Inhalt
 
A Neurophysiologic Model of the Circuitry of Oxytocin in Arousal, Female Distress and Depression
Rainer K. Liedtke, MD, Munich Germany
PHARMED INSTITUTE OF CYBERNETICS
 
PIC Res. Comm. 3/2004
(rev. DPEA 99/00)
 
 
Abstract. A neurohormonal Entity Relationship Modeling for the natural peptide neuromodulator Oxytocin (OXT) reveals that its central administration is suitable for a therapy of female distress and depressive mood. Centrally administered OXT has a controlling role in sexual arousal and mood with a direct and interactive link to peripheral neuromuscular and hypothalamo pituitary axis actions. The biological effects of OXT therefore go beyond its known therapeutic effects. This needs a reconciliation of OXT’s traditional pharmacological role.
 
Introduction
Oxytocin (OXT) was known until quite recently only as a peripheral hormone with the traditional therapeutic focus on the pregnant myometrium and the myoepithelial cells of the lactating breast. Actual neurophysiological research, in particular concerning OXT’s mood modulating and prosexual effects revealed, that OXT is present in a range of neurons and axons in the brain, mostly in the limbic system but also in the spinal cord indicating that the biological effects of OXT go beyond the known therapeutic effects. This needs a reconciliation of OXT’s traditional pharmacological role. Due to the lack of suitable method of central administration the therapeutic consequences of a possibly distinct outcome of centrally administering OXT have not been investigated or considered. The following focuses on the aspect of female reproductive behavior as peripheral interaction with OXT’s central action. It does not discuss the hormonal aspect of OXTs hypothalamo pituitary axis (HPA) influence by ACTH suppression, and also not OXTs involvement in nociception.
Reproductive behavior and specific pharmacological effects
Animal studies show that OXT centrally induces female reproductive behavior, including sexual arousal, orgasm, gamete transport and specific maternal behaviors such as breast-feeding and bonding between mother and infant, which can be abolished by OXT antagonists (1-3). OXT is also involved in human female sexual arousal and sexual activity. Human studies showed that OXT is already involved in the phase of sexual arousal and that such psychological change corresponds with OXT levels (4). Its peripheral levels change during sexual activity and orgasm (5), and its application effected sexual arousal (6), also showed correlation with emotional personality measures in women (7).
The central aspect of sexual arousal induced by OXT obviously represents a more basic mechanism. A specific peripheral pharmacodynamic effect is OXT’s modification of neuromuscular transmission. This effect is not limited to stimulate muscular uterine activity at birth or myoepthelial muscle for milk ejection. Consequently the hypothesis was formulated that the OXT induced central arousal processes should be directly linked to its specific peripheral pharmacological effect to stimulate contraction of smooth muscles. This are in this case specifically the muscles in the genital pelvic area, which are involved in the psychological and physiological process of sexual arousal (8).
This aspect appears as confirmed: The female orgasm basically includes contractions of the pelvic floor (9), i.a. e.g. of the pubococcygeus muscle (10). It could be demonstrated that OXT is also able to exert its pharmacological effects on various specific muscles which are involved in such processes. This are e.g. the anococcygeal muscle (11), preparations of isolated animal and human vagina (12), human cervix (13), and female rat bladder (14). As a vice versa confirmation a pelvic neurectomy blocked the OXT induced sexual receptivity in female mice (15) and, in addition, the orgasm in women with spinal cord injuries is also reduced compared to able-bodied women (16).
We concluded that OXT presumably sensitizes from its hypothalamic origin, primarily the Paraventricular Nucleus (PVN) and the Supraoptic Nucleus (SON) , but presumably also the Ventromedial Nucleus (VMN), neurons associated with the pelvic floor muscle contractions. The PVN contributes oxytocinergic neurons to the dorsal horn and preganglionic sympathetic and parasympathetic cell columns. Oxytocinergic innervation was also identified from lumbosacral nuclei controlling penile erection in rats (17), and a PVN stimulation also induces penile erection presumably triggered by activation of spinal neurons (18). More specific it was found that also pudendal nuclei are binding sites for OXT receptors (19). A neural feedback may activate, possibly via i.a. VMN (20) also axons to higher cortical projections responsible for the cognitive feelings of sexual arousal. Important in this context is the finding that sensoric information arising from penile tactile stimulus at the rat excites OXT cells in the SON (21).
The fact that OXT does not reveal effect consistency in some target organs can be explained that it’s receptors are partly transient. The effects are modulated on the receptor level by endogenous sex steroids, in particular 17ß-Estradiol (22) and Progesteron. Consequently circulating OXT levels are also dependent from exogenous steroids (23-25).
Importance of the application route
An essential aspect for the effect is a route of OXT administration which provides an initial OXT signal log-in at the CNS level. For this purpose a specific trans-nasal application appears suitable. Conventional nasal OXT application is already in use to induce milk ejection, but this was only considered as a more convenient technical alternative to injections, therefore pursued a peripheral effect. The reason why CNS effects were not seen in patients after peripheral OXT injection can be explained that peptides usually do not cross the brain-blood barrier. In fact the central route reveals a different therapeutic quality than a systemic injection targeting peripheral receptors. There is evidence for a direct brain pathway for peptide effects in humans (26). More specific mono-synaptic projections to supraoptic neurons from the olfactory bulb exist (27), which is the site where OXT induces a rapid onset of maternal behavior (28), and in which obviously also the norepinephrine system is involved (29). This means that OXT enters the brain on a privileged route and acts as a specific external CNS stimulator of hypothalamic nuclei.
Conclusions
OXT represents in the CNS a basic link for the neuro-humoral interaction of psychological and physiological processes in human sexual arousal and mood. The mechanism is directed from the CNS and realized on two routes, by pharmacological effects to modify neuromuscular transmission in specific muscular targets and by HPA suppression (Fig. 1) This interacts through neuromuscular
Fig 1. A simplified neuro-humoral circuitry of OXT action
Legend: A central input and its feed backs. RO (Regio Olfactoria), BO (Bulbus Olfactorius), TOF (Tractus Olfactorius), PVN (Paraventricular Nucleus), SON (Supraoptic Nucleus), VMN (Ventromedial Nucleus), ORLN (spinal OXT receptor; lumbosacral parasympathetic nucleus), GA (Gonadal Apparatus), E2 (17ß-Estradiol), P (Progesteron), TST (Tractus Spinothalamicus), PG (Posterior Pituitary Gland), HPA (Hypothalamo-Pituitary Axis), CORT (Cortisol) NA (Noradrenergic System), TO (Target Organ).
CNS feed back and can be considered as a biological mechanism of stress balance regulation. Sex steroids induce effect modifications on the OXT receptor level. Such process can be described by a complex integrated neuronal circuit. Symptoms of sexual distress may therefore represent a decline of OXT’s CNS activity level compared to physiological conditions, in essence a temporary OXT “exhaustion syndrom”. Consequently a temporary CNS OXT stimulation should therefore, under these conditions, lead to a dual effect consisting of an increase of cortical arousal and HPA mediated reduction of depressive distress. In this context it is of interest that OXT showed in two animal models antidepressant effects which were comparable with those of Imipramin (30). It was recently suggested that OXT is a mediator of SSRI induced antidepressant effects of citalopram (31). These pharmacologically induced anti-stress effects seem to be comparable with effects seen at lactating women since this physiological process which is essentially influenced by OXT, also suppresses the HPA stress axis with a prompt decline of Cortisol (32). Receptor influencing hormones (e.g. Estradiol-17ß, Progesterone) are involved in the process, thus the concomitant actual status of regulating sex steroids and their OXT interaction has to be included in practical therapeutic considerations.
In summary OXT's central neurotransmitter actions to induce central arousal thus is controlled by specific hypothalamic nuclei and obviously this represent its basic mechanism of action. This triggers in a defined cascade of neuronal and hormonal events the peripheral effects to modify neuromuscular transmission. From a therapeutic view centrally administered OXT leads to an interactive effect consisting of a reduction of stress and an increase of central arousal.
References (1) Benelli A. et al., Neuropeptides 1994, 27(4) 245, (2) Caldwell J.D. et al., Brain Res. 1990 (512) 291, (3) Arletti R. et al. Neuropeptides 1985, 6 (3) 247, (4) Camichael M.S et al., J. Clin.Endocrinol. Metab. 1987, 64(1)27, (5) Blaicher W. et al., Gynecol. Obstet. Invest. 1999, 47 (2) 126, (6) Anderson-Hunt M. et al., Br. Med. J. 1994, (309) 929, (7) Turner R.A. et al. Psychiatry 1999, 62 (2), (8) Carmichael M.S. et al., Arch. Sex. Behav. 1994, 23(1)59, (9) Bohlen J.G. et al., Arch. Sex. Behav. 1982 11(5) 367, (10) Graber B. et al.,J. Clin. Psychiatry,1979,40(8) 349, (11) Gibson A. Br. J. Pharmacol. 1986 88(1) 155), (12) Latocha W., Ginekol Pol. 1968 39(8) 837, (13) Bryman I. et al. , Obstet. Gynecol. 1990 75(2) 240, (14) Pandita R.K. et al., Neuroscience 1998, 85(4) 1113, (15) Moody K.M. et al, Physiol. Behav. 1994, 56 (5) 1057, (16) Sipski M.L. et al.,Arch. Phys. Med. Rehabil, 1995, 76 (12) 1097, (17) Tang Y. et al., Neuroscience, 1998, 82(1) 241, (18) Veronneau-Longueville F. et al., Neuroscience, 1999 93(4) 1437, (19) Tribollet E. et al Neuroscience, 1997, 78(2) 499, (20) Kow L.M et al., Neuroendocrinology 1991, 54(5) 526, (21) Honda K. et al. Brain Res. Bull., 1999, 48(3) 309, (22) McCarthy M.M., Adv. Exp.Med, Biol. 1995 (395), 235, (23) Bossmar T. et al. Acta Obstet. Gynecol. Scand, 1995, 74 (7) 544, (24) Stock S. et al. Gynecol. Endocrinol. 1994 8(2) 121, (25) Stock S. et al., Acta Obstet.Gynecol. Scand, 1989, 68(1)75, (26) Pietrowsky R. et al., Biol. Psychiatry 1996, 39(5) 332, (27) Hatton, G.J. et al., Progr. Brain Res. 1998 (119) 77, (28) Yu G.Z et al. Neuroscience 1996 72(4) 1083, (29) Dluzen, D.E. et al., Neurosci. Lett. 1998 254(3) 161 , (30) Arletti R. et al., Life Sci. 1987, 41 (14) 1725, (31) Uvnas-Moberg K.et al, Psychopharmacology, 1999, 142 (1) 95. (32) Uvnas-Moberg K., Acta Physiol. Scand, Suppl. 1997 (640) 38.
 
APPENDIX
POSTPARTAL DEPRESSION - A CLINICAL PARADIGM
Pregnancy and childbirth has significant psychological and physiological effects on a woman’s body. Postpartum depression is fairly common though not yet well understood. A causal link between the hormonal changes and the change in mood has been suggested. The mood disorders associated with childbearing are traditionally divided in three categories that reflect severity: postpartum blues, postpartum depression and postpartum psychosis. It is estimated that while 80% of women may experience negative fluctuations postpartum, 10%-20% may criteria for major depression and 0.1%-0.2 % will show signs of psychosis. Blues and slight depressions usually may disappear after two to fours weeks whereas treated depressions may show improvement in three to six months. Both depressed mothers and their babies have increased amounts of Cortisol in their blood and the high Cortisol levels make the infants vulnerable to overreacting to stress later in life. OXT causes a dose-response reduction of ACTH and consequently of Cortisol. Also breast feeding can suppress the stress axis, as suckling induces an attenuation of plasma Cortisol in postpartum lactating women. (1,2). OXT is elevated in early postpartum in women (3) and a rise of OXT plasma levels was found suckling-related. (4,5) This effect persisted during the whole lactation period, and is also seen in animals (6). No significant differences concerning the free 17ß-Estradiol and Progesterone could be found between women with and without postpartum blues (7). A postnatal application of Norethisteron, given within 48 hours of delivery, was considered to be associated with a higher risk to develop postnatal depression (8). In the framework of the basic therapeutic issue also postpartum sexuality should be included in considerations. It was reported from an interview study that women who were breast-feeding showed less sexual activity than women who were not (9). Also a nipple stimulation in non-pregnant women can lead to a rise of OXT level (10). It is also known that nursing may enhance female cortical arousal and in animal studies it was found that OT inhibits infanticide in female mice (11).
Conclusions . The symptoms of depressive mood may be due to an acute decline of OXT activity level compared with physiological conditions, therefore may represent in essence an actual OXT “exhaustion effect” or a “withdrawal effect”. In this context the Postpartum depression may be considered as an acute case of a particularly extensive OXT withdrawal effect after delivery compared to the high activity levels existing in the last months of pregnancy and at parturition. A temporary OT substitution in the postnatal phase should reduce HPA stress axis and endogenous OXT stimulation due to breast-feeding should be included in the consideration of effects.
References. (1) Amico J.A. et al, Endocrin. Res., 1994, 20(1) 79 - (2) Chiodera P. et al, Horm. Res. 1991, 35 (3)119) – (3) Nissen E.et al.,Acta Obstet.Gynecol.Scand, 1995,74(7)530 – (4) Johnston J.M, J. Clin. Endocrinol. Metab. 1986, 62(4) 653 – (5) Uvnas-Moberg K, Acta Obstet. Gynecol. Scand.1990, 69(4)301 – (6) Okrasa S. et al., Exp. Clin. Endocrinol. 1989, 93(1) 95 – (7) Heidrich A. et al., J. Affect. Disord. 1994, 30 (2) 93 – (8) Lawrie T. et al., Br. J. Obstet. Gynaecol. 1998, 105 (10) 1082 – (9) Byrd J.E et al. J. Fam. Pract. 1998, 47(4) 305 – (10) Amico J.A. et al, Clin Endocrinol.(Oxf) 1986, 25(2) 97 – (11) McCarthy M.M., Horm. Behav. 1990, 24(3) 365
 
© 2010 Rainer K. Liedtke