| Objective To investigate the effects of multiple factors [e.g. etiological factors, parameters of electroconvulsive therapy (ECT), and anesthetics] on behavior, learning and memory, and hippocampal brain derived neurotrophic factor (BDNF) expression in depressed rats undergoing ECT pretreated with propofol and the potential interaction. The effects of ECT pretreated with propofol on long term potentiation (LTP) in hippocampal slices and expression of mRNA and protein level of related synaptic proteins were also included, so as to study propofol's regulation of ECT's efficacy and improvement of ECT-induced learning and memory deficits in depressed rats, and the possible mechanism in the view of synaptic plasticity.MethodsPart I: Healthy adult male Wistar rats (2-3 months, 200-250 g) were randomly divided into 11 groups (n=8). Except for the normal breeding of rats in the control group (group C) for 28 d, the other rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the rodent model of depression. The 10 groups of depressed rats were assigned to treatments according to (2×5) factorial design, with drug factor (normal saline or propofol) and stimulus intensities of ECT (0, 60, 120, 180, and 240 mC) as the two factors. These depressed rats were assigned into two major groups, each received ECTs with pretreatment with either propofol (10 g/l)(group M) or normal saline (group E) (9 ml/kg, i.p.). There were five sub-groups in each major group, the rats of which received ECTs with different stimulus intensities (0 mC, 60 mC, 120 mC, 180 mC, 240 mC) once daily for 7 days. Other parameters of ECT: square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.4, 0.8, 1.2, 1.6 s (for 60 mC, 120 mC, 180 mC, 240 mC). Sucrose preference test (SPT) and open field test (OFT) were performed to assess depressive behavior. Morris water maze task (MWM) was used to measure learning and memory. Hippocampal BDNF protein level was measured with enzyme linked immunosorbent assay (ELISA).Part II: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 9 groups (n=9). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. The 8 groups of depressed rats were assigned to treatments according to (2×2×2) factorial design, with (environmental or genetic factors), ECT (or sham ECT), and drug factor (normal saline or propofol) as the three factors. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CD with Wistar rats; genetic: group KD with WKY rats); depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CP with Wistar rats; genetic: group KP with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CE with Wistar rats; genetic: group KE with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CM with Wistar rats; genetic: group KM with WKY rats). SPT and OFT were performed to assess depressive behavior. MWM was used to measure learning and memory. Number of hippocampal neurons was observed with Nissl stain, and BDNF protein level was measured with ELISA.Part III: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 5 groups (n=11, except for 11 Wistar rats in group C, each of the other 4 groups included 5 WKY rats and 6 Wistar rats). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) in group D; depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group P; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) in group E; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group M. 5 Wistar rats in group C and the WKY rats in the other 4 groups were used for measuring LTP in hippocampus with electrophysiological methods; all the rest Wistar rats in each group were used for assaying mRNA and protein level of Synapsin I, PSD-95, GluR1, CREB (p-CREB), NR2A/B with western blotting and real-time RT-PCR.ResultsPart I: The CUMS-treated rats exhibited depressive behavior and impairment of learning and memory; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; When ECT was pretreated with propofol, by the increase of stimulus intensities, propofol's effects on the anti-anhedonia efficacy and elevating effects on hippocampal BDNF of ECT were turnovered from weakening to strengthening; both the weakening effects on ECT's improving effects on spontaneous exploring activities and protective effects against ECT's impairment of learning and memory of propofol were weaken. Propofol and stimulus intensities interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.Part II: Both the environmental and genetic rodent model of depression exhibited depressive behavior, reduced number of hippocampal neurons and BDNF expression, and deficits of learning and memory. Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; the improving effects of ECT on depressive behavior and hippocampal BDNF were weaker, while ECT-induced learning and memory deficits were more severe in WKY rats; When ECT was pretreated with propofol, propofol could enhance the anti-anhedonia, elevating hippocampal BDNF effects of ECT, and attenuate ECT's improving effects on spontaneous exploring activities and ECT-induced learning and memory impairment, while these effects were weaker in WKY rats than CUMS-treated Wistar rats (except for effects on spontaneous exploring activities); all the treatments exerted no signinficant effects on hippocampal neurons: etiological factors for depression, ECT, and propofol interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.Part III: In the depressed rats, both hippocampal LTP and the expression of related synaptic protein and their mRNA were inhibited to different extent; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could not relieve the changes of expression of mRNA of synaptic proteins; Without reversing the other proteins'lower expression, ECT recovered Synapsin I protein expression to the level as group C, but more severely inhibited LTP and down-regulated expression of PSD-95 and p-CREB proteins; When ECT was pretreated with propofol, propofol could up-regulate LTP and expression of mRNA of PSD-95 and NR2A to the level of group C, down-regulate expression of Synapsin I protein, and up-regulate expression of the other proteins to different extent (except for PSD-95, all the other proteins were regulated to the level of group C).Conclusions Propofol has interaction with stimulus intensities to differently regulate ECT's efficacy and amnesic effects in both behavioral and molecular levels; Response to ECT and propofol's regulation in ECT were less significant in genetic rodent model of depression than environmental model; Propofol's regulation of ECT's effects is exerted by regulation of hippocampal synaptic plasiticity and related synaptic proteins.
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