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Oxytocin, the most powerful uterotonic agent known, is released from the pituitary gland in large amounts during parturition in all placental mammals studied so far, including humans. Although parturition can proceed in its absence, oxytocin is thought to play an important role (see Russell & Leng, 1998). In the rat, pregnancy normally lasts for 21 days. About 24 h before the pups are born, increased production of prostaglandins by the uterus induces luteolysis, and ovarian progesterone production falls dramatically. This fall is an essential prelude to parturition; if prevented, then the rat pups will remain unborn. The fall leads to a further increase in prostaglandin production, and, directly or indirectly, to a host of changes that prepare the uterus and birth canal for parturition. In the last few hours of pregnancy, oxytocin receptors appear in high concentrations in the uterus, and establish a positive-feedback loop between the uterus and the hypothalamic oxytocin system. Uterine contractions, triggered by prostaglandins, excite the oxytocin cells, and oxytocin release triggers further prostaglandin production and further uterine contraction. Thus progesterone plays a critical role in the timing of parturition through its peripheral actions (see Leng & Brown, 1997).
A paper in this issue of The Journal of Physiology (Brussaard et al. 1999) suggests that actions of progesterone at the oxytocin cells in the hypothalamus may also be important for parturition. Classically, progesterone acts through specific intracellular receptors to regulate gene expression. However, metabolites of progesterone can also have membrane actions, and in particular, allopregnanolone can act at GABAA receptors to potentiate the actions of GABA, depending upon the particular subunit composition of the receptor. GABA is an important neurotransmitter for oxytocin cells - about 45 % of all synapses onto them contain GABA, and the total number of GABA synapses in the supraoptic nucleus is substantially higher in lactating animals than in virgins (El Majdoubi et al. 1997). The GABA innervation appears to play a role in patterning the pulsatile discharge of oxytocin cells that is observed both during parturition and during suckling-induced reflex milk ejection (Moos, 1995; Voisin et al. 1995).
Brussaard et al. (1999) recorded GABAA receptor-mediated spontaneous monoquantal inhibitory postsynaptic currents (sIPSCs) from rat supraoptic neurones in hypothalamic slices in vitro. They found a higher incidence of sIPSCs in pregnant rats than in virgin rats, consistent with the observations of an increase in the density of GABA-containing synaptic boutons. Importantly, the sIPSCs were markedly prolonged in the presence of allopregnanolone. Taking into account the frequency and amplitude of sIPSCs, the action of allopregnanolone and the hypertrophy of oxytocin neurones in lactation (reflected in increased capacitance), Brussaard et al. (1999) inferred that the effective GABAA receptor-mediated synaptic current density was much greater in pregnant rats than in virgin or lactating rats.
Thus the collapse of progesterone production at term may abruptly reduce the effectiveness of GABA inhibition, and thereby enhance the excitability of oxytocin cells. Clearly this may be important during parturition, but the effect may not persist for long. Indeed, within a day the duration of sIPSCs is significantly longer in the absence of allopregnanolone, which now has no significant effect. This seems to be due to a rapid switch in the types of 
subunits inserted into the GABAA receptors. By mid-lactation, a massive change in expression of GABAA receptor subunit mRNAs is apparent. With competitive polymerase chain reaction Brussaard and colleagues found that, while the expression of both 1 and 2 subunit mRNAs was increased, the ratio of 1 : 2 subunit mRNA expression was changed 8-fold in favour of 2 subunit mRNA. This change evidently underlies the enhancement of GABAA receptor-mediated inhibition similar to that achieved by allopregnanolone in pregnancy, and together with a sustained increase in sIPSC frequency, provides a basis for increased GABA action in lactation.
The story, though intriguing, is far from complete. The supraoptic nucleus contains vasopressin cells as well as oxytocin cells, and it is not clear that the changes in GABA efficacy are specific to oxytocin cells. In addition, GABA receptors are expressed not only on the cell bodies and dendrites of supraoptic neurones, but also on the nerve terminals, where they may modulate stimulus-secretion coupling (Jackson & Zhang, 1995); the physiological significance of this site of action of GABA is still unclear. The mechanisms that are responsible for the switch from 1 to 2 GABAA receptor subunit expression at the end of pregnancy, and for the reversal of the altered pattern at the end of lactation, also remain unknown. Finally, what physiological stimuli regulate the activity of the afferent GABA neurones?
| Brussaard, A. D., Devay, P., Leyting-Vermeulen, J. L. & Kits, K. S. (1999). The Journal of Physiology 516, 513-524 | [Medline] |
| El Majdoubi, M., Poulain, D. A. & Theodosis, D. T. (1997). Neuroscience 80, 1137-1147 | [Medline] |
| Jackson, M. B. & Zhang, S. T. (1995). The Journal of Physiology 483, 597-611 | [Medline] |
| Leng, G. & Brown, D. (1997). Journal of Neuroendocrinology 9, 493-513. | |
| Moos, F. (1995). The Journal of Physiology 488, 103-114 | [Medline] |
| Russell, J. A. & Leng, G. (1998). Journal of Endocrinology 157, 343-359 | [Medline] |
| Voisin, D. L., Herbison, A. E. & Poulain, D. A. (1995). The Journal of Physiology 483, 211-224 | [Medline] |
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