Pregnancy reduces brain sigma receptor function

1 Sigma (sigma) receptors have recently been cloned, though their endogenou s ligand(s) remain unidentified. However, some neuroactive steroids, such a s progesterone, have a high affinity for these receptors. Some sigma ligand s, such as DTG, (+)-pentazocine and DHEA, act as sigma 'agonists' by potent iating the neuronal response to NMDA. Others, such as haloperidol, NE-100 a nd progesterone, act as sigma 'antagonists' by reversing the potentiations induced by sigma 'agonists'. 2 We compared the effects of sigma 'agonists' in four series of female rats : in controls, at day 18 of pregnancy, at day 5 post-partum, and in ovariec tomized rats following a 3-week treatment with a high dose of progesterone. 3 In pregnant rats and following a 3-week treatment with progesterone, 10 f old higher doses of DTG, (+)-pentazocine and DHEA were required to elicit a selective potentiation of the NMDA response comparable to that obtained in control females. Conversely, at day 5 post-partum and following the 3-week treatment with a progesterone and after a 5-day washout, the potentiation of the NMDA response induced by the sigma 'agonist' DTG was greater than in control females. 4 The present data suggest that endogenous progesterone acts as an 'antagon ist' at sigma receptors. The resulting changes in the function of sigma rec eptors during pregnancy and post-partum may be implicated in emotional phen omena occurring during these periods.