PeptideBrazilian hormones Journal of andMedical behavior and Biological Research (2001) 34: 1369-1377 1369 ISSN 0100-879X Virtual Symposium
The brain decade in debate: VIII. Peptide hormones and behavior: cholecystokinin and prolactin
M.C. Beinfeld1, 1Department of Pharmacology and Experimental Therapeutics, J.C. Bittencourt2, Tufts University School of Medicine, Boston, MA, USA R.S. Bridges3, 2Departamento de Anatomia, Instituto de Ciências Biomédicas, P.L. Faris4, Universidade de São Paulo, São Paulo, SP, Brasil A.B. Lucion5, 3Department of Biomedical Sciences, Tufts University School of A.G. Nasello6, Veterinary Medicine, North Grafton, MA, USA A. Weller7 and 4Division of Neuroscience Research, MMC 392, Department of Psychiatry, L.F. Felicio8 University of Minnesota, Medical School, Minneapolis, MN, USA 5Departamento de Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil 6Departamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brasil 7Developmental Psychobiology Laboratory, Department of Psychology, Bar Ilan University, Ramat, Gan, Israel 8Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP, Brasil
Abstract
Correspondence This article is a transcription of an electronic symposium held on Key words L.F. Felicio November 28, 2000 in which active researchers were invited by the · CCK Departamento de Patologia Brazilian Society of Neuroscience and Behavior (SBNeC) to discuss · PRL Faculdade de Medicina the advances of the last decade in the peptide field with particular · Dopamine Veterinária e Zootecnia, USP focus on central actions of prolactin and cholecystokinin. The com- · Maternal behavior Av. Orlando Marques Paiva, 87 · ments in this symposium reflect the diversity of prolactin and chole- Bulimia 05508-900 São Paulo, SP · Motivation Brasil cystokinin research and demonstrate how the field has matured. Since both peptides play a role in reproductive behaviors, particularly mother- The names of the authors are infant interactions, this was the starting point of the discussion. Recent presented in alphabetical order, findings on the role of the receptor subtypes as well as interaction with except for the last one that other peptides in this context were also discussed. Another issue corresponds to the symposium discussed was the possible role of these peptides in dopamine-medi- organizer. ated rewarding systems. Both prolactin and cholecystokinin are in-
Publication supported by FAPESP. volved in mechanisms controlling food intake and somatic pain thresholds. The role of peripheral inputs through vagal afferents modulating behavior was stressed. The advent of knockout animals as potential generators of new knowledge in this field was also ad- Received August 8, 2001 dressed. Finally, interactions with other neuropeptides and investiga- Accepted August 27, 2001 tion of the role of these peptides in other fields such as immunology were mentioned. Knowledge about the central functions of prolactin and cholecystokinin has shown important advances. The role of these peptides in neurological and psychiatric syndromes such as anorexia, drug abuse and physiological disturbances that lead to a compromised maternal behavior seems relevant.
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Introduction medial preoptic area of steroid-primed vir- gin female rats stimulate a rapid onset of The versatility of peptide hormones is maternal behavior (1-5). I am interested in such that almost every peptide hormone is how we want to proceed with our discussion also a neuropeptide. It has been proposed of prolactin, cholecystokinin and behavior. that some of them may be neurotransmitters, Aron Weller: My relevant research fo- although, in general, they act as neuromodu- cuses on early, postnatal behavioral devel- lators. Actions of peptide hormones on the opment in the rat, and the role of cholecysto- central nervous system are almost always kinin in mediating various aspects: infant- related to their physiological functions at the mother interaction, stress and comfort, natu- periphery. Both peripheral and brain pep- ral and learned preferences, feeding, and tides are involved in behaviorally meaning- satiety. Dear Dr. Bridges, if I recall cor- ful nervous system functions. This is par- rectly, your research on cholecystokinin and ticularly true for cholecystokinin and prolac- maternal behavior found that it acts as an tin. These hormones induce satiety and fa- antagonist of opiate inhibition, and that it cilitate maternal behavior, respectively. Nev- affects maintenance, but not initiation of ertheless, a range of central cholecystokinin maternal behavior (6,7). These findings, re- and prolactin effects has been described re- ported in your studies with Felicio, are a few cently. Both cholecystokinin and prolactin years old. Is there an update? Is there a are involved in dopaminergic transmission. connection with prolactin? With humans? The interrelations of the cholecystokinin and Robert Bridges: Dr. Weller, we have not dopaminergic systems are responsible for pursued these studies to any extent over the the role of these peptides in several neuro- past few years. Rather, we have focused our logical and psychiatric syndromes such as efforts on the involvement of the prolactin Parkinson’s disease, Huntington’s chorea, receptor in regulating the onset of maternal schizophrenia, bulimia, anorexia and anxi- behavior. Our most recent efforts have dem- ety. Besides their interactions with the dopa- onstrated that central (medial preoptic area, minergic systems, there are important rela- MPOA) infusions of the prolactin receptor tions among prolactin, thyroid and gonadal antagonist, S179D-prolactin (5), delay the hormones since prolactin regulates the physi- onset of maternal care in steroid-primed nul- ological and pathological effects of these liparous rats. The interaction between pro- hormones. The relation between prolactin lactin and cholecystokinin certainly would and stress is well known. In addition, both be of interest to pursue. peptides have modulatory effects on each Aron Weller: Dr. Bridges and Dr. Felicio, other’s best-known central functions. in a manner analogous to your studies on initiation and maintenance of maternal be- From your results, which behavior(s) havior, Dr. Raymond Nowak of CNRS, is being affected by a particular Tours, France, has been studying the role of hormone? What is the systemic cholecystokinin receptors in the develop- mechanism of it? ment of preference for the mother (“bond- ing”) in sheep, and we have been studying Robert Bridges: My research focus that the role of cholecystokinin in infant-mother is relevant to this discussion pertains to the attraction/preference in rats (maintenance). role of prolactin and placental lactogens in We actually get a complicated pattern. Nowak the central regulation of maternal behavior (8) reports a blockade of bonding (prefer- in mammals. We have found that infusions ence toward the mother) by a CCK1 receptor of prolactin or rat placental lactogen into the antagonist, and a facilitation with a CCK2
Braz J Med Biol Res 34(11) 2001 Peptide hormones and behavior 1371 antagonist. We found increased preference interaction of neonatal stress and cholecys- rates toward aspects of the mother and nest tokinin on bonding and mother-infant inter- induced by antagonists of both receptor types action? (9,10). Dr. Felicio, Dr. Bridges said earlier Aron Weller: Dr. Lucion, regarding cen- that he hasn’t followed up your findings on tral cholecystokinin receptors: brain chole- cholecystokinin and maternal behavior. Do cystokinin receptors appear to have a prima- you have any recent (last few years) findings rily postnatal ontogeny. Studies of specific in that area? binding of cholecystokinin to rat forebrain Luciano Felicio: Both CCK1 and CCK2 and midbrain have shown an increase from
(previously named CCKA and CCKB) (11) birth, peaking around days 12-13, staying receptor antagonists potentiate morphine in- high until about day 17-20, followed then by hibitory effects on ongoing maternal behav- a gradual decrease to adult levels in the ior. This is consistent with previous results fourth week of life. Simultaneously, the dis- that demonstrated antagonistic effects of tribution of brain cholecystokinin receptors cholecystokinin and beta-endorphin on this becomes gradually more extensive as the behavior. These results suggest that both pup matures: cholecystokinin receptors are subtypes of cholecystokinin receptors might first found in the central cingulate and pyri- be involved in this multiple peptidergic con- form cortices on postnatal day 1, confined to trol of maternal behavior in lactating rats limbic areas up to day 10, after which a rapid (12). In addition, we found that pretreatment development is noted, approximating the with the CCK1 antagonist lorglumide during adult’s distribution by day 15 (16-18). Re- late pregnancy disrupts maternal behavior in garding cholecystokinin, stress, bonding and rats (13). mother-infant interaction: an intriguing and Aldo Lucion: I have been studying the promising field! Not much is known, let’s role of oxytocin in maternal aggressive be- study it! havior. Dr. Weller, do you think cholecysto- Patricia Faris: Dr. Weller, I am very kinin would act directly on neurons or by interested in making some sense out of CCK1 means of stimulatory effects on oxytocin versus CCK2 antagonists. Our early data neurons, or maybe both? suggested the CCK1 receptor was involved Aron Weller: Dr. Lucion, that is simply in blocking opiate analgesias (19) but, as you too general a question. It depends on the know, Benoliel and Wiesenfeld-Hallin (20- particular circuit and/or behavioral system. I 22) have presented evidence for the two think virtually all possibilities exist: periph- receptors in this phenomenon. How do you eral and central, CCK1 and CCK2, direct interpret your finding that both are involved and mediated (by oxytocin, and more) op- in your measure of infant-mother preference tions. In the case of satiety, it seems that both in rats? peripheral and central cholecystokinin re- Aron Weller: Dr. Faris, well, any inter- ceptors may be involved (14,15). I do not pretation I will give will be pretty specula- know if some of them activate an oxytocin- tive. There are several possibilities. Here is ergic circuit. Regarding most behaviors stud- my favorite one: it is possible that the CCK1 ied in infant rats, this is simply unknown, receptors involved are part of circuits medi- and as yet unstudied. ating the reward/incentive value of maternal Aldo Lucion: Dr. Weller, very interest- cues, and that the CCK2 circuit is an anxiety ing results. Could you comment on chole- mediating one. That way, a similar effect cystokinin receptors in the central nervous could be produced by different pathways. system of infant rats? Are they expressed as Margery Beinfeld: Dr. Weller, Hi! I like in adults? And finally would there be an that idea. I think the dopamine reward sys-
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tem is doing a lot. related to them (29-36). Aron Weller: Dr. Beinfeld, thanks, I Patricia Faris: We conduct both basic also think that cholecystokinin, dopamine anatomical and behavioral studies in the rat and reward systems have a future in infancy and clinical trials in human subjects. The research and beyond. main focus of my laboratory is on vagal Robert Bridges: Dr. Lucion, would you afferent modulation of higher central ner- update us on the role of oxytocin in maternal vous system processes. As such, we are fo- aggression? Have you identified what neural cused on the role of peripheral enteroendo- region is mediating this response? I assume crine cholecystokinin in food intake and that oxytocin is stimulating maternal aggres- modulation of somatic pain thresholds, a sion, if it is involved in this behavioral re- function modulated by vagal afferent activ- sponse. ity. Specifically, we are interested in interac- Aldo Lucion: Dr. Bridges, in fact, the tions between cholecystokinin, opiates, and stimulatory effect of oxytocin on maternal serotonin. The clinical disorder we focus on aggression was our hypothesis. However, it is bulimia nervosa. For clinical implications, turned out that oxytocin injected into the cholecystokinin ligands are likely to be novel medial amygdala and also into the BNST treatments for modulating opioid analgesia, (bed nucleus stria terminalis) decreased ma- inhibiting some forms of unrestrained eat- ternal aggression in a dose-response manner ing, and blocking panic attacks. The latter is (23-25). marginal to my area of expertise (37-40). Robert Bridges: Dr. Lucion, what mech- Jackson Bittencourt: My assumption on anism do you think may underlie the actions this subject is that peptide hormones can of oxytocin on maternal aggression? Have participate in many brain functions, and this you examined the involvement of the MPOA will depend mainly on the distribution of in this process? their receptors and the interactions with any Aldo Lucion: Dr. Bridges, the inhibitory given behavior should be related to the brain effect of oxytocin on maternal aggression areas with the richest receptor innervation. was very surprising for us. We have been My main flow of research is mapping by in thinking of the effect of oxytocin on situ hybridization, immunohistochemistry GABAergic neurons in the amygdala but we and neuronal tracer neuropeptides and/or have not yet studied this in the MPOA. Dr. hormones in the central nervous system of Weller, could cholecystokinin be involved mammals (mainly as models the rat and mon- in apoptosis in the brain? key brains). I have helped to discover two Aron Weller: Dr. Lucion, CCK may be neuropeptides in the mammalian brain, involved in apoptosis. However, the data I urocortin and melanin-concentrating hor- am familiar with only relate to apoptosis in mone (41-45). Right now the scientific com- the pancreas, not the brain. CCK is a known munity has jumped on these two peptides peripheral trophic factor. Interestingly, both and their relation to feeding behavior or, supraphysiological concentrations (26) and better yet, to energy balance control. Dr. the lack of receptors (27) or withdrawal from Faris, it would be very interesting to see the high levels of CCK (28) have all been impli- interactions between cholecystokinin and cated in apoptosis in the pancreas. urocortin in food intake since urocortin is Antonia G. Nasello: We have been work- expressed in the cells of the enteric nervous ing on prolactin at least for the last 15 years system, or at least in the cells in the wall of and on cholecystokinin at least for 7 years. the gut. We studied the effects of these two peptides Patricia Faris: Have you looked at the on several behaviors and some mechanisms effects on food intake with urocortin in va-
Braz J Med Biol Res 34(11) 2001 Peptide hormones and behavior 1373 gotomized rats? Could you please briefly increased in amphetamine-treated rats we summarize the effects of urocortin on food are going to try to evaluate the cholecystoki- intake? Does it affect a component of the nin interaction with both drugs in perfusate meal or body weight with chronic adminis- obtained by microdialysis. tration? Margery Beinfeld: Dr. Nasello, good Jackson Bittencourt: It seems clear that luck. I am sure it will be complicated. An- all mechanisms involved in the controls of other thing to consider is what is happening any behavior are not entirely understood. In to cholecystokinin release with these treat- the case of urocortin, a new peptide member ments. It has now become possible to do of the corticotropin-releasing factor (CRF) these studies (although they are not easy) in family, such kind of interactions should oc- awake rats and even mice. It is also possible cur with the CRF receptors that urocortin has that amphetamine causes some neurotoxic- affinity for, mainly the CRF-R2 receptor. ity, so perhaps cocaine might give a slightly This receptor is distributed in subcortical different picture. fields, such as lateral septal nucleus and the Antonia G. Nasello: Dr. Beinfeld, we ventromedial nucleus of the hypothalamus, agree with you but in our country it is very and in the gut (46). difficult to get cocaine for scientific pur- Antonia G. Nasello: Dr. Beifeld, in rela- pose! It is really amazing! tion to cholecystokinin, dopamine and re- Margery Beinfeld: Dr. Nasello, that is ward systems, we had some results with amazing. But you never know. amphetamine and apomorphine-induced ster- Antonia G. Nasello: Dr. Faris, can you eotyped behavior and cholecystokinin icv explain to us the differences of cholecystoki- treatment and their antagonists peripherally nin involvement in bulimia and nervous an- administered. Cholecystokinin-8 increased orexia? the amphetamine-induced stereotyped be- Patricia Faris: Dr. Nasello, cholecysto- havior and decreased the apomorphine-in- kinin in anorexia versus bulimia. We have duced one. The tetrapeptide CCK4 had the conceptualized these disorders as involving same effect on amphetamine- but not on long-term energy balance abnormalities in apomorphine-induced behavior (47). The anorexia, whereas bulimia patients are typi- results with CCK1 and CCK2 antagonists cally of normal body weight but do not feel agreed with previous reports. Our results full in response to a normal meal. Thus, this suggest that cholecystokinin has opposite latter disorder could be considered a meal influences on presynaptic and postsynaptic patterning disorder, a process known to be mechanisms. These results agree with previ- modulated by cholecystokinin. Recent evi- ous ones obtained with specific antagonists dence suggests that cholecystokinin may in- for CCK1 and CCK2 receptors (34). teract with long-term energy balance as evi- Margery Beinfeld: Dr. Nasello, it is denced by obesity in rats lacking the CCK1 clearly a complicated system and you may receptor (48). be right to propose that the influences could The role of cholecystokinin in anorexia is be pre- and postsynaptic. It would be inter- not very clear. This population is a difficult esting to try to do some mechanistic experi- group to do mechanistic studies on, since ments. It is likely that modulation of dopa- they will not voluntarily consume enough mine release is involved, so that would be diet to evoke cholecystokinin release. The one approach. results of blood levels are ambiguous. In Antonia G. Nasello: Dr. Beinfeld, since bulimia, a clearer picture is emerging. Chole- dopamine release is diminished in apomor- cystokinin release and ratings of satiety are phine-treated rats and dopamine release is blunted following a test meal in bulimia
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subjects. This appears to be secondary to Antonia G. Nasello: Dr. Beinfeld, it is the delayed gastric emptying. We have hypoth- best approach and we wish you good luck. esized that vagal afferent tone is abnormal in Patricia Faris: Dr. Beinfeld, I agree to- bulimia nervosa, leading to alterations in the tally with the need to measure levels of gastric accommodation relaxation, delayed cholecystokinin. Also the knockouts that are gastric emptying, and blunted cholecystoki- devoid of cholecystokinin may be another nin and satiety. Clearly, the role of cholecys- approach independent of using antagonists. tokinin in this disorder is an exciting area of With regard to cholecystokinin, I am im- research. Cholecystokinin stimulates oxyto- pressed by the emerging story on CCK4 and cin release in rats, both from the posterior panic disorder. Bradwejn and colleagues (52- pituitary and also in the dorsal medullarly 54) have provided an elegant series of ex- nucleus of the solitary tract. This response periments including receptor 2 polymor- has been suggested to be equivalent to the phisms in this patient population. Still the emetogenic response in vomiting animals, question of the origin of endogenous chole- including humans. cystokinin for initiating a panic attack is Luciano Felicio: A curious aspect of unknown and, as mentioned by Dr. Beinfeld, both cholecystokinin and prolactin actions is levels of cholecystokinin need to be meas- that the acute and chronic behavioral effects ured. Yet, a clear picture has emerged which are usually different and sometimes para- strongly implicates cholecystokinin in the doxical. Recently, we have reported that sen- generation of panic episodes. sitization to morphine can be induced by Margery Beinfeld: Dr. Bittencourt, I previous treatment with either CCK1 or agree in general, but I am not sure density of CCK2 antagonists (49). innervation is the whole story. Some pep- Antonia G. Nasello: Dr. Beinfeld, you tides (like cholecystokinin) are so abundant have described tolerance for the effects of that even a little innervation might be enough cholecystokinin (50). Can you make some to activate the receptors. We have started a comments about the possible mechanisms breeding colony of cholecystokinin peptide involved? receptor knockout mice and, the NIH will- Margery Beinfeld: Dr. Nasello, toler- ing, we will try to answer some questions. ance usually means receptor internalization However, I worry a bit if the receptors seem and the cholecystokinin receptor is certainly to oppose themselves in many behaviors internalized but otherwise, I really don’t what the responses will be in the absence of know. One of the things that I have noticed is the peptide. It is too bad the cholecystokinin that the vast majority of work on the behav- receptor knockout mice are not more easily ioral effects of cholecystokinin is done with available. agonists and antagonists with very little in- Robert Bridges: Maybe this session formation about if and how much cholecys- could serve as a basis for a subsequent ses- tokinin is actually released by physiologi- sion on cholecystokinin, prolactin and be- cally relevant stimuli. I know that it is not havior or common themes underlying the always possible to do that, but I think at least regulation of behaviors regulated by these some of us should be thinking about that. We peptides. Certainly prolactin is also involved have started doing cholecystokinin microdi- in feeding in some species, including birds. alysis in awake freely moving rats and are Patricia Faris: I would like to conclude getting some good results (51) but are plan- by raising the possibility that some of the ning to try to develop some better detection effects of oxytocin could occur through va- methods - perhaps using capillary zone elec- gal afferents. I just wanted to make a last trophoresis. comment supporting the idea that peripheral
Braz J Med Biol Res 34(11) 2001 Peptide hormones and behavior 1375 inputs through vagal afferents modulate be- we sampled the males, they were all of the havior as shown for learning and memory. same age, with the same treatment. The only Antonia G. Nasello: Dr. Bridges, you difference was that a group was of virgin rats have described that prolactin peaks during and the other was of experienced rats. We pregnancy and is significantly diminished think that experienced rats were more ex- after reproductive experience (55). In male posed to endogenous steroids than the virgin rats we induced hyperprolactinemia using ones. 60-day domperidone treatment and the in- Luciano Felicio: Both prolactin and crease of prolactin was higher in sexually cholecystokinin influence feeding and re- experienced rats than in virgin rats (32). productive behaviors in various species. The Apparently this is the opposite of what you multiple peptidergic control of such behav- have described for females after reproduc- iors involves complex genetic mechanisms tive experience. Could you please give your that generate and allow different strategies opinion about these results? and degrees of success in competition. In Robert Bridges: Gladys, the alterations addition to their complex peripheral central in prolactin secretion in reproductively ex- interaction, both peptides seem to play im- perienced females may be the result of expo- portant roles in various immunological pro- sure to gonadal steroids and/or lactogenic cesses. hormones (4,56). Perhaps, the males ren- dered hyperprolactinemic would display re- Acknowledgments duced prolactin levels if they were also primed with steroids. When did you sample The authors and the SBNeC organizers are the males relative to their state of hyperpro- grateful to Dr. Claudio da Cunha for help with lactinemia? the organization of the chat. CNPq-Prossiga is Antonia G. Nasello: Dr. Bridges, when also acknowledged for providing the chat room.
References
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