Mild chronic stress leads to desensitisation of presynaptic autoreceptors and a long-lasting increase in noradrenaline synthesis in rat cortical synaptosomes.

An i.p. injection of normal saline combined with 1 min handling when repeated 14 times results in an increase in noradrenaline synthesis in synaptosomes prepared from the cortex of stressed rats; at 24 h synthesis acceleration is greater than at 48 h after the last stress. The activity of tyrosine hydroxylase solubilised from the hippocampus is the same in the control and the stressed group, when assayed at the optimal pH of 5.8 and with saturating concentration (2 mM) of the cofactor 6 MPH(4). However enzyme from stressed rats shows a relative increase in the activity at pH 7.4 assayed in the presence of 0.2 mM 6 MPH(4). This indicates activation, not induction, of the enzyme. 8-Br-cAMP produced the same increase in noradrenaline synthesis in cortical synaptosomes from control and stressed rats; however 50 mM K(+) did not increase synthesis rate in stressed rats. Furthermore in synaptosomes from stressed rats neither isoprenaline (which increases noradrenaline synthesis) nor clonidine with 50 mM K(+) (which leads to a depression of the K(+)-accelerated synthesis) had any effect on synthesis rate. The results suggest that the increased noradrenaline synthesis rate in cortical synaptosomes from stressed rats represents a Ca(2+)-dependent activation of tyrosine hydroxylase resulting from the desensitisation of alpha(2)-autoreceptors.