Oxytocin and carbetocin ameliorating effects on restraint stress-induced short- and long-term behavioral changes in rats.

OBJECTIVES: Carbetocin (CBT), an oxytocin (OXY) analog, was designed to exert prolonged peripheral actions. It has also been proposed as potential therapeutic mean in certain psychiatric disorders where OXY role has been implicated. This study examined the effects of both peptides on behavior of naive and restraint stress exposed rats in the open field (OF) and elevated plus maze (EPM) tests.

METHODS: Spontaneous behavior in the OF and EPM was measured in Wistar rats after intraperitoneal (i.p.) application of OXY or CBT and/or repeated restraint stress. Behavioral parameters were recorded and subsequently elaborated by an automated activity monitoring system (AnyMaze, Stoelting, U.S.A.). Changes in the total movement distance (TMD) and movement in the center area (CMD) were postulated as indicators of the anxiety level.

RESULTS: OXY (0.05 mg/kg) and CBT (0.3 mg/kg) increased TMD but not CMD 60 min after the i.p. treatment; the increased locomotion/exploration indicate participation of arousal/vigilance. Daily stress exposures for three consecutive days, followed by behavioral tests, reduced locomotion of rats in OF and EPM tests; OXY and CBT partly prevented these effects. Five days after the last stress, rats exhibited an increase of both TMD and CMD in the OF. CBT but not OXY prevented these long-term post-stress changes. In the EPM the stressed rats exhibited an increase in time spent in open arms; CBT accelerated this time development. Similar prevention of stress behavioral sequel in OF were obtained in study when stress and peptides were applied for three consecutive days but behavioral testing was postponed for several days to determine the long-lasting effects. CBT reduced the developed locomotor enhancement (6-11 days post-stress) irrespectively whether injected before or after stress.

CONCLUSIONS: Repeated restraint stress exposure produced acute and persisting effects on Wistar rat behavior in the OF and EPM tests. CBT either injected before or after stress practically abolished the developed changes in the mobility parameters. The CBT effectiveness to ameliorate the late post-stress behavioral alteration supports the notion of its therapeutic potential in psychiatric disorders in which the role of OXY has been implicated.