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Oxytocin facilitates behavioural, metabolic and physiological adaptations during lactation
Applied Animal Behaviour Science 72 (2001) 225±234
Oxytocin facilitates behavioural, metabolic and physiological adaptations during lactation Kerstin UvnaÈs-Moberga, Birgitta Johanssonb, Berit Lupolib, Kerstin Svennersten-Sjaunjab,* a
Department of Animal Physiology, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden b Department of Management and Nutrition, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden
Abstract The aim of this article is to propose that oxytocin not only stimulates milk let down, but also adapts behaviour and physiology to facilitate lactation in mammals including dairy cattle. Circulating oxytocin as well as neurogenic oxytocin participates in these regulatory processes. In short, oxytocin stimulates maternal interaction and attachment between mother and young. It also participates in the metabolic prerequisites for milk production by e.g. stimulating glucagon release and thereby, mobilisation of glucose. Digestive and anabolic aspects of metabolism are also stimulated, e.g. by increased vagal nerve activity. Adaptations consistent with an antistress like pattern are also induced. Cortisol levels are decreased as well as blood pressure, and behaviours characterised by calm, reduced levels of anxiety and more social activity are promoted. These effects seem to be present in monogastric animals as well as in ruminants. The expression of various aspects of these adaptations vary according to the special needs and living environmental circumstances of different species. The mechanisms behind the effect spectrum of oxytocin are being explored in other experimental models. A second aim of this paper is to suggest that ef®ciency of lactation can be promoted by facilitating oxytocin release in connection with milking by enhancing the amount of sensory stimulation. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Oxytocin; Lactation; Metabolism; Behaviour; Sensory stimulation; Cattle
* Corresponding author. Present address: Department of Animal Management and Nutrition, KungsaÈngens Research Centre, S-753 23 Uppsala, Sweden. Tel.: 46-18-67-2003. E-mail address: [email protected] (K. Svennersten-Sjaunja).
0168-1591/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 8 - 1 5 9 1 ( 0 1 ) 0 0 1 1 2 - 5
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1. General aspects of oxytocin The pituitary hormone oxytocin is a nonapeptide consisting of nine amino acids. Oxytocin is produced in the supraoptic nuclei (SON) and paraventricular nuclei (PVN) of the hypothalamus and is released into the circulation from neurons which extend down into the posterior pituitary (Sofroniew, 1983). In addition, oxytocin neurons project from the PVN to many different regulatory sites in the brain, such as other areas in the hypothalamus, the striatum, the raphe nuclei, the locus coeruleus, vagal centres in the brain stem and sensory neurons and the sympathetic chain in the spinal cord (Sofroniew, 1983). This anatomical arrangement allows oxytocin release, e.g. in the suckling±milking situation, to integrate hormonal and neurogenic effects. It should be pointed out that oxytocin exerts a broad range of effects in both females and males, lactation being just one physiological state where a clear-cut pattern of oxytocinmediated effects are expressed. This means that knowledge about basic functions of oxytocin and the mechanisms involved also in non-lactating females as well as in males may be of value for understanding the role of oxytocin during lactation. In further support of a fundamental role of oxytocin in behaviour and physiology is the fact that the molecular structure of oxytocin is strongly conserved. The oxytocin molecule has the same structure in all mammals and the amino acids sequence of oxytocin in birds and reptiles differs by only two amino acids (Acher, 1985). 2. Oxytocin as an integrator of behavioural and physiological adaptation during lactation 2.1. Oxytocin and behaviour Oxytocin may enhance positive social interactions, such as maternal behaviour, sexual behaviour and social interactions in general (Pedersen and Prange, 1979; Agriolas and Gessa, 1991; Witt et al., 1992). The types of behaviours that are induced are dependent on the prevalent steroid pattern and on the environmental cues. Thus, e.g. the expression of maternal behaviour in response to oxytocin requests pre-treatment with oestrogen and the presence of offspring. Oxytocin may also promote bonding between individuals, between mother and young, as has been shown in for example sheep, but also between females and males of some species (Kendrick et al., 1987; Carter, 1992). Oxytocin also exerts a number of more basic behavioural effects in both male and female animals (Richard et al., 1991). Administration of oxytocin in rats may for example induce anxiolytic and sedative effects (UvnaÈs-Moberg et al., 1992; UvnaÈs-Moberg et al., 1994). Further, during the periods when oxytocin release is continuously triggered, as during breast-feeding women are calmer and more social than are non-breast-feeding women. Some correlation data support the assumption that oxytocin play a role in regulating behaviour during this period. The level of calmness is related to basal level of oxytocin in the breast-feeding women and in contrast the number of oxytocin peaks is related to their social competence suggesting that calm and social interaction represent different aspects of the oxytocin pattern (Nissen et al., 1998).
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2.2. Oxytocin and effects on the anterior pituitary Some oxytocin neurons originating in the PVN also terminate in the hypothalamic± pituitary portal system and oxytocin may by this pathway in¯uence the release of hormones produced in the anterior pituitary, for example, adrenocorticotrophic hormone (ACTH) and as a consequence, cortisol. It has been demonstrated that oxytocin has a dual effect on cortisol levels. An immediate rise of cortisol occurs in rats after oxytocin administration, followed by a sustained decrease of cortisol (Petersson et al., 1999a). In humans, it has been shown that exogenous oxytocin induces a decrease of cortisol (Legros et al., 1988). Further, oxytocin has been suggested to be an important prolactin releasing factor in rats and pigs (Mori et al., 1990). Also growth hormone secretion can be in¯uenced by oxytocin (BjoÈrkstrand et al., 1997). 2.3. Oxytocin and antistress Oxytocin may also decrease blood pressure in rats by a central pathway. This effect becomes more prominent after repeated administration of oxytocin. The effects caused by a 5 day treatment with oxytocin lasts for 10 and 20 days after the last treatment in males and females, respectively (Petersson et al., 1996a). In addition, the elevation of pain threshold and also some of the effects on vagal hormones as well as the lowered cortisol levels and anxiolytic like effect in response to repeated administration of oxytocin are long-lasting (Petersson et al., 1996b; Petersson et al., 1996a; UvnaÈs-Moberg et al., 1998). The mechanisms behind these sub-chronic effects are beginning to be elucidated. The elevated pain threshold is related to enhanced activity in the endogenous opioid systems, whereas the effect on blood pressure, cortisol and vagal hormones seems to be linked to an enhanced expression of the central subgroup of adrenergic receptors called a2-adrenoceptors. When these receptors are activated, the ®ring in the central noradrenergic neurons originating in the locus coereleus as well as the activity in the sympathetic nervous system is inhibited and the activity in the parasympathetic nervous system increased, thereby causing an integrated antistress like pattern (BjoÈrkstrand et al., 1996a; Petersson et al., 1996b; Petersson et al., 1998; Petersson et al., 1999b; UvnaÈs-Moberg, 1997; UvnaÈs-Moberg, 1998a; UvnaÈs-Moberg, 1998b). 3. Oxytocin and digestion, anabolic metabolism and growth Oxytocin has been shown to in¯uence the release of gastrointestinal hormones, such as CCK, gastrin and somatostatin, in rats, probably by promoting vagal nerve activity (BjoÈrkstrand et al., 1996a). Oxytocinergic neurons from the PVN project to both the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS) (Sofroniew, 1983), and central oxytocin is suggested to increase and decrease insulin levels through the DMX and NTS, respectively (BjoÈrkstrand et al., 1996b). Such effects promote anabolic metabolism and growth. Peripheral oxytocin has an effect on the release of glucagon from the pancreas and may, thereby, elevate blood glucose levels (BjoÈrkstrand et al., 1996b). Thus, oxytocin may promote both mechanisms by which nutrients are
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mobilised as well as stored, two seemingly opposite functions which are both required for milk production. In non-lactating female rats weight gain is increased following administration of oxytocin (UvnaÈs-Moberg et al., 1996). 4. Effects of oxytocin in the post-natal period As mentioned above oxytocin-induced antistress like effects in response to repeated administration of oxytocin last for weeks after the last treatment. If instead a 5±10 day long treatment with oxytocin is given immediately post-partum, lifelong effects are induced, although they sometimes do not become manifest until onset of puberty. Thus, rat pups exposed to post-natal oxytocin treatment have been shown to have lower blood pressure, lower cortisol levels and higher pain threshold as adults when compared to saline-treated controls. In addition, oxytocin injections given to new-born rat pups have been shown to increase growth after puberty and to result in higher levels of CCK and insulin in the rats when they are adults (BjoÈrkstrand and UvnaÈs-Moberg, 1996; UvnaÈs-Moberg et al., 1998; SohlstroÈm et al., 2000). Thus, administration of oxytocin in the post-natal period induces permanent antistress like effects and stimulates growth, i.e. the animals use energy for growth (UvnaÈs-Moberg et al., 1998). The reason why permanent effects are induced at a very young age may be that neuroendocrine circuits are not fully mature and, therefore, open to in¯uence. 5. The role of oxytocin in dairy cattle As described above, the role of oxytocin is not restricted to milk ejection as previously thought. In fact, behaviour and physiology are also in¯uenced by oxytocin in the lactating animal to facilitate milk production and interaction between mother and young. Furthermore, the role of oxytocin seems not to be restricted to lactating animals, since it also induce analogous effects in non-lactating females and males. Oxytocin is not only released to milking. Also sensory stimuli from other areas in the body seems to cause a release of oxytocin. In the following paragraphs, we will summarise some data obtained in dairy cattle, which show that the more general effects of oxytocin on physiology and behaviour seem to be operating also in these species. 5.1. Milking and oxytocin release in cows Milk ejection in dairy cows has been studied extensively since the ef®ciency of milk let down has signi®cant practical and economical consequences. Since oxytocin is released by various types of tactile stimuli, we have studied the effect of different types of sensory stimulation on oxytocin levels. We have compared the effect of machine milking and hand milking on the assumption that more sensory stimulation is applied by the hands than by the machine, which largely operates by under pressure. For a similar reason, we investigated the effect of suckling by the calf. In a third type of experiments, extra sensory stimulation was given by feeding the cow during milking. As will be presented below, all
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these experimental situations were accompanied by enhanced oxytocin secretion. In some of the experiments, oxytocin related enhancements of milk production and other physiological and behavioural changes consistent with the effect pattern of oxytocin were also induced. 5.2. Hand milking and manual pre-stimulation It is well known that manual pre-stimulation of the teats before the milking machine is attached improves milk ejection and oxytocin secretion (Mayer et al., 1984; Mayer et al., 1985; Phillips, 1965; Sagi et al., 1980). However, also hand milking during the entire milking process has been shown to enhance the plasma levels of the hormones oxytocin and prolactin more than machine milking does (Gorewit et al., 1992). The increased secretion of hormones in response to hand milking is probably related to the enhanced sensory stimulation caused by this procedure. In addition, hand milking has been shown to result in higher milk yield and fat content in the milk compared with machine milking (Hamann and Tolle, 1980; Svennersten et al., 1990a), effects which might be related to the enhanced oxytocin secretion. The effects may be secondary and due to improved udder evacuation, but also direct effects of oxytocin on production and metabolism are conceivable. That oxytocin might be involved in the regulation of milk yield has been indicated by the ®nding that milking related oxytocin levels were positively correlated to milk yield in dairy cows (Johansson et al., 2000), while in humans, the number of oxytocin pulses during suckling were correlated to both prolonged lactation and amount of milk delivered during breastfeeding (Nissen et al., 1996; Nissen et al., 1998). Furthermore, administration of oxytocin to dairy cows between milkings (Morag, 1968) as well as just before or after milking (Nostrand et al., 1991; Ballou et al., 1993) has resulted in increased production. However, it has been questioned whether the enhanced milk yield is an effect of direct action on mammary metabolism (Knight, 1994). 5.3. Suckling Suckling is ought to be the most ef®cient stimulation for milk ejection, since the calf suckling is the natural way to stimulate the teat. The suckling procedure has been described in detail and it has been found that it includes three different phases, pre-stimulation, milk intake and post-stimulation (Lidfors, 1994). Machine milking does not include all these phases. In support of a superior ef®ciency of suckling, suckling caused a greater oxytocin release compared to machine milking (Lupoli et al., 2000). There are some indications that cows which are suckled by the calf have a higher milk production than machine milked animals. Long-term suckling without additional milking in high producing dairy cows may enhance milk yields, as measured from weaning time and later on (Everitt and Phillips, 1971; Walsh, 1974; Krohn, 1999). Suckling may also improve lactation persistency when practised as restricted suckling, i.e. the calf is allowed to suckle on one teat or suckle after milking (Das et al., 1999a). In further support of a positive effect of suckling on milk yield are data showing that routines including both suckling and milking result in higher milk yield as well as elevated oxytocin release
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compared to only milking in dairy cows (Bar-Peled et al., 1995) as well as in ewes (Marnet et al., 1999). 6. Feeding during milking Feeding alone is associated with a release of oxytocin in dogs and sows (UvnaÈs-Moberg et al., 1985) and a feeding-related oxytocin release has been found also in dairy cows, although the rise is much smaller than the milking-induced release (Svennersten et al., 1990b). Two mechanisms may be involved in the feeding-induced oxytocin secretion. One way to increase the release of oxytocin is to activate sensory nerves in the oral mucosa. Since these ®bres project directly to the nucleus of the solitary tract (NTS), which is linked to the PVN, oxytocin may be released. Also an afferent neural vagal link between the stomach, the NTS and PVN has been demonstrated in the rat (Verbalis et al., 1986; Renaud et al., 1987). The vagal in¯uence on oxytocin secretion has been validated in experiments where electrical afferent vagal nerve stimulation increased plasma levels of oxytocin (Stock and UvnaÈs-Moberg, 1988). 6.1. Feeding during milking reinforces milking oxytocin release Milk ejection is also facilitated by feeding during milking. Already during the 1970's, it was found that feeding the cows concentrates immediately before milking had positive effects on milk removal (Velitok, 1977; Brandsma, 1978). And recently, the bene®cial in¯uence of feeding during milking received further support, since it was shown that higher milk production, increased milk ¯ow, and shorter milking time occurred when cows were fed during milking (Samuelsson et al., 1993; Svennersten et al., 1995; Johansson et al., 1999b). Taken together these data indicate that the reason why feeding strengthens milk ejection may be a potentiated oxytocin release and indeed when milking and feeding were combined much more oxytocin was released as during milking only. 6.2. Behavioural and endocrine consequences of the enhanced oxytocin secretion induced by feeding in connection with milking Oxytocin might also in¯uence behaviour as discussed above. When feeding and milking were combined, oxytocin levels were higher and the cows were lying and ruminating more after milking, as an indication for a higher degree of calmness. They also showed more social interactions. In contrast, they had a lower percentage of oral activity, such as feed searching behaviour. That oxytocin does in¯uence behaviour is further strengthened by the positive correlation between oxytocin levels and behavioural expression of calmness (lying down and ruminating while lying down) in the experiments mentioned above (Johansson et al., 1999a; Johansson et al., 2000). In the studies in which milking and feeding were performed at the same time also, the expected milking related rise of cortisol levels was almost absent (Johansson et al., 1999a). Furthermore, the positive correlations between oxytocin and cortisol and between prolactin
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and cortisol observed when milking is performed alone disappeared (Johansson et al., 2000). The lowered cortisol secretion when cows were fed and milked at the same time may be an expression of an enhanced stimulation of the antistress like pattern of oxytocinmediated effects as a response to the increased amount of sensory stimulation. 6.3. Consequences of suckling-induced oxytocin in the calf The feeding-induced release of oxytocin is more pronounced in calves compared to adult cows. Furthermore, suckling results in signi®cantly higher feeding related oxytocin secretion in the calf than bucket drinking does (Lupoli et al., 2000). It is likely that the sensory nerves of the oral mucosa of the calf are more ef®ciently activated when the calf is suckling compared with drinking milk from a bucket. Several studies demonstrate that suckling has long-term effects on the calf. Both calves from high-producing dairy cows and calves from a tropical breed such as Zebu calves have an improved growth rate when suckling is allowed (Das et al., 1999a; Krohn et al., 1999). It is not fully understood why suckling may increase the weight gain of the calves. Suckling may increase the amount of food intake or make the calves more resistant to infections which may lead to healthier calves which grow much better (Everitt and Phillips, 1971; Metz, 1984a; Metz, 1987). Further, Foldager and Krohn (1991) found that suckling in early life results in a higher milk yield during the ®rst lactation period. As discussed above, administration of oxytocin to new-born rats causes permanent effects. The animals grow more and are less stressed. It is not impossible that the observed effects on growth in calves allowed to suckle could be explained by the enhanced oxytocin secretion during suckling compared to bucket feeding. In support of this, more insulin, an important metabolic hormone, was released by suckling in the calves and also oxytocin levels correlated strongly to insulin in the suckling calves (Johansson et al., 2000). As yet, a relationship between suckling-induced oxytocin release and improved growth rate remains a speculation. Further studies are needed to prove this hypothesis, i.e. that the suckling related oxytocin release play a similar role to oxytocin injections given to new-born rats, which are reported above, stimulates growth in new-born pups. References Acher, R., 1985. The non-mammalian Ð mammalian transition through neurohypophysial peptides. Peptides 6, 304±314. Agriolas, A., Gessa, G.L., 1991. Central functions of oxytocin. Neurosci. Biobehav. Rev. 15, 217±231. Ballou, L.U., Bleck, J.L., Bleck, G.T., Bremel, R.D., 1993. The effects of oxytocin injections before and after milking on milk production, milk plasmin and milk composition. J. Dairy Sci. 76, 1544±1549. Bar-Peled, U., Maltz, E., Brackental, I., Folman, Y., Kali, Y., Gacitua, H., Lehrer, A.R., Knight, C.H., Robinzon, B., Voet, H., Tagari, H., 1995. Relationship between frequent milking or suckling in early lactation and milk production of high producing dairy cows. J. Dairy Sci. 78, 2726±2736. BjoÈrkstrand, E., Ahlenius, S., Smedh, U., UvnaÈs-Moberg, K., 1996a. The oxytocin receptor antagonist 1deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin inhibits effects of the 5-HT1A receptor agonist 8-OH-DPAT on plasma levels of insulin, cholecystokinin and somatostatin. Regul. Pept. 63, 47±52. BjoÈrkstrand, E., Eriksson, M., UvnaÈs-Moberg, K., 1996b. Evidence of a peripheral and a central effect of oxytocin on pancreatic hormone release in rats. Neuroendocrinology 63, 377±383.
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UvnaÈs-Moberg, K., 1997. Oxytocin-linked antistress effects ± the relaxation and growth response. Acta Physiol. Scand. Suppl. 640, 161. UvnaÈs-Moberg, K., 1998a. Antistress pattern induced by oxytocin. News Physiol. Sci. (NIPS) 13, 22±26. UvnaÈs-Moberg, K., 1998b. Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23, 819±835. UvnaÈs-Moberg, K., Ahlenius, S., Hillegaart, V., Alster, P., 1994. High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol. Biochem. Behav. 49, 101±106. UvnaÈs-Moberg, K., Alster, P., Hillegaart, V., Ahlenius, S., 1992. Oxytocin reduces exploratory motor behaviour and shifts the activity towards the centre of the arena in male rats. Acta Physiol. Scand. 145, 429±430. UvnaÈs-Moberg, K., Alster, P., Petersson, M., 1996. Dissociation of oxytocin effects on body weight in two variants of female Sprauge-Dawley rats. Integr. Physiol. Behav. Sci. 31, 44±55. UvnaÈs-Moberg, K., Alster, P., Petersson, M., SohlstroÈm, A., BjoÈrkstrand, E., 1998. Postnatal oxytocin injections cause sustained weight gain and increased nociceptive thresholds in male and female rats. Pediatr. Res. 43, 344±348. UvnaÈs-Moberg, K., Stock, S., Eriksson, M., LindeÂn, A., Einarsson, S., Kunavongkrit, A., 1985. Plasma levels of oxytocin increase in response to suckling and feeding in dogs and sows. Acta Physiol. Scand. 124, 391±398. Velitok, I.G., 1977. Feeding with concentrates. In: Machine Milking and its Effects on Cows. Amerind Publishing Co. Pvt. Ltd., New Delhi, pp. 115±116. Verbalis, J.G., McCann, M.J., McHale, C.M., Stricker, E.M., 1986. Oxytocin secretion in response to cholecystokinin and food: differentiation of nausea from satiety. Science 232, 1417±1419. Walsh, J.P., 1974. Milk secretion in machine-milked and suckled cows. Ir. J. Agric. Res. 13, 77±89. Witt, D., Winslow, J., Insel, T., 1992. Enhanced social interactions in rats following chronic, centrally infused oxytocin. Pharmacol. Biochem. Behav. 43, 855±861.
Oxytocin facilitates behavioural, metabolic and physiological adaptations during lactation Kerstin UvnaÈs-Moberga, Birgitta Johanssonb, Berit Lupolib, Kerstin Svennersten-Sjaunjab,* a
Department of Animal Physiology, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden b Department of Management and Nutrition, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden
Abstract The aim of this article is to propose that oxytocin not only stimulates milk let down, but also adapts behaviour and physiology to facilitate lactation in mammals including dairy cattle. Circulating oxytocin as well as neurogenic oxytocin participates in these regulatory processes. In short, oxytocin stimulates maternal interaction and attachment between mother and young. It also participates in the metabolic prerequisites for milk production by e.g. stimulating glucagon release and thereby, mobilisation of glucose. Digestive and anabolic aspects of metabolism are also stimulated, e.g. by increased vagal nerve activity. Adaptations consistent with an antistress like pattern are also induced. Cortisol levels are decreased as well as blood pressure, and behaviours characterised by calm, reduced levels of anxiety and more social activity are promoted. These effects seem to be present in monogastric animals as well as in ruminants. The expression of various aspects of these adaptations vary according to the special needs and living environmental circumstances of different species. The mechanisms behind the effect spectrum of oxytocin are being explored in other experimental models. A second aim of this paper is to suggest that ef®ciency of lactation can be promoted by facilitating oxytocin release in connection with milking by enhancing the amount of sensory stimulation. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Oxytocin; Lactation; Metabolism; Behaviour; Sensory stimulation; Cattle
* Corresponding author. Present address: Department of Animal Management and Nutrition, KungsaÈngens Research Centre, S-753 23 Uppsala, Sweden. Tel.: 46-18-67-2003. E-mail address: [email protected] (K. Svennersten-Sjaunja).
0168-1591/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 8 - 1 5 9 1 ( 0 1 ) 0 0 1 1 2 - 5
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1. General aspects of oxytocin The pituitary hormone oxytocin is a nonapeptide consisting of nine amino acids. Oxytocin is produced in the supraoptic nuclei (SON) and paraventricular nuclei (PVN) of the hypothalamus and is released into the circulation from neurons which extend down into the posterior pituitary (Sofroniew, 1983). In addition, oxytocin neurons project from the PVN to many different regulatory sites in the brain, such as other areas in the hypothalamus, the striatum, the raphe nuclei, the locus coeruleus, vagal centres in the brain stem and sensory neurons and the sympathetic chain in the spinal cord (Sofroniew, 1983). This anatomical arrangement allows oxytocin release, e.g. in the suckling±milking situation, to integrate hormonal and neurogenic effects. It should be pointed out that oxytocin exerts a broad range of effects in both females and males, lactation being just one physiological state where a clear-cut pattern of oxytocinmediated effects are expressed. This means that knowledge about basic functions of oxytocin and the mechanisms involved also in non-lactating females as well as in males may be of value for understanding the role of oxytocin during lactation. In further support of a fundamental role of oxytocin in behaviour and physiology is the fact that the molecular structure of oxytocin is strongly conserved. The oxytocin molecule has the same structure in all mammals and the amino acids sequence of oxytocin in birds and reptiles differs by only two amino acids (Acher, 1985). 2. Oxytocin as an integrator of behavioural and physiological adaptation during lactation 2.1. Oxytocin and behaviour Oxytocin may enhance positive social interactions, such as maternal behaviour, sexual behaviour and social interactions in general (Pedersen and Prange, 1979; Agriolas and Gessa, 1991; Witt et al., 1992). The types of behaviours that are induced are dependent on the prevalent steroid pattern and on the environmental cues. Thus, e.g. the expression of maternal behaviour in response to oxytocin requests pre-treatment with oestrogen and the presence of offspring. Oxytocin may also promote bonding between individuals, between mother and young, as has been shown in for example sheep, but also between females and males of some species (Kendrick et al., 1987; Carter, 1992). Oxytocin also exerts a number of more basic behavioural effects in both male and female animals (Richard et al., 1991). Administration of oxytocin in rats may for example induce anxiolytic and sedative effects (UvnaÈs-Moberg et al., 1992; UvnaÈs-Moberg et al., 1994). Further, during the periods when oxytocin release is continuously triggered, as during breast-feeding women are calmer and more social than are non-breast-feeding women. Some correlation data support the assumption that oxytocin play a role in regulating behaviour during this period. The level of calmness is related to basal level of oxytocin in the breast-feeding women and in contrast the number of oxytocin peaks is related to their social competence suggesting that calm and social interaction represent different aspects of the oxytocin pattern (Nissen et al., 1998).
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2.2. Oxytocin and effects on the anterior pituitary Some oxytocin neurons originating in the PVN also terminate in the hypothalamic± pituitary portal system and oxytocin may by this pathway in¯uence the release of hormones produced in the anterior pituitary, for example, adrenocorticotrophic hormone (ACTH) and as a consequence, cortisol. It has been demonstrated that oxytocin has a dual effect on cortisol levels. An immediate rise of cortisol occurs in rats after oxytocin administration, followed by a sustained decrease of cortisol (Petersson et al., 1999a). In humans, it has been shown that exogenous oxytocin induces a decrease of cortisol (Legros et al., 1988). Further, oxytocin has been suggested to be an important prolactin releasing factor in rats and pigs (Mori et al., 1990). Also growth hormone secretion can be in¯uenced by oxytocin (BjoÈrkstrand et al., 1997). 2.3. Oxytocin and antistress Oxytocin may also decrease blood pressure in rats by a central pathway. This effect becomes more prominent after repeated administration of oxytocin. The effects caused by a 5 day treatment with oxytocin lasts for 10 and 20 days after the last treatment in males and females, respectively (Petersson et al., 1996a). In addition, the elevation of pain threshold and also some of the effects on vagal hormones as well as the lowered cortisol levels and anxiolytic like effect in response to repeated administration of oxytocin are long-lasting (Petersson et al., 1996b; Petersson et al., 1996a; UvnaÈs-Moberg et al., 1998). The mechanisms behind these sub-chronic effects are beginning to be elucidated. The elevated pain threshold is related to enhanced activity in the endogenous opioid systems, whereas the effect on blood pressure, cortisol and vagal hormones seems to be linked to an enhanced expression of the central subgroup of adrenergic receptors called a2-adrenoceptors. When these receptors are activated, the ®ring in the central noradrenergic neurons originating in the locus coereleus as well as the activity in the sympathetic nervous system is inhibited and the activity in the parasympathetic nervous system increased, thereby causing an integrated antistress like pattern (BjoÈrkstrand et al., 1996a; Petersson et al., 1996b; Petersson et al., 1998; Petersson et al., 1999b; UvnaÈs-Moberg, 1997; UvnaÈs-Moberg, 1998a; UvnaÈs-Moberg, 1998b). 3. Oxytocin and digestion, anabolic metabolism and growth Oxytocin has been shown to in¯uence the release of gastrointestinal hormones, such as CCK, gastrin and somatostatin, in rats, probably by promoting vagal nerve activity (BjoÈrkstrand et al., 1996a). Oxytocinergic neurons from the PVN project to both the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS) (Sofroniew, 1983), and central oxytocin is suggested to increase and decrease insulin levels through the DMX and NTS, respectively (BjoÈrkstrand et al., 1996b). Such effects promote anabolic metabolism and growth. Peripheral oxytocin has an effect on the release of glucagon from the pancreas and may, thereby, elevate blood glucose levels (BjoÈrkstrand et al., 1996b). Thus, oxytocin may promote both mechanisms by which nutrients are
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mobilised as well as stored, two seemingly opposite functions which are both required for milk production. In non-lactating female rats weight gain is increased following administration of oxytocin (UvnaÈs-Moberg et al., 1996). 4. Effects of oxytocin in the post-natal period As mentioned above oxytocin-induced antistress like effects in response to repeated administration of oxytocin last for weeks after the last treatment. If instead a 5±10 day long treatment with oxytocin is given immediately post-partum, lifelong effects are induced, although they sometimes do not become manifest until onset of puberty. Thus, rat pups exposed to post-natal oxytocin treatment have been shown to have lower blood pressure, lower cortisol levels and higher pain threshold as adults when compared to saline-treated controls. In addition, oxytocin injections given to new-born rat pups have been shown to increase growth after puberty and to result in higher levels of CCK and insulin in the rats when they are adults (BjoÈrkstrand and UvnaÈs-Moberg, 1996; UvnaÈs-Moberg et al., 1998; SohlstroÈm et al., 2000). Thus, administration of oxytocin in the post-natal period induces permanent antistress like effects and stimulates growth, i.e. the animals use energy for growth (UvnaÈs-Moberg et al., 1998). The reason why permanent effects are induced at a very young age may be that neuroendocrine circuits are not fully mature and, therefore, open to in¯uence. 5. The role of oxytocin in dairy cattle As described above, the role of oxytocin is not restricted to milk ejection as previously thought. In fact, behaviour and physiology are also in¯uenced by oxytocin in the lactating animal to facilitate milk production and interaction between mother and young. Furthermore, the role of oxytocin seems not to be restricted to lactating animals, since it also induce analogous effects in non-lactating females and males. Oxytocin is not only released to milking. Also sensory stimuli from other areas in the body seems to cause a release of oxytocin. In the following paragraphs, we will summarise some data obtained in dairy cattle, which show that the more general effects of oxytocin on physiology and behaviour seem to be operating also in these species. 5.1. Milking and oxytocin release in cows Milk ejection in dairy cows has been studied extensively since the ef®ciency of milk let down has signi®cant practical and economical consequences. Since oxytocin is released by various types of tactile stimuli, we have studied the effect of different types of sensory stimulation on oxytocin levels. We have compared the effect of machine milking and hand milking on the assumption that more sensory stimulation is applied by the hands than by the machine, which largely operates by under pressure. For a similar reason, we investigated the effect of suckling by the calf. In a third type of experiments, extra sensory stimulation was given by feeding the cow during milking. As will be presented below, all
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these experimental situations were accompanied by enhanced oxytocin secretion. In some of the experiments, oxytocin related enhancements of milk production and other physiological and behavioural changes consistent with the effect pattern of oxytocin were also induced. 5.2. Hand milking and manual pre-stimulation It is well known that manual pre-stimulation of the teats before the milking machine is attached improves milk ejection and oxytocin secretion (Mayer et al., 1984; Mayer et al., 1985; Phillips, 1965; Sagi et al., 1980). However, also hand milking during the entire milking process has been shown to enhance the plasma levels of the hormones oxytocin and prolactin more than machine milking does (Gorewit et al., 1992). The increased secretion of hormones in response to hand milking is probably related to the enhanced sensory stimulation caused by this procedure. In addition, hand milking has been shown to result in higher milk yield and fat content in the milk compared with machine milking (Hamann and Tolle, 1980; Svennersten et al., 1990a), effects which might be related to the enhanced oxytocin secretion. The effects may be secondary and due to improved udder evacuation, but also direct effects of oxytocin on production and metabolism are conceivable. That oxytocin might be involved in the regulation of milk yield has been indicated by the ®nding that milking related oxytocin levels were positively correlated to milk yield in dairy cows (Johansson et al., 2000), while in humans, the number of oxytocin pulses during suckling were correlated to both prolonged lactation and amount of milk delivered during breastfeeding (Nissen et al., 1996; Nissen et al., 1998). Furthermore, administration of oxytocin to dairy cows between milkings (Morag, 1968) as well as just before or after milking (Nostrand et al., 1991; Ballou et al., 1993) has resulted in increased production. However, it has been questioned whether the enhanced milk yield is an effect of direct action on mammary metabolism (Knight, 1994). 5.3. Suckling Suckling is ought to be the most ef®cient stimulation for milk ejection, since the calf suckling is the natural way to stimulate the teat. The suckling procedure has been described in detail and it has been found that it includes three different phases, pre-stimulation, milk intake and post-stimulation (Lidfors, 1994). Machine milking does not include all these phases. In support of a superior ef®ciency of suckling, suckling caused a greater oxytocin release compared to machine milking (Lupoli et al., 2000). There are some indications that cows which are suckled by the calf have a higher milk production than machine milked animals. Long-term suckling without additional milking in high producing dairy cows may enhance milk yields, as measured from weaning time and later on (Everitt and Phillips, 1971; Walsh, 1974; Krohn, 1999). Suckling may also improve lactation persistency when practised as restricted suckling, i.e. the calf is allowed to suckle on one teat or suckle after milking (Das et al., 1999a). In further support of a positive effect of suckling on milk yield are data showing that routines including both suckling and milking result in higher milk yield as well as elevated oxytocin release
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compared to only milking in dairy cows (Bar-Peled et al., 1995) as well as in ewes (Marnet et al., 1999). 6. Feeding during milking Feeding alone is associated with a release of oxytocin in dogs and sows (UvnaÈs-Moberg et al., 1985) and a feeding-related oxytocin release has been found also in dairy cows, although the rise is much smaller than the milking-induced release (Svennersten et al., 1990b). Two mechanisms may be involved in the feeding-induced oxytocin secretion. One way to increase the release of oxytocin is to activate sensory nerves in the oral mucosa. Since these ®bres project directly to the nucleus of the solitary tract (NTS), which is linked to the PVN, oxytocin may be released. Also an afferent neural vagal link between the stomach, the NTS and PVN has been demonstrated in the rat (Verbalis et al., 1986; Renaud et al., 1987). The vagal in¯uence on oxytocin secretion has been validated in experiments where electrical afferent vagal nerve stimulation increased plasma levels of oxytocin (Stock and UvnaÈs-Moberg, 1988). 6.1. Feeding during milking reinforces milking oxytocin release Milk ejection is also facilitated by feeding during milking. Already during the 1970's, it was found that feeding the cows concentrates immediately before milking had positive effects on milk removal (Velitok, 1977; Brandsma, 1978). And recently, the bene®cial in¯uence of feeding during milking received further support, since it was shown that higher milk production, increased milk ¯ow, and shorter milking time occurred when cows were fed during milking (Samuelsson et al., 1993; Svennersten et al., 1995; Johansson et al., 1999b). Taken together these data indicate that the reason why feeding strengthens milk ejection may be a potentiated oxytocin release and indeed when milking and feeding were combined much more oxytocin was released as during milking only. 6.2. Behavioural and endocrine consequences of the enhanced oxytocin secretion induced by feeding in connection with milking Oxytocin might also in¯uence behaviour as discussed above. When feeding and milking were combined, oxytocin levels were higher and the cows were lying and ruminating more after milking, as an indication for a higher degree of calmness. They also showed more social interactions. In contrast, they had a lower percentage of oral activity, such as feed searching behaviour. That oxytocin does in¯uence behaviour is further strengthened by the positive correlation between oxytocin levels and behavioural expression of calmness (lying down and ruminating while lying down) in the experiments mentioned above (Johansson et al., 1999a; Johansson et al., 2000). In the studies in which milking and feeding were performed at the same time also, the expected milking related rise of cortisol levels was almost absent (Johansson et al., 1999a). Furthermore, the positive correlations between oxytocin and cortisol and between prolactin
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and cortisol observed when milking is performed alone disappeared (Johansson et al., 2000). The lowered cortisol secretion when cows were fed and milked at the same time may be an expression of an enhanced stimulation of the antistress like pattern of oxytocinmediated effects as a response to the increased amount of sensory stimulation. 6.3. Consequences of suckling-induced oxytocin in the calf The feeding-induced release of oxytocin is more pronounced in calves compared to adult cows. Furthermore, suckling results in signi®cantly higher feeding related oxytocin secretion in the calf than bucket drinking does (Lupoli et al., 2000). It is likely that the sensory nerves of the oral mucosa of the calf are more ef®ciently activated when the calf is suckling compared with drinking milk from a bucket. Several studies demonstrate that suckling has long-term effects on the calf. Both calves from high-producing dairy cows and calves from a tropical breed such as Zebu calves have an improved growth rate when suckling is allowed (Das et al., 1999a; Krohn et al., 1999). It is not fully understood why suckling may increase the weight gain of the calves. Suckling may increase the amount of food intake or make the calves more resistant to infections which may lead to healthier calves which grow much better (Everitt and Phillips, 1971; Metz, 1984a; Metz, 1987). Further, Foldager and Krohn (1991) found that suckling in early life results in a higher milk yield during the ®rst lactation period. As discussed above, administration of oxytocin to new-born rats causes permanent effects. The animals grow more and are less stressed. It is not impossible that the observed effects on growth in calves allowed to suckle could be explained by the enhanced oxytocin secretion during suckling compared to bucket feeding. In support of this, more insulin, an important metabolic hormone, was released by suckling in the calves and also oxytocin levels correlated strongly to insulin in the suckling calves (Johansson et al., 2000). As yet, a relationship between suckling-induced oxytocin release and improved growth rate remains a speculation. Further studies are needed to prove this hypothesis, i.e. that the suckling related oxytocin release play a similar role to oxytocin injections given to new-born rats, which are reported above, stimulates growth in new-born pups. References Acher, R., 1985. The non-mammalian Ð mammalian transition through neurohypophysial peptides. Peptides 6, 304±314. Agriolas, A., Gessa, G.L., 1991. Central functions of oxytocin. Neurosci. Biobehav. Rev. 15, 217±231. Ballou, L.U., Bleck, J.L., Bleck, G.T., Bremel, R.D., 1993. The effects of oxytocin injections before and after milking on milk production, milk plasmin and milk composition. J. Dairy Sci. 76, 1544±1549. Bar-Peled, U., Maltz, E., Brackental, I., Folman, Y., Kali, Y., Gacitua, H., Lehrer, A.R., Knight, C.H., Robinzon, B., Voet, H., Tagari, H., 1995. Relationship between frequent milking or suckling in early lactation and milk production of high producing dairy cows. J. Dairy Sci. 78, 2726±2736. BjoÈrkstrand, E., Ahlenius, S., Smedh, U., UvnaÈs-Moberg, K., 1996a. The oxytocin receptor antagonist 1deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin inhibits effects of the 5-HT1A receptor agonist 8-OH-DPAT on plasma levels of insulin, cholecystokinin and somatostatin. Regul. Pept. 63, 47±52. BjoÈrkstrand, E., Eriksson, M., UvnaÈs-Moberg, K., 1996b. Evidence of a peripheral and a central effect of oxytocin on pancreatic hormone release in rats. Neuroendocrinology 63, 377±383.
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