90, 8856–8860.
161
Rossier, J., French, E.D., Rivier, C., Ling, N., Guillemin, R., Bloom, F.E., 1977. Foot-shock induced stress increases betaendorphin levels in blood but not brain. Nature 270, 618–620. Rowland, N.E., Antelman, S.M., 1976. Stress-induced hyperphagia and obesity in rats: a possible model for understanding human obesity. Science 191, 310–312. Sakurai, T., Amemiya, A., Ishii, M., et al., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. Schioth, ¨ H.B., Muceniece, R., Wikberg, J.E., 1996. Characterisation of the melanocortin 4 receptor by radioligand binding. Pharmacol. Toxicol. 79, 161–165. Shibasaki, T., Yamauchi, N., Kato, Y., et al., 1988. Involvement of corticotropin-releasing factor in restraint stress-induced anorexia and reversion of the anorexia by somatostatin in the rat. Life Sci. 43, 1103–1110. Schwippert, W.W., Ewert, J.P., 1995. Effect of neuropeptide-Y on tectal field potentials in the toad. Brain Res. 669, 150–152. Schwippert, W.W., Rottgen, A., Ewert, J.P., 1998. Neuropeptide Y (NPY) or fragment NPY 13-36, but not NPY 18-36, inhibit retinotectal transfer in cane toads Bufo marinus. Neurosci. Lett. 253, 33–36. Spina, M., Merlo-Pich, E., Chan, R.K., et al., 1996. Appetitesuppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561–1564. Troop, N.A., Treasure, J.L., 1997. Psychosocial factors in the onset of eating disorders: responses to life-events and difficulties. Br. J. Med. Psychol. 70, 373–385. Tuinhof, R., Ubink, R., Tanaka, S., Atzori, C., van Strien, F.J., Roubos, E.W., 1998. Distribution of pro-opiomelanocortin and its peptide end products in the brain and hypophysis of the aquatic toad, Xenopus laevis. Cell Tissue Res. 292, 251–265. Uematsu, K., Todo, T., 1997. Identification of the midbrain locomotor nuclei and their descending pathways in the teleost carp, Cyprinus carpio. Brain Res. 773, 1–7. Vallarino, M., 1987. Immunocytochemical evidence for amelanocyte-stimulating hormone in the hypothalamus of the frog Rana esculenta. Cell Tissue Res. 248, 559–563. Venkatesan, S., Carr, J.A., 2001. Distribution of neuronal melanocortins in the spadefoot toad, Spea multiplicata and effects of stress. Brain Behav. Evol., in press. Vergoni, A.V., Poggioli, R., Bertolini, A., 1986. Corticotropin inhibits food intake in rats. Neuropeptides 7, 153–158. Vergoni, A.V., Bertolini, A., Wikberg, J.E.S., Schioth, H.B., ¨ 1999. Selective melanocortin MC4 receptor blockage reduces immobilization stress-induced anorexia in rats. Eur. J. Pharmacol. 369, 11–15. Vergoni, A.V., Schioth, H.B., Bertolini, A., 2000. Melanocor¨ tins and feeding behavior. Biomed. Pharmacother. 54, 129–134. Wang, D.L., Arbib, M.A., 1991. How does the toad’s visual system discriminate different worm-like stimuli? Biol. Cybern. 64, 251–261.
162
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162
Wang, D., Ewert, J.P., 1992. Configurational pattern discrimination responsible for dishabituation in common toads Bufo bufo (L.): behavioral tests of the predictions of a neural model. J. Comp. Physiol. wAx 170, 317–325. White, J.D., 1993. Neuropeptide Y: a central regulator of energy homeostasis. Regul. Pept. 49, 93–107. Wikberg, J.E.S., Muceniece, R., Mandrika, I., et al., 2000. New aspects on the melanocortins and their receptors. Pharmacol. Res. 42, 393–420.
Xia, Y., Wikberg, J.E., 1996. Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. Cell Tissue Res. 286, 63–68. Yui, R., 1983. Immunohistochemical studies on peptide neurons in the hypothalamus of the bullfrog Rana catesbeiana. Gen. Comp. Endocrinol. 49, 195–209. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
Review
Neuropeptides and amphibian prey-catching behavior夞 James A. Carr*, Cary L. Brown, Roshi Mansouri, Srividhya Venkatesan Department of Biological Sciences, Texas Tech University, Box 4-3131, Lubbock, TX 79409, USA Received 27 January 2001; received in revised form 15 May 2001; accepted 24 May 2001
Abstract In mammals, a number of hypothalamic neuropeptides have been implicated in stress-induced feeding disorders. Recent studies in anurans suggest that stress-related neuropeptides may act on elemental aspects of visuomotor control to regulate feeding. Corticotropin-releasing hormone (CRH) and a-melanocyte-stimulating hormone, potent anorexic peptides in mammals, inhibit visually-guided prey-catching in toads. Neuropeptide Y (NPY), an orexic peptide in mammals, may be an important neuromodulator in inhibitory pre-tectal–tectal pathways involved in distinguishing predator and prey. Melanocortin, NPY and CRH neurons project onto key visuomotor structures within the amphibian brain, suggesting physiological roles in the modulation of prey-catching. Thus, neuropeptides involved in feeding behavior in mammals influence the efficacy of a visual stimulus in releasing prey-catching behavior. These neuropeptides may play an important role in how frogs and toads gather and process visual information, particularly during stress. 䊚 2002 Elsevier Science Inc. All rights reserved. Keywords: Amphibian; Melanocortin; Melanocortin receptor; Corticotropin-releasing hormone; Neuropeptide Y; Optic tectum; Thalamus; Feeding; Stress; Anti-predator
1. Introduction Anuran prey-catching behavior has been used extensively to study the neuronal decision making events that underlie the visual identification of a prey-item. When a toad or frog is presented with a moving visual stimulus of the appropriate size and configuration, it responds immediately with a series of quantifiable behaviors that include orienting towards the prey, approaching, and snapping (Ewert, 1980). This behavior is exquisitely sensi夞 This paper was submitted as part of the proceedings of the 20th Conference of European Comparative Endocrinologists, organized under the auspices of the European Society of Comparative Endocrinology, held in Faro, Portugal, 5–9 September 2000. *Corresponding author. Tel.: q1-806-742-2724; Fax: q1806-742-2963. E-mail address: [email protected] (J.A. Carr).
tive to the size and shape of the prey-item. Changing a small rectangular prey-dummy from a horizontal (longitudinal axis parallel to movement directionsworm) to a vertical orientation (longitudinal axis perpendicular to movement directionsanti-worm) releases cryptic posturing (avoidance behavior) in which the animal crouches to the ground and remains motionless (Ewert, 1980). Although the motor commands driving preycatching behavior reside solely within the central nervous system (CNS), the ability of appropriate sensory stimuli to release these behaviors depends upon the homeostatic and endocrine status of the organism. For example, during the breeding season, prey-catching and avoidance behaviors are both suppressed in favor of allowing the animal to approach large objects, such as a potential mate, a visual stimulus that would otherwise release avoid-
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ance behavior (Ewert, 1980). Satiety can also influence the efficacy with visual stimuli release prey-catching behavior. Overfeeding or the infusion of the stomach with glucose reduces all facets (orienting, approaching, and snapping) of preycatching behavior in Bufo bufo (Laming and Cairns, 1998). Toads emerging from a simulated winter hibernation and fed meal worms ad libitum will increase their food intake steadily for 4 weeks after emergence, whereupon they stop eating even if food continues to be made available ad libitum (Guha et al., 1980). These studies suggest that motivation has an important impact on the ability of the visuomotor system to discriminate and respond to otherwise optimal prey configurations. In many animals, exposure to an intensely acute or chronic stressor inhibits feeding behavior through complex mechanisms that almost certainly involve hypothalamic neuropeptides but are otherwise poorly understood. The anuran prey-catching model offers promise for investigating how neuropeptides affect feeding behavior in a relatively simple model. The goal of this review was to summarize existing knowledge of neuropeptides and prey-catching behavior within the context of what is known about stress and feeding behavior in mammals. 2. Experimental analysis of prey-catching behavior There are several features of amphibian preycatching behavior that are amendable to experimental analysis. First, prey-catching behavior can be used to assess the effects of a test substance on the drive to follow a prey-item. This is measured by determining the frequency of prey-oriented behaviors in response to an optimal releasing stimulus. As mentioned previously, prey-catching itself is composed of several independent ballistic movements (orient, approach, snap) that could theoretically be affected in different ways by a test substance. Studies in sated toads indicate that reduced motivation associated with over-feeding reduces all components of prey catching (Laming and Cairns, 1998). Secondly, prey-catching behavior can be used to assess the effects of a test substance on a simple form of learning, habituation. Habituation occurs after repeated exposure of a toad to a moving prey-item and consists of two independently testable components: acquisition and extinction. Dur-
ing acquisition, there is a gradual decline in the number of prey-oriented turning movements if the stimulus is presented continuously over a period of 1–2 h. The recovery phase (extinction) generally requires a stimulus-free period of 4–8 h after testing. Neuroactive peptides known to improve learning and memory in mammals have the same general effect on acquisition and extinction in toads (Horn et al., 1979; Carpenter and Carr, 1996). The neurophysiological and neuroanatomical basis for habituation of prey-catching behavior has been extensively studied (Ewert and Ingle, ¨ 1971; Finkenstadt and Ewert, 1983; Lara and ¨ and Ewert, 1988; Wang Arbib, 1985; Finkenstadt and Arbib, 1991; Wang and Ewert, 1992) providing a template for addressing how and where neuropeptides may act to influence visual learning. Finally, the toad is an excellent model for investigating electrophysiological correlates of sub-cortical visuomotor processing, especially as they apply to behavior in a freely-moving animal. Ewert and others (reviewed in Ewert, 1997) have successfully used a neurophysiological approach to investigate the sensorimotor coding of tectal neurons. Successfully locating and acquiring a prey item requires that different types of tectal neurons (each responding to different aspects of prey size, shape, and movement) converge on medullary premotor systems to encode distinct response features (snap, turn) of prey-catching. More importantly, techniques are now available for studying how these ‘ bug-detector ’ cells respond to changes in feeding activity and motivational state. 3. Hypothalamic neuropeptides and preycatching The role of the hypothalamus in eating disorders has been known for years based on clinical data from patients with hypothalamic lesions (Celesia et al., 1981) as well as lesioning studies in laboratory rodents (Kalra et al., 1999). Intensive research into the hypothalamic mechanisms mediating leptin action (Zhang et al., 1994) have implicated a number of hypothalamic neuropeptides in the physiological control of feeding behavior. Some of these, including neuropeptide Y (NPY), the melanocortins, and the corticotropinreleasing hormone (CRH) family, have effects on feeding behavior that were well-described prior to the discovery of leptin (Vergoni et al., 1986; Negri et al., 1985; Kalra et al., 1991, reviewed in Inui,
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1999). Others, such as cocaine and amphetamineregulated transcript (CART, Kuhar et al., 2000) and the orexinsyhypocretins (de Lecea et al., 1998; Sakurai et al., 1998) have been discovered more recently (see Lin et al., 2000 for a recent review). The realization that some of these same peptides are important neuroendocrine mediators of the stress response has implicated them in stressinduced feeding disorders. 3.1. The melanocortins The melanocortins include peptides related to corticotropin (ACTH) and a-melanocyte-stimulating hormone (aMSH) that are derived through post-translational processing of pro-opiomelanocortin (POMC). Five melanocortin receptors have been cloned in mammals (see Wikberg et al., 2000, for a recent review). Melanocortin (MC) MC-2 receptors preferentially bind ACTH and are found primarily on adrenal steroidogenic cells (Xia and Wikberg, 1996). The MC-1, MC-3, and MC4 receptors preferentially bind MSH peptides but have different tissue distributions. MC-1 receptors are located principally on melanocytes and mediate the effects of aMSH on melanin synthesis and dispersion. MC-3 and MC-4 receptors both are found within the CNS, although regional patterns of expression are quite different for the two receptor types; MC-3 expression is restricted to the hypothalamus and limbic system (Roselli-Rehfuss et al., 1993) whereas MC-4 is ubiquitously expressed through the brain and spinal cord (Mountjoy et al., 1994). MC-3 receptor expression has also been reported in the placenta, GI tract, and heart. MC-5 receptors are widely expressed in peripheral tissues including adrenal glands, adipose tissue, and exocrine glands (Wikberg et al., 2000). Although it has been known since the 1950s that melanocortins affect learning and memory, it wasn’t until the 1980s that Vergoni et al. (1986) showed an inhibitory effect of ACTH on food intake. The recent discovery that the targeted disruption of the MC-4 receptor causes a form of adult-onset obesity (Huszar et al., 1997) launched a flurry of work into the satiety effects of these peptides. It is now known that neuronal melanocortins play a key role in regulating energy metabolism and feeding behavior in mammals (see Hagan et al., 1999; Inui, 1999; Benoit et al., 2000; Vergoni et al., 2000 for recent reviews). The inhibitory effects of melanocortins on feeding may
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be particularly important during stress. Administration of a selective MC-4 receptor antagonist partially blocks stress-induced reductions in feeding behavior in rats (Vergoni et al., 1999). The first study to demonstrate an effect of melanocortin peptides on toad prey-catching behavior was by Horn et al. (1979), showing that dorsal lymph sac (DLS) administration of ACTH enhanced the acquisition and delayed the extinction of habituation. Subsequent work demonstrated that the inhibitory effects of ACTH are contained within the heptapeptide core sequence of the peptide (Horn and Horn, 1982). While ACTH, aMSH, and ACTH w4–10x were all effective in facilitating acquisition, (Nle4, D-Phe7)a-MSH (NDP-MSH) and des-acetyl a-MSH were not (Carpenter and Carr, 1996). We (Olsen et al., 1999) have more recently shown that aMSH facilitates habituation in a dose-dependent manner with corresponding dose-dependent elevations in plasma aMSH (Olsen et al., 1999). The effects of aMSH are not mediated by adrenal corticosteroids, but are probably mediated centrally, as radiolabeled aMSH can be detected in the third ventricle by microdialysis within minutes after injection (Olsen et al., 1999). The receptor mediating the effects of aMSH on prey-catching behavior has not been identified. In rats, the feeding effects of the melanocortins are mediated by the MC-4 receptor. It would be surprising if the MC-4 receptor is involved in toad prey-catching behavior, however, as NDP-MSH, the most selective ligand for the mammalian MC¨ et al., 1996), has no effect on 4 receptor (Schioth prey-oriented turning (Carpenter and Carr, 1996). The possibility exists that an as-yet unidentified melanocortin receptor mediates these effects and possibly other learning effects of the melanocortins in mammals. For example, our present knowledge of the ligand selectivity for the MC-4 and MC-3 ¨ et al., 1996) does not accomreceptors (Schioth modate the fact that the melanocortin heptapeptide core sequence is as effective as ACTH in certain learning paradigms (see De Wied and Jolles, 1982). Furthermore, substituting L-Phe with its Denantiomer improves aMSH binding to MC-3 and MC-4 receptors, but results in behavioral effects opposite to those observed with the native peptides (De Wied and Jolles, 1982; Kobobun et al., 1983). Although it was initially speculated that D-Phe substitute analogs might antagonize binding to melanocortin receptors, it is clear that NDP-MSH as well as NDP-MSH fragments containing the D-
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Phe7 substitution are agonists at both the MC-1 (melanocyte) and MC-4 receptors (Haskell-Luevano et al., 1997). While virtually all studies suggest that melanocortins reduce food intake, b-endorphin (bE), another peptide cleaved from POMC, seems to have just the opposite effect. Intra-cerebroventricular administration of bE increases food intake in fish (de Pedro et al., 1995), birds (Deviche and Schepers, 1984), and mammals (McKay et al., 1981), and may play a physiological role in stressinduced over-eating (see below) as naloxone reverses stress-induced over-eating in rats (Morley et al., 1983). The effects of bE on prey-catching have not yet been investigated. 3.2. CRH-related peptides CRH has potent inhibitory effects on feeding, as does urocortin, a CRH-related neuropeptide (Spina et al., 1996). A physiological role for CRH is suggested by the fact that a-helical CRH, a selective receptor antagonist, can partially reduce restraint stress-induced reductions in feeding while immunoneutralization of endogenous CRH completely reverses stress-induced anorexia (Shibasaki et al., 1988). In humans, anorexia nervosa is associated with increased levels of CRH in CSF and increased blood cortisol levels (Gold et al., 1986; Hotta et al., 1986). Fig. 1 shows the effect of ovine CRH on preycatching behavior. A single dose of CRH (10 mg) reduced the mean number of prey-oriented turning movements when administered 30 min prior to testing. In these studies, we noticed that all of the CRH-treated animals exhibited maximal pupil dilation, a response known to be mediated by badrenergic receptors in toads (Morris, 1976). To determine if the effects of CRH on prey-catching were mediated by b-adrenergic stimulation, toads were injected DLS with isoproterenol (10 mg) or 0.6% NaCl. Isoproterenol had no effect on preycatching (Fig. 1), suggesting the effects of CRH were not secondary to activation of b-adrenergic receptors. It is also unlikely that the effects of CRH are mediated by adrenal corticosteroids, as the administration of corticosterone (10 mg), at a dose that elevates blood plasma corticosterone to levels (Carpenter and Carr, 1996) observed during stress (Olsen et al., 1999), has no effect on preycatching behavior (Fig. 1).
3.3. NPY In mammals, NPY is a potent stimulator of feeding behavior (Inui, 1999). Electrophysiological evidence in toads suggests that NPY may convey inhibitory signals from the pre-tectum to the tectum. NPY applied directly to the surface of the optic tectum inhibits tectal excitation elicited by stimulation of the optic nerve (Schwippert and Ewert, 1995). These effects are presumably mediated by Y2 receptors, as NPY and NPY 13–36 but not NPY 18–36 inhibit retino-tectal transfer in Bufo marinus (Schwippert et al., 1998). The effects of NPY mimic the pattern of tectal inhibition that occurs after electrical stimulation of the pre-tectum (Schwippert and Ewert, 1995). The effects of NPY on prey-catching behavior are not known. 4. Anatomical considerations 4.1. Prey-catching circuitry The neuroanatomical basis of prey-catching behavior has been the subject of recent reviews (Ewert, 1997; Ewert et al., 1999). Anatomical, electrophysiological and behavioralylesion studies support a retinal–tectumypre-tectum–medullary– spinal cord pathway for responding to prey. At least seven types of tectal neurons that respond to various aspects of prey-configuration and project to medullary motor control areas have been identified (Ewert, 1997). Inhibitory pre-tectal–tectal pathways prevent the spread of electrical excitation in the tectum, in effect sharpening tectal motor output. The ventral telencephalon (striatum) appears to indirectly modulate tectal bug-detector cells by tonically inhibiting the pre-tectum through fibers carried in the lateral forebrain bundle (Ewert et al., 1999). In the intact animal, this allows a cautious approach to the prey-item (Ewert, 1997). Lesioning studies also support a role for the nucleus of the medial longitudinal fasciculus (nMLF) in relaying tectal output to the medulla (Kostyk and Grobstein, 1987; Masino and Grobstein, 1989). The wealth of data on the anatomy of the toad visual system provides a strong foundation for addressing the question of how and where hypothalamic neuropeptidergic systems may influence sub-cortical visuomotor processing.
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Fig. 1. Influence of ovine CRH (A), isoproterenol (B), and corticosterone (C) on prey-catching behavior in the Texas Toad, Bufo speciosus. Toads were injected via the dorsal lymph sac with 10 mgy200 ml of the test substance or vehicle solution 30 min prior to testing. Prey-catching behavior was tested as previous described (Carpenter and Carr, 1996). (A) The effects of a single injection of oCRH on the percentage of animals responding to a prey-item ()5 turnsy5 min) and the total number of prey-oriented turns in the first 5 min of testing. oCRH significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (two-tailed t-test, P-0.05). (B) The effects of a single injection of isoproterenol on the percentage of animals responding to a prey-item and the total number of prey-oriented turning reactions in the first 5 min of testing. Isoproterenol had no effect on either parameter (P)0.05). (C) The effects of a single injection of corticosterone on the percentage of animals responding to a prey-item and the total number of prey-oriented turning reactions in the first 5 min of testing. Corticosterone was dissolved in absolute ethanol and diluted 1:100 in 0.6% NaCl. Vehicle injected toads received the same percentage of ethanol dissolved in 0.6% NaCl. Corticosterone had no effect on either parameter (P)0.05).
4.2. Melanocortins In mammals, aMSH and other peptides derived from POMC are produced by hypothalamic neurons in the arcuate nucleus (Jacobowitz and O’Donohue, 1978; O’Donohue et al., 1979; O’Donohue and Jacobowitz, 1980; Joseph et al., 1985). Comparative neuroanatomical studies suggest the location of these hypothalamic cells is evolutionarily conserved, as all amphibian species studied so far possess an infundibular POMC cell group (Hayes and Loh, 1990; D’Aniello et al., 1994; Kim and Carr, 1997; Tuinhof et al., 1998; Venkatesan and Carr, 2001). In addition, several amphibian species possess an additional POMC cell group in the pre-
optic hypothalamus (Doerr-Schott et al., 1981; Yui, 1983; Benyamina et al., 1986; Vallarino, 1987; Hayes and Loh, 1990; D’Aniello et al., 1994; Tuinhof et al., 1998; Venkatesan and Carr, 2001). Although POMC neurons send isolated fibers to the pre-tectum and tectum (Kim and Carr, 1997), the most striking projection is to the ventral telencephalon, specifically the amphibian homolog of the basal ganglia (nucleus accumbens and striatum) (Benyamina et al., 1986; Kim and Carr, 1997; Tuinhof et al., 1998). The basal ganglia regulate tectal function via both direct and indirect pathways (Marin et al., 1997; Marin et al. 1998). By innervating the basal ganglia, neuronal melanocortins may gain access to multiple modes of
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tectal regulation and thereby influence prey-catching behavior. 4.3. CRH-related peptides CRH belongs to a family of peptides that includes sauvagine, urotensin I and urocortin (Lovejoy and Balment, 1999). Consistent with its action as a hypophysiotropic peptide, CRH-immunoreactivity (ir) is found in hypothalamic neurons, predominately in the anterior pre-optic area and magnocellular nucleus (reviewed in Andersen et al., 1992). CRH- and sauvagine-ir also have been observed in the optic tectum of frogs (Bhargava and Rao, 1993; Gonzalez et al., 1996). Interestingly, CRH- and sauvagine-ir neurons have been identified in the nMLF in the mesencephalic tegmentum. Neurons in the nMLF have been shown to drive spinal motor and interneurons in fish (Bosch et al., 1995; Uematsu and Todo, 1997) and may participate in mediating tecto-spinal information flow during prey-orienting behaviors (Kostyk and Grobstein, 1987). NMLF lesions that spare descending tectospinal tracts produce ipsilateral turning deficits toward a prey-stimulus in frogs (Masino and Grobstein, 1989). Whether CRH- or sauvagine neurons in the nMLF of anurans project to spinal motor neurons remains to be seen, but deserves consideration given the well-documented effects of CRH on locomotor activity in amphibians (Moore et al., 1984; Lowry et al., 1990) and mammals (Dunn and Berridge, 1990). In newts, CRH alters the discharge patterns of medullary neurons involved in locomotor behaviors (Lowry et al., 1996). 4.4. NPY NPY is the most abundant and widely expressed neuropeptide in the mammalian brain (White, 1993). NPY neurons are also widely distributed in a number of hypothalamic and extra-hypothalamic sites in anurans. Hypothalamic NPY neurons are found in the suprachiasmatic nucleus and infundibulum (Andersen et al., 1992). Extra-hypothalamic NPY neurons have been observed in the pallium, pre-tectal thalamus, the optic tectum, torus semicircularis, and mid-brain tegmentum (Danger et al., 1985; Andersen et al., 1992). Of significance is the intense NPY-ir innervation of the retinorecipient layer of the tectum. Lesioning studies indicate that these fibers arise from NPY-immu-
noreactive cells in the pre-tectum (Kozicz and Lazar, 1994). Electrophysiological studies indicate that NPY cells may contribute to pre-tectal inhibition of the tectum, both in anurans (Schwippert and Ewert, 1995) and urodeles (Luksch and Roth, 1996). NPY innervation of the pre-tectum and tectum is also seen in birds (Britto et al., 1989; Boswell et al., 1998) and mammals (Chronwall et al., 1985; Botchkina and Morin 1995; Morin and Blanchard, 1997; Borostyankoi et al., 1999), suggesting that this peptide may have an evolutionarily conserved role in modulating sub-cortical visuomotor processing. 5. Stress and prey-catching behavior Stress affects feeding behavior in all vertebrates in a manner that depends upon both the duration and intensity of the stressor. Generally, exposure to a severe acute or a chronic stressor reduces feeding behavior, ultimately leading to reduced body weight, a condition called stress-induced anorexia. For example, exposure to painful (strong tail pinching) or psychological stressors (repeated immobilization, novel environment) both lead to severe anorexia, even mimicking, in some cases, pain-induced anorexia (Holland et al., 1977) and anorexia nervosa (Donohoe, 1984), respectively, in humans. In contrast, exposure to a mild stressor, such as mild tail-pinch in rats, can actually enhance feeding behavior and cause animals to overeat (Rowland and Antelman, 1976). Stress-induced over eating has also been well-described in humans (Troop and Treasure, 1997). Potentially threatening visual stimuli reduce prey-catching behavior. Toads will ignore an otherwise effective prey-stimulus if simultaneously presented with a visual stimulus that resembles a predator (Ewert, 1980, 1997). Recent work in our laboratory has revealed that acute exposure to unrelated noxious or stressful agents also reduces prey-catching behavior. Acute exposure to ether vapors, which activates the hypothalamo–hypophysial–adrenal axis in toads (Olsen et al., 1999), leads to a dramatic reduction in the percentage of animals responding to a prey-item when tested 1 h after the ether exposure. This stressor also significantly reduced the total number of preyoriented turns observed in the first 5 min of testing (Fig. 2a). To rule out the possibility that the effects of ether were due to a sedative effect, we also examined prey-catching behavior after exposure to
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Fig. 2. Influence of ether exposure (a) and crowding (b) on prey-catching behavior in the Texas Toad, Bufo speciosus. Prey-catching behavior was tested as previous described (Carpenter and Carr, 1996). (a) The effects of a 2-min exposure to ether vapors (Olsen et al., 1999) on the percentage of animals responding to a prey-item ()5 turnsy5 min) and the total number of prey-oriented turns in the first 5 min of testing. Toads were tested after a 1-h recovery from the ether exposure. Exposure to ether vapors significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (two-tailed t-test, P-0.05). (b) The effects of crowding on the percentage of animals responding and the total number of prey-oriented turns in the first 5 min of testing. Test animals were individually identified by placing a loose-fitting colored elastic band around the right leg and then were placed in a white plastic cage (20.5=23.5=45 cm) containing 10 other randomly selected toads. Test animals were removed after 60 min and prey-catching behavior tested immediately. Crowding significantly reduced the percentage of animals responding to a prey-item (Fisher’s Exact Test, P-0.05) and the total number of prey-oriented turns in the first 5 min (twotailed t-test, P-0.05).
an unrelated stressor, crowding. As shown in Fig. 2b, exposure to a 60-min crowding stress significantly reduced the percentage of animals responding to a moving prey-item and significantly reduced the number of prey-oriented turns per min. 6. Hypothalamic neuropeptides and stress In rats, stress alters hypothalamic POMC synthesis (Hollt et al., 1986; Baubet et al., 1994; Larsen and Mau, 1994) and brain content of the POMC peptides aMSH (Khorram et al., 1985) and bE (Rossier et al., 1977; Millan et al., 1981). We have examined the effects of various stressors on neuronal POMC systems in Bufo (Kim and
Carr, 1997; Olsen et al., 1999). We initially observed that although brain and plasma aMSH are not altered as a result of habituation, confinement within the prey-catching test arena causes a decrease in the aMSH content of the telencephalon, suggesting enhanced secretion of the peptide by ascending POMC neurons (Kim and Carr, 1997). Exposure to an acute stressor (5 min ether vapors), sufficient to elevate plasma corticosterone levels, also causes a decrease in telencephalic aMSH content (Olsen et al., 1999). Whether alterations in release of aMSH contribute to stressinduced inhibition of prey-catching (see above) remains to be tested. In mammals, exposure to an acute stressor alters the synthesis and release of
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CRH (Koob, 1999) and NPY (Conrad and McEwen, 2000) within the brain. Changes in CRH and NPY content during stress in toads have not been investigated. 7. Satiety or anti-predator peptides? The need to eat is a powerful motivating drive in all animals. In the laboratory, the amount of food recently ingested is, arguably, the major determinant in feeding. In nature, however, toads must assess the trade-off between predation risk and feeding behavior. Predation risk can have a significant impact on foraging and feeding strategies, especially in juvenile toads, as they often feed during the day to maximize growth rate (Lillywhite et al., 1973). Toads have few natural predators because of the toxic material contained within the paratoid glands. Snakes (particularly garter snakes, Thamnophis sp., and hognose snakes, Heterodon platyrhinos and H. nasicus) are the major predators of toads in North America. Elegant behavioral ecology studies have shown that garter snakes use visual cues when hunting toads (Heinen, 1995). It is not surprising then that, when encountered with a snake, toads assume a cryptic posture, crouching close to the ground and remaining still (Heinen, 1994a). This is just one component of cryptic anti-predator behavior. Toads also will choose substrates that are physically complex (Heinen, 1993) and can background adapt (Heinen, 1994b), thereby reducing the likelihood that they will be captured by garter snakes (Heinen, 1993, 1994b). An interesting feature of this anti-predator behavior is that the releasing features are not species specific — toads will perform the same behavior in response to non-predatory snakes (Heinen, 1994a). The cryptic posturing (reducing movement, crouching) observed in the presence of a snake is identical to the behavior elicited by electrical stimulation of the pre-tectum or presentation of an anti-worm stimulus (Ewert, 1980). Considering the strong selection pressure to reduce unnecessary movement in the presence of a predator, the adaptive significance of being able to override prey-catching behavior (tectum-driven) in favor of cryptic behavior (pre-tectum-driven) becomes apparent. What is fascinating about the toad’s visual system is that exposure of a naive toads to seemingly unrelated noxious stimuli such as crowding or ether vapors also inhibits prey-catch-
ing behavior. Thus, when faced with a novel, but potentially threatening stimulus, toads reduce preyoriented movement just as they would when presented with a predator. Moreover, neuropeptides known to be involved in stress-induced inhibition of feeding in mammals also inhibit prey-catching behavior. By facilitating habituation to non-relevant visual stimuli, melanocortins reduce unnecessary movement and may make the animal less conspicuous to a potential predator, as suggested by behavioral ecology studies (Heinen, 1994a, 1995). This is not an unfamiliar role for melanocortins, as these peptides were originally discovered as pituitary intermediate lobe factors that cause skin darkening and background adaptation in frogs. Skin darkening is another form of crypsis that presumably aids in predator avoidance when the animal is on a dark background. Interestingly, toads prefer dark vs. light substrates and move less frequently on a dark background, presumably making them less conspicuous to a potential predator (Heinen, 1994b). It is intriguing to speculate that melanocortins have a primitive role as antipredator peptides. 8. Concluding remarks Making the right behavioral decision at the right time can be a life or death situation, especially when an animal is in a confrontational situation. Visual circuitry in toads has evolved to ensure that prey-catching behavior is inhibited in favor of cryptic behavior when a predator is detected. Ecological studies show that avoidance and escape behaviors reduce the risk of predation. A similar reduction in prey-catching behavior occurs when toads are exposed to non-specific stressors. Two families of hypothalamic neuropeptides, CRH and the melanocortins, rapidly affect prey-catching behavior, but in different ways. CRH affects the drive to follow a moving prey-item while the melanocortins affect habituation. Whether these peptides contribute to stress-induced inhibition of prey-catching is not clear, but can be tested in future studies with the use of selective receptor antagonists. More importantly, future studies should address whether stress andyor CRH actually reduce feeding motivation or promote the emergence of other behaviors (escape, avoidance) that override prey-catching behavior.
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Acknowledgments The work described in this review was supported by grants from the Texas Tech University (TTU) Department of Biological Sciences, TTU Research Enhancement Fund, the Howard Hughes Medical Institute through the Undergraduate Biological Sciences Education Program to TTU (C. Brown) and the Clark’s Scholar’s program (R. Mansouri). References Andersen, A.C., Tonon, M.C., Pelletier, G., Conlon, J.M., Fasolo, A., Vaudry, H., 1992. Neuropeptides in the amphibian brain. Int. Rev. Cytol. 138, 89–210. ` Baubet, V., Fevre-Montange, M., Gay, N., Debilly, G., Bobillier, P., Cespuglio, R., 1994. Effects of an acute immobilization stress upon proopiomelanocortin (POMC) mRNA levels in the mediobasal hypothalamus: a quantitative in situ hybridization study. Brain Res. Mol. Brain Res. 26, 163–168. Benoit, S., Schwartz, M., Baskin, D., Woods, S.C., Seeley, R.J., 2000. CNS melanocortin system involvement in the regulation of food intake. Horm. Behav. 37, 299–305. ´ Benyamina, M., Delbende, C., Jegou, S., et al., 1986. Localization and identification of a-melanocyte-stimulating hormone (a-MSH) in the frog brain. Brain Res. 366, 230–237. Bhargava, S., Rao, P.D., 1993. Distribution of corticotropinreleasing factor immunoreactive neurons in the brain of the tiger frog, Rana tigrina. Neurosci. Lett. 154, 27–30. Boswell, T., Millam, J.R., Li, Q., Dunn, I.C., 1998. Cellular localization of neuropeptide Y mRNA and peptide in the brain of the Japanese quail and domestic chicken. Cell Tissue Res. 293, 31–38. Borostyankoi, Z.A., Gorcs, T.J., Hamori, J., 1999. Immunocytochemical mapping of NPY and VIP neuronal elements in the cat subcortical visual nuclei, with special reference to the pretectum and accessory optic system. Anat. Embryol. 200, 495–508. Bosch, T.J., Maslam, S., Roberts, B.L., 1995. A polyclonal antibody against mammalian FOS can be used as a cytoplasmic neuronal activity marker in a teleost fish. J. Neurosci. Methods 58, 173–179. Botchkina, G.I., Morin, L.P., 1995. Organization of permanent and transient neuropeptide Y-immunoreactive neuron groups and fiber systems in the developing hamster diencephalon. J. Comp. Neurol. 357, 573–602. Britto, L.R., Hamassaki, D.E., Keyser, K.T., Karten, H.J., 1989. Neurotransmitters, receptors, and neuropeptides in the accessory optic system: an immunohistochemical survey in the pigeon (Columba livia). Vis. Neurosci. 3, 463–475. Carpenter, A.M., Carr, J.A., 1996. The effects of melanocortin peptides and corticosterone on habituation in the great plains toad, Bufo cognatus. Horm. Behav. 30, 236–243. Celesia, G.G., Archer, C.R., Chung, H.D., 1981. Hyperphagia and obesity. Relationship to medial hypothalamic lesions. J. Am. Med. Assoc. 246, 151–153. Chronwall, B.M., DiMaggio, D.A., Massari, V.J., Pickel, V.M., Ruggiero, D.A., O’Donohue, T.L., 1985. The anatomy of
159
neuropeptide-Y-containing neurons in rat brain. Neuroscience 15, 1159–1181. Conrad, C.D., McEwen, B.S., 2000. Acute stress increases neuropeptide Y mRNA within the arcuate nucleus and hilus of the dentate gyrus. Brain Res. Mol. Brain Res. 79, 102–109. D’Aniello, B., Imperatore, C., Fiorentino, M., Vallarino, M., Rastogi, R.K., 1994. Immunocytochemical localization of POMC-derived peptides (adrenocorticotropic hormone, amelanocyte-stimulating hormone and b-endorphin) in the pituitary, brain and olfactory epithelium of the frog, Rana esculenta, during development. Cell Tissue Res. 278, 509–516. Danger, J.M., Guy, J., Benyamina, M., et al., 1985. Localization and identification of neuropeptide Y (NPY)-like immunoreactivity in the frog brain. Peptides 6, 1225–1236. de Lecea, L., Kilduff, T.S., Peyron, C., et al., 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327. de Pedro, N., Delgado, M.J., Alonso-Bedate, M., 1995. Central administration of beta-endorphin increases food intake in goldfish: pretreatment with the opioid antagonist naloxone. Regul. Pept. 55, 189–195. Deviche, P., Schepers, G., 1984. Intracerebroventricular injection of ostrich beta-endorphin to satiated pigeons induces hyperphagia but not hyperdipsia. Peptides 5, 691–694. De Wied, D., Jolles, J., 1982. Neuropeptides derived from proopiocortin: behavioral, physiological, and neurochemical effects. Physiol. Rev. 62, 976–1059. Doerr-Schott, J., Dubois, M.P., Lichte, C., 1981. Immunohistochemical localisation of substances reactive to antisera against a- and b-endorphin and met-enkephalin in the brain of Rana temporaria L. Cell Tissue Res. 217, 79–92. Donohoe, T.P., 1984. Stress-induced anorexia: implications for anorexia nervosa. Life Sci. 34, 203–218. Dunn, A.J., Berridge, C.W., 1990. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Brain Res. Rev. 15, 71–100. Ewert, J.P., 1980. Neuroethology. Springer-Verlag, New York. Ewert, J.P., 1997. Neural correlates of key stimulus and releasing mechanism: a case study and two concepts. Trends Neurosci. 20, 332–339. Ewert, J.P., Ingle, D., 1971. Excitatory effects following habituation of prey-catching activity in frogs and toads. J. Comp. Physiol. Psychol. 77, 369–374. Ewert, J.P., Buxbaum-Conradi, H., Glagow, M., Rottgen, A., Schurg-Pfeiffer, E., Schwippert, W.W., 1999. Forebrain and midbrain structures involved in prey-catching behaviour of toads: stimulus-response mediating circuits and their modulating loops. Eur. J. Morphol. 37, 172–176. ¨ T., Ewert, J.P., 1983. Visual pattern discrimination Finkenstadt, through interactions of neural networks: a combined electrical brain stimulation, brain lesion, and extracellular recording study in Salamandra salamandra. J. Comp. Physiol. wAx 153, 99–110. ¨ T., Ewert, J.P., 1988. Stimulus-specific long-term Finkenstadt, habituation of visually guided orienting behavior toward prey in toads: a 14C–2DG study. J. Comp. Physiol. wAx 163, 1–11.
160
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162
Gold, P.W., Gwirtsman, H., Avgerinos, P.C., et al., 1986. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. N. Engl. J. Med. 314, 1335–1342. Gonzalez, G.C., Bountzioukas, S., Gonzalez, E.S., et al., 1996. Hypothalamic and extrahypothalamic sauvagine-like immunoreactivity in the bullfrog (Rana catesbeiana) central nervous system. J. Comp. Neurol. 365, 256–267. Guha, K., Jorgensen, C.B., Larsen, L.O., 1980. Relationship between nutritional state and testes function, together with observations on patterns of feeding, in the toad, Bufo bufo. J. Zool. Lond. 192, 147–155. Hagan, M.M., Rushing, P.A., Schwartz, M.W., et al., 1999. Role of the CNS melanocortin system in the response to overfeeding. J. Neurosci. 19, 2362–2367. Haskell-Luevano, C., Hendrata, S., North, C., et al., 1997. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. Med. Chem. 40, 2133–2139. Hayes, W.P., Loh, Y.P., 1990. Correlated onset and patterning of proopiomelanocortin gene expression in embryonic Xenopus brain and pituitary. Development 110, 747–757. Heinen, J.T., 1993. Substrate choice and predation risk in newly-metamorphosed American toads, Bufo americanus: an experimental analysis. Am. Midl. Natur. 130, 184–192. Heinen, J.T., 1994a. Antipredator behavior of newly metamorphosed American toads (Bufo a. americanus), and mechanisms of hunting by Eastern garter snakes (Thamnophis s. sirtalis). Herpetologica 50, 137–145. Heinen, J.T., 1994b. The significance of color change in newly metamorphosed American toads (Bufo a. americanus). J. Herp. 28, 87–93. Heinen, J.T., 1995. Predator cues and prey-responses: a test using Eastern garter snakes (Thamnophis s. sirtalis) and American toads (Bufo a. americanus). Copeia 1995, 738–741. Holland, J.C., Rowland, J., Plumb, M., 1977. Psychological aspects of anorexia in cancer patients. Cancer Res. 37, 2425–2428. Horn, E., Greiner, B., Horn, I., 1979. The effect of ACTH on habituation of the turning reaction in the toad Bufo bufo L. J. Comp. Physiol. 131, 129–135. Horn, I., Horn, E., 1982. The influence of ACTH fragments on habituation of the prey catching behaviour in the European toad (Bufo bufo L.). Physiol. Behav. 28, 497–500. Hotta, M., Shibasaki, T., Masuda, A., et al., 1986. The responses of plasma adrenocorticotropin and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa patients. J. Clin. Endocrinol. Metab. 62, 319–324. Hollt, V., Przewlocki, R., Haarman, I., et al., 1986. Stress induced alterations in the levels of mRNA coding for POMC and prolactin in rat pituitary. Neuroendocrinology 43, 277–282. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., et al., 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141. Inui, A., 1999. Feeding and body-weight regulation by hypothalamic neuropeptides-mediation of the actions of leptin. Trends Neurosci. 22, 62–67.
Jacobowitz, D.M., O’Donohue, T.L., 1978. Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc. Natl. Acad. Sci. 75, 6300–6304. Joseph, S.A., Pilcher, W.H., Knigge, K.M., 1985. Anatomy of the corticotropin-releasing factor and opiomelanocortin systems of the brain. Fed. Proc. 44, 100–107. Kalra, S.P., Dube, M.G., Sahu, A., Phelps, C.P., Kalra, P.S., 1991. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. USA 88, 10931–10935. Kalra, S.P., Dube, M.G., Pu, S., Xu, B., Horvath, T.L., Kalra, P.S., 1999. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20, 68–100. Khorram, O., Bedran de Castro, J.C., McCann, S.M., 1985. Stress-induced secretion of alpha-melanocyte-stimulating hormone and its physiological role in modulating the secretion of prolactin and luteinizing hormone in the female rat. Endocrinology 117, 2483–2489. Kim, Y., Carr, J.A., 1997. Alterations in brain and plasma concentrations of alpha-melanocyte-stimulating hormone during habituation of prey catching behavior in toads. Brain Behav. Evol. 49, 149–161. Kobobun, K., O’Donohue, T.L., Handelmann, G.E., Sawyer, T.K., Hruby, V.J., Hadley, M.E., 1983. Behavioral effects of w4-norleucine, 7-D-phenylalaninex-a-melanocyte-stimulating hormone. Peptides 4, 721–724. Koob, G.F., 1999. Corticotropin-releasing factor, norepinephrine, and stress. Biol. Psychiatry 46, 1167–1180. Kozicz, T., Lazar, G., 1994. The origin of tectal NPY immunopositive fibers in the frog. Brain Res. 635, 345–348. Kostyk, S.K., Grobstein, P., 1987. Neuronal organization underlying visually elicited prey orienting in the frog — II. Anatomical studies on the laterality of central projections. Neuroscience 21, 57–82. Kuhar, M.J., Adams, L.D., Hunter, R.G., Vechia, S.D., Smith, Y., 2000. CART peptides. Regul. Pept. 89, 1–6. Laming, P.R., Cairns, C., 1998. Effects of food, glucose, and water ingestion on feeding activity in the toad (Bufo bufo). Behav. Neurosci. 112, 1266–1272. Lara, R., Arbib, M.A., 1985. A model of the neural mechanisms responsible for pattern recognition and stimulus specific habituation in toads. Biol. Cybern. 51, 223–237. Larsen, P.J., Mau, S.E., 1994. Effect of acute stress on the expression of hypothalamic messenger ribonucleic acids encoding the endogenous opioid precursors preproenkephalin A and proopiomelanocortin. Peptides 15, 783–790. Lillywhite, H.B., Licht, P., Chelgren, P., 1973. The role of behavioral thermoregulation in the growth energetics of the toad, Bufo boreas. Ecology 54, 375–383. Lin, X., Volkoff, H., Narnaware, Y., Bernier, N.J., Peyon, P., Peter, R.E., 2000. Brain regulation of feeding behavior and food intake in fish. Comp. Biochem. Physiol. A 126, 415–434. Lovejoy, D.A., Balment, R.J., 1999. Evolution and physiology of the corticotropin-releasing factor (CRF) family of neuropeptides in vertebrates. Gen. Comp. Endocrinol. 115, 1–22. Lowry, C.A., Deviche, P., Moore, F.L., 1990. Effects of corticotropin-releasing factor (CRF) and opiates on amphibian locomotion. Brain Res. 513, 94–100.
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162 Lowry, C.A., Rose, J.D., Moore, F.L., 1996. Corticotropinreleasing factor enhances locomotion and medullary neuronal firing in an amphibian. Horm. Behav. 30, 50–59. Luksch, H., Roth, G., 1996. Pretecto-tectal interactions: effects of lesioning and stimulating the pretectum on field potentials in the optic tectum of salamanders in vitro. Neurosci. Lett. 217, 137–140. McKay, L.D., Kenney, N.J., Edens, N.K., Williams, R.H., Woods, S.C., 1981. Intracerebroventricular beta-endorphin increases food intake of rats. Life Sci. 29, 1429–1434. Marin, O., Gonzalez, A., Smeets, W.J.A.J., 1997. Basal ganglia organization in amphibians: efferent connections of the striatum and the nucleus accumbens. J. Comp. Neurol. 380, 23–50. Marin, O., Smeets, W.J.A.J., Gonzalez, A., 1998. Evolution of the basal ganglia in tetrapods: a new perspective based on recent studies in amphibians. Trends Neurosci. 21, 487–494. Masino, T., Grobstein, P., 1989. The organization of descending tectofugal pathways underlying orienting in the frog, Rana pipiens. II. Evidence for the involvement of a tecto-tegmento-spinal pathway. Exp. Brain. Res. 75, 245–264. Millan, M.J., Przewlocki, R., Jerlicz, M., Gramsch, C., Hollt, V., Herz, A., 1981. Stress-induced release of brain and pituitary beta-endorphin: major role of endorphins in generation of hyperthermia, not analgesia. Brain Res. 208, 325–338. Moore, F.L., Roberts, J., Bevers, J., 1984. Corticotropinreleasing factor (CRF) stimulates locomotor activity in intact and hypophysectomized newts (Amphibia). J. Exp. Zool. 231, 331–333. Morin, L.P., Blanchard, J.H., 1997. Neuropeptide Y and enkephalin immunoreactivity in retinorecipient nuclei of the hamster pretectum and thalamus. Vis. Neurosci. 14, 765–777. Morley, J.E., Levine, A.S., Rowland, N.E., 1983. Stress induced eating. Life Sci. 32, 2169–2182. Morris, J.L., 1976. Motor innervation of the toad iris (Bufo marinus). Am. J. Physiol. 231, 1272–1278. Mountjoy, K.G., Mortrud, M.T., Low, M.J., Simerly, R.B., Cone, R.D., 1994. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308. Negri, L., Noviello, L., Noviello, V., 1985. Effects of sauvagine, urotensin I and CRF on food intake in rats. Peptides Suppl. 3, 53–57. O’Donohue, T.L., Miller, R.L., Jacobowitz, D.M., 1979. Identification, characterization and stereotaxic mapping of intraneuronal alpha-melanocyte stimulating hormone-like immunoreactive peptides in discrete regions of the rat brain. Brain Res. 176, 101–123. O’Donohue, T.L., Jacobowitz, D.M., 1980. Studies of alphaMSH-containing nerves in the brain. Prog. Biochem. Pharmacol. 16, 69–83. Olsen, C.M., Lovering, A.T., Carr, J.A., 1999. a-melanocytestimulating hormone and habituation of prey-catching behavior in the Texas toad, Bufo speciosus. Horm. Behav. 36, 62–69. Roselli-Rehfuss, L., Mountjoy, K.G., Robbins, L.S., et al., 1993. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. USA 90, 8856–8860.
161
Rossier, J., French, E.D., Rivier, C., Ling, N., Guillemin, R., Bloom, F.E., 1977. Foot-shock induced stress increases betaendorphin levels in blood but not brain. Nature 270, 618–620. Rowland, N.E., Antelman, S.M., 1976. Stress-induced hyperphagia and obesity in rats: a possible model for understanding human obesity. Science 191, 310–312. Sakurai, T., Amemiya, A., Ishii, M., et al., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. Schioth, ¨ H.B., Muceniece, R., Wikberg, J.E., 1996. Characterisation of the melanocortin 4 receptor by radioligand binding. Pharmacol. Toxicol. 79, 161–165. Shibasaki, T., Yamauchi, N., Kato, Y., et al., 1988. Involvement of corticotropin-releasing factor in restraint stress-induced anorexia and reversion of the anorexia by somatostatin in the rat. Life Sci. 43, 1103–1110. Schwippert, W.W., Ewert, J.P., 1995. Effect of neuropeptide-Y on tectal field potentials in the toad. Brain Res. 669, 150–152. Schwippert, W.W., Rottgen, A., Ewert, J.P., 1998. Neuropeptide Y (NPY) or fragment NPY 13-36, but not NPY 18-36, inhibit retinotectal transfer in cane toads Bufo marinus. Neurosci. Lett. 253, 33–36. Spina, M., Merlo-Pich, E., Chan, R.K., et al., 1996. Appetitesuppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561–1564. Troop, N.A., Treasure, J.L., 1997. Psychosocial factors in the onset of eating disorders: responses to life-events and difficulties. Br. J. Med. Psychol. 70, 373–385. Tuinhof, R., Ubink, R., Tanaka, S., Atzori, C., van Strien, F.J., Roubos, E.W., 1998. Distribution of pro-opiomelanocortin and its peptide end products in the brain and hypophysis of the aquatic toad, Xenopus laevis. Cell Tissue Res. 292, 251–265. Uematsu, K., Todo, T., 1997. Identification of the midbrain locomotor nuclei and their descending pathways in the teleost carp, Cyprinus carpio. Brain Res. 773, 1–7. Vallarino, M., 1987. Immunocytochemical evidence for amelanocyte-stimulating hormone in the hypothalamus of the frog Rana esculenta. Cell Tissue Res. 248, 559–563. Venkatesan, S., Carr, J.A., 2001. Distribution of neuronal melanocortins in the spadefoot toad, Spea multiplicata and effects of stress. Brain Behav. Evol., in press. Vergoni, A.V., Poggioli, R., Bertolini, A., 1986. Corticotropin inhibits food intake in rats. Neuropeptides 7, 153–158. Vergoni, A.V., Bertolini, A., Wikberg, J.E.S., Schioth, H.B., ¨ 1999. Selective melanocortin MC4 receptor blockage reduces immobilization stress-induced anorexia in rats. Eur. J. Pharmacol. 369, 11–15. Vergoni, A.V., Schioth, H.B., Bertolini, A., 2000. Melanocor¨ tins and feeding behavior. Biomed. Pharmacother. 54, 129–134. Wang, D.L., Arbib, M.A., 1991. How does the toad’s visual system discriminate different worm-like stimuli? Biol. Cybern. 64, 251–261.
162
J.A. Carr et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 151–162
Wang, D., Ewert, J.P., 1992. Configurational pattern discrimination responsible for dishabituation in common toads Bufo bufo (L.): behavioral tests of the predictions of a neural model. J. Comp. Physiol. wAx 170, 317–325. White, J.D., 1993. Neuropeptide Y: a central regulator of energy homeostasis. Regul. Pept. 49, 93–107. Wikberg, J.E.S., Muceniece, R., Mandrika, I., et al., 2000. New aspects on the melanocortins and their receptors. Pharmacol. Res. 42, 393–420.
Xia, Y., Wikberg, J.E., 1996. Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. Cell Tissue Res. 286, 63–68. Yui, R., 1983. Immunohistochemical studies on peptide neurons in the hypothalamus of the bullfrog Rana catesbeiana. Gen. Comp. Endocrinol. 49, 195–209. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.