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Chronic desipramine treatment increases activity of noradrenergic postsynaptic cells
Pergamon Press
Life Sciences, Vol . 25, pp . 709-716 Printed in the U .S .A .
CHRONIC DESIPRAMINE TREATMENT INCREASES ACTIVITY OF NORADRENERGIC POSTSYNAPTIC CELLS Yuag H. Huang Department of Psychiatry Yale University School of Medicine New Haven, Connecticut 06510 (Received in final form July 19, 1979) Summar~ Chronic administration of tricyclic antidepressant drugs has been shown to exert multiple influences on various mechanisms of noradreaergic nervous systems. To determine the overall effect of these influences, this study ezamined the effect of long-term desipramine administration on the firing rate of noradreaergic poataynaptic neurons, specifically, those in the rat hippocampua Daily injections that were inhibited by the nucleus locus coeruleus . for 3 weeks of 5 or 10 mg/kg desipramine resulted in a 32x or 49% increase, respectively, of hippocampal cell activity, suggesting that long-term deaipramine treatment is antagonistic to noradrenergic functions . Chronic treatment with the tricyclic antidepressant drugs (TADe) imipramiae and deaipramine has bees shown to produce multiple effects on various mechanisms of noradreaergic nervous systems. Some of these effects may be seen as inhibi For instance, tory to noradrenergic functions, while others are facilitatory . long-term tricyclic treatment has been found to decrease tyrosine hydroxylase activity (1) or the firing rate of noradreaergic neurons (2), which may lead to as eventual reduction in the amount of norepinephrine (NE) available to target cells. On the other hand, chronic tricyclic administration has been found to increase NE turnover (3), inhibit amine reuptake (3), decrease S-adenosyll~methionine (4), or reduce the sensitivity of presynaptic a-receptors (5), all of which may result is an increase in the amount of transmitter in the synapse . Since both facilitatory and inhibitory effects are produced, the question is raised as to whether these opposing effects cancel each other out or whether one of them dominates, leading to a net effect of facilitation or suppression. The question is not settled by recent biochemical reports on the receptor Long-term administration of sensitivity of noradrenergic postsynaptic neurons. TADs has been found to decrease the accumulation of adenosine cyclic 3' :5'~mono phosphate in response to NE (6,7) and to inhibit the binding of ß~adrenergic antagonists (7-9) . If these decreases indicate suppression of noradrenergic poetsynaptic sensitivity, such sensitivity alteration could participate in determining the net effect of the drug, but would not indicate the nature of the net effect . The baseline firing rate of noradrenergic posteyaaptic neurone should be a function of both the responeivenesa to NE of these neurons and the NE levels in the synapse. It is, of course, the final outcome of events of pre- and 0024-3205/79/080709-07$02 .00/0 Copyright (c) 1979 Pergamon Press Ltd
71 0
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
postsynaptic neurons which is transmitted to other parts of the brain . Thus, postsynaptic activity measurements should be useful is determining the set effect . The aim of the present study was to determine the baseline firing rate of hippocampal pyramidal cells in rate chronically treated with desipramine (DMI) . The hippocampal pyramidal cells inhibited by stimulation of the locus coeruleus (LC) were assumed to be noradrenergic postaynaptic neurons . Compared with cells obtained from saline-injected rata, those from DMI-treated animals showed a substantial increase in their baseline firing rates, suggesting that chronic treatment with DMI eventually suppresses noradrenergic functions . Methode Electrical stimulation of the nucleus locus coeruleus Male alblno rats weighing 250-400 grams were anesthetized with urethane (1 .6 gm/kg, i .p .) and a concentric bipolar electrode was implanted into the LC . The stereotaaic coordinates were determined for each rat by monitoring the electrical activity of single neurons in and near the LC via a microelectrode. The bipolar electrode consisted of 100 um tungsten wire carried within the lumen of a 350 um stainless steel tube with the wire protruding about 300 um from the tube . Both the wire and the tube were insulated except at the cut ends . The stimulus current was biphasic with a phase duration of 0 .05 - 0.2 meet, an intensity of 0 .05 - 0 .2 mA, sad a frequency of 5 - 30 Hz . The stimulus train was usually applied for 30 sec . Recording CA1 pyramidal cell activity Unit activity is the hippocampal CA1 area, ipsilateral to the side of LC stimulation, was monitored via micropipettes filled with a Fast Greeasaturated, 2 M NaCl solution . Each unit was monitored for at least 20 min so that a representative discharge level could be obtained . This was required because some hippocampal cells showed a large variation is their activity . Amplified unit activity was led to a stimulus artifact auppreasor which allowed quantitative analyses of unit activity during high frequency stimulation (10) . The output from the artifact suppreesor was in turn fed to a storage oscilloscope, an audio monitor, and a Schmitt circuit for amplitude and duration discrimination . The output from the circuit, integrated over 1 or 10 sec intervals, was recorded on both a Gould event recorder and a Datel digital printer. Histology At the conclusion of the recording experiments, a discrete electrolytic lesion was made at the stimulation site by passing a negative 20 uA current for 7 sec and Fast Green was deposited at the recording site by passing a negative 20 uA current for 12 min. These sites were later identified hietologically by examining 50 Um sections stained with cresyl violet . Data were analyzed only from the animals with correct placements of the stimulating electrode is the LC (Fig . lA) and recording electrodes is the stratum pyramidale of CA1 (Fig . 1B) . Drug used Rate were given daily intraperitoaeal injections of deaipramine HC1 (Geigy) 5 mg/kg or 10 mg/kg. Control animals received daily intraperitoaeal injections of saline is amounts equivalent to that of the DMI solution . The injections were continued for 21 days and~aubaequently the recording experiment was performed on the 22nd day .
Vol . 25, No . 8, 1979
Desipramine and Hippocampal Cells
711
Data analyses Each CA1 pyramidal cell encountered was tested to determine whether it was first inhibited by LC stimulation . The magnitude of inhibition, referred to as overall inhibition, waa calculated from : 1 - the firing rate during the stimulation/prestimulation rate, where the prestimulation rate was derived from a 60 sec record immediately preceding stimulation . Only those unite which showed at least a 30Z overall inhibition (Fig . 1C) and whose activity was recorded for at least 20 min were used to assess baseline firing rates .
LC
Lc
FIG . 1 _A and B : Photographs taken from sections of brain tissues stained with cresyl violet . _A shows a stimulated site is the locus coeruleus (LC), which was marked by a small electrolytic lesion . _B shows a recorded site, deposited with Fast Green, in the stratum pyramidale of CA1 of the hippocampus . _C and _D : Photographic records of electrical activity of a CA1. pyramidal cell taken from a storage oscilloscope . A current applied to the LC of 0 .1 mast pulse duration, 0 .1 mA, and repeated at 10 Hz (~ or 30 Hz D(, produced a marked decrease of hippocampal cell activity . _E and F show another example of LC-induced inhibition ; the stimulus current was 0 .1 meet pulse duration, 0,1 mA, and repeated at 30 Hz . The calibration at F are 2 sec .4 mV for C-D, and 10 sec 1 mV for E-F .
71 2
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
Results This report was based on 52 CA1 pyramidal cells in 11 saline-injected rate, 60 in 13 rats chronically treated with 5 mg/kg DMI, and 53 in 9 rate chronically given 10 mg/kg DMI . The effects of LC stimulation on hippocampal pyramidal cells is DMI-treated rats . Since each hippocampal pyramidal cell encountered was studied for its responses to LC stimulation, it was possible to compare the responses among the three groups of animals . Activation of the LC suppressed similar per ceatages of hippocampal pyramidal cells in the three groups : 81X of cells in the saline group, 75X in the 5 mg/kg DMI group, and S1X in the 10 mg/kg DMI group . LC stimulation produced a similar magnitude of inhibition among the three groups . At the current of a 0.15 msec pulse duration, 0.15 mA and 10 Hz for 30 sec, the overall inhibition was 59 .1X (+_ 9 .2, N ~ 42) for the control group, 58 .2X ~ 8 .7, N ~ 45) for the 5 mg/kg DMI group, and 54 .7X 8 .3, N 43) for the 10 mg/kg DMI group. Although the drug-treated animals showed leas inhibition than did the control, the difference was not significant .
L
The baseline firing rates of LC-responsive hippocampal pyramidal cells follow chron ic DMI treatment.
ing
Figure 2A compares the mean firing rates of LC-responsive hippocampal pyramidal cells recorded from the three groups . The mean baseline rate for saline-injected rats was 5 .88 Hz ~± 1.01, N ~ 34). . The mean firing rate for 5 mg/kg DMI rata was 8 .11 Hz (+_ 1.16, N ~ 40), 32X faster than the control, but this difference was not significant statistically. The mean rate for 10 mg/kg DMI animals was 9 .19 Hz ~± 0.88, N - 34), 49X faster than the control and the difference was significant (t ~ 2.03, d .f . ~ 68, p < .05) . The difference between the two drug-treated groups was not significant. Figure 2B shows the percentages of units plotted against three ranges of firing rates, 0 - 4 .9, 5 .0 - 9 .9, and 10 Hz or more . The majority of units in the control rats fired at the lowest range while the opposite wse itos with 10 mg/kg DMI animals . The results with the 5 mg/kg DMI group appears to lie between the saline and the 10 mg/kg DMI groups . The Chi square test indicates that the difference between the saline and the 10 mg/kg DMI groups was significant (X 2 - 7 .03, d .f . ~ 2, p < .05), but that the differences between the saline and the 5 mg/kg DMI groups or between the two drug groups were not .
Diacuasion Chronic treatment with DMI altered neither the percentages of units affected nor the magnitude of inhibition produced by LC stimulation . This is of interest is view of the data on the sensitivity of noradrenergic postsynaptic neurone . If poatsynaptic sensitivity is indeed reduced by chronic DMI, as suggested by biochemical studies (6-9), the similar efficacy of LC stimulation to induce hippocampal inhibition would indicate that the amount of NE released per nerve impulse sad then made available to hippocampal cell receptors is greater in DMI-treated preparations than in controls . This interpretation is consistent with the currentlq available data concerning the effects of chronic
Desipramine and Hippocampal Cells
Vol . 25, No . 8, 1979
A
10
N W H
5
0
B
SALI NE
D~A I 5 Mß/KG
SALINE
DMI 5MG/KG
D1A I 10 MO/KG
60
40
Z
~ 20
0
DMI 10 MG/KG
FIG . 2 A shows the~mean firing rates of locus coeruleue-responsive hippocampal pyramidal cells recorded from different groups of rata . B shows the percentages of unite firing at 0 - 4 .9, 5 .0 - 9 .9 or faster Hz . The difference between the saline and the 10 mg/kg DMI groups was significant ~ 2 .03, d .f . ~ 68, p < .05 for A ; Xz 7. .03, d .f . ~ 2, p < .05 for ~ . See the tent for details .
L
713
71 4
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
DMI on noradrenergic systems . Long-term DMI treatment has been shown to block amine reuptake (3), decrease S-adenosyl-l-methioaine levels (4), and inhibit presynaptic a-receptors (5), all of which should enhance the effect of LC stimulation by increasing the amount of NE in the synapse . Other drug effects such as decreases in noradrenergic cell activity (2) or tyrosine hydroxylase activity (1), which should reduce the amount of synaptic NE, are counteracted by LC activation . Thus each nerve impulse in noradrenergic neurons may result in more NE available to postaynaptic cells in DMI-treated rata than in controls . However, this increased efficacy of presynaptic nerve impulses appears to be almost completely offset by decreased sensitivity of postaynaptic neurons, as suggested by the present finding that LC stimulation elicited similar degrees of inhibition in similar percentages of hippocampal pyramidal cells . The present study also found that the baseline firing rate of hippocampal pyramidal cells was significantly enhanced by long-term administration of 10 mg/kg DMI . Chronic administration with 5 mg/kg DMI produced only a slight increase in hippocampal cell activity . These results suggest that chronic deaipramine treatment is antagonistic to noradrenergic functions. A single dose of DMI given either i .p . (5 or 10 mg/kg) or i .v . (0 .3 or 0.6 mg/kg) produced an immediate but transient decrease in hippocampal cell firing (submitted for publication) suggesting that acute administration of DMI is facilitatory to noradrenergic functions . Thus, the antagonistic effect seen after chronic treatment does not occur after a single dose . Experiments are under way to determine the time course of the change from acute facilitatory to chronic inhibitory effect . The effects of TADs on different noradrenergic mechanisms have been used to generate differing or opposing hypotheses . For instance, the increase in NE turnover following chronic imipramine administration has been used as supportive evidence that the clinical efficacy of this sad other related drugs is due to their ability to increase noradrenergic functions (3) . On the other hand, the decrease in tyrosine hydroaylase activity after chronic treatment with desipramine has suggested to some investigators (1) that the antidepressant actions of this drug are mediated by its ability to decrease noradrenergic functions. Recent data on the sensitivity of postsyaaptic neuron receptors have also been mentioned as potential mechanisms related to the beneficial effects of these drugs (7) . Perhaps the overall evaluation of net TAD effect on noradrenergic functions will help to avoid or resolve these conflicting interpretations . Ackaowledgemeata The author is grateful to Drs . D. R. Snyder and J . W. Maae for their helpful advice and to G. Hu for technical assistance . This work was supported by MH 31104.
References 1. 2. 3. 4.
D .S . SEGAL, R. RUCZENSRI, sad A.J . MANDELL, Biol . Paychiat . 9, 147-159 (1974) . T .H . SVENSSON and T . USDIN, Science _202, 1089-1091 (1978) . J .J . SCHILDRRAUT, A . WINORUR, and C.W . APPLEGoATE, Science 168, 867-869 (1970) . R.M . TAYLOR and P.R . RANDALL, J . Pharmacol. Ex~. Therap . 194, 303-310 (1975) .
Vol . 25, No . 8, 1979 5. 6. 7. 8. 9. 10 .
Desipramine and Hippocampal Cells
715
F .T . CREWS and C .B . SMITH, Science 202, 322-324 (1978) . G . VETQLANI, R .J . STAWARZ, J .V . DINGELL and F . SULSER, Naunyn SchmiedeberA's Arch . Pharmacol . 293, 109-114 (1976) . B .B . F~OLFE, T .R . HARDEN, J .R . SPORN aad P .B . MOLINOFF, _J . Pharmacol . EEC. Ther . 207, 446-457 (1978) . S .R . BAREGGI, R . MARREY and E . GENOVESE, Europ . J . Pharmacol . 50, 301-306 (1978) . J .E . ROSENBLATT, C .B . PERT, J .F . TALLMAN, A . PERT and W .E . BUNNEY JR ., Brain Res . 160, 186-191 (1979) . Y .H . HÛANG and J .P . FLYNN, Brain Res . 93, 419-440 (1975) .
Life Sciences, Vol . 25, pp . 709-716 Printed in the U .S .A .
CHRONIC DESIPRAMINE TREATMENT INCREASES ACTIVITY OF NORADRENERGIC POSTSYNAPTIC CELLS Yuag H. Huang Department of Psychiatry Yale University School of Medicine New Haven, Connecticut 06510 (Received in final form July 19, 1979) Summar~ Chronic administration of tricyclic antidepressant drugs has been shown to exert multiple influences on various mechanisms of noradreaergic nervous systems. To determine the overall effect of these influences, this study ezamined the effect of long-term desipramine administration on the firing rate of noradreaergic poataynaptic neurons, specifically, those in the rat hippocampua Daily injections that were inhibited by the nucleus locus coeruleus . for 3 weeks of 5 or 10 mg/kg desipramine resulted in a 32x or 49% increase, respectively, of hippocampal cell activity, suggesting that long-term deaipramine treatment is antagonistic to noradrenergic functions . Chronic treatment with the tricyclic antidepressant drugs (TADe) imipramiae and deaipramine has bees shown to produce multiple effects on various mechanisms of noradreaergic nervous systems. Some of these effects may be seen as inhibi For instance, tory to noradrenergic functions, while others are facilitatory . long-term tricyclic treatment has been found to decrease tyrosine hydroxylase activity (1) or the firing rate of noradreaergic neurons (2), which may lead to as eventual reduction in the amount of norepinephrine (NE) available to target cells. On the other hand, chronic tricyclic administration has been found to increase NE turnover (3), inhibit amine reuptake (3), decrease S-adenosyll~methionine (4), or reduce the sensitivity of presynaptic a-receptors (5), all of which may result is an increase in the amount of transmitter in the synapse . Since both facilitatory and inhibitory effects are produced, the question is raised as to whether these opposing effects cancel each other out or whether one of them dominates, leading to a net effect of facilitation or suppression. The question is not settled by recent biochemical reports on the receptor Long-term administration of sensitivity of noradrenergic postsynaptic neurons. TADs has been found to decrease the accumulation of adenosine cyclic 3' :5'~mono phosphate in response to NE (6,7) and to inhibit the binding of ß~adrenergic antagonists (7-9) . If these decreases indicate suppression of noradrenergic poetsynaptic sensitivity, such sensitivity alteration could participate in determining the net effect of the drug, but would not indicate the nature of the net effect . The baseline firing rate of noradrenergic posteyaaptic neurone should be a function of both the responeivenesa to NE of these neurons and the NE levels in the synapse. It is, of course, the final outcome of events of pre- and 0024-3205/79/080709-07$02 .00/0 Copyright (c) 1979 Pergamon Press Ltd
71 0
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
postsynaptic neurons which is transmitted to other parts of the brain . Thus, postsynaptic activity measurements should be useful is determining the set effect . The aim of the present study was to determine the baseline firing rate of hippocampal pyramidal cells in rate chronically treated with desipramine (DMI) . The hippocampal pyramidal cells inhibited by stimulation of the locus coeruleus (LC) were assumed to be noradrenergic postaynaptic neurons . Compared with cells obtained from saline-injected rata, those from DMI-treated animals showed a substantial increase in their baseline firing rates, suggesting that chronic treatment with DMI eventually suppresses noradrenergic functions . Methode Electrical stimulation of the nucleus locus coeruleus Male alblno rats weighing 250-400 grams were anesthetized with urethane (1 .6 gm/kg, i .p .) and a concentric bipolar electrode was implanted into the LC . The stereotaaic coordinates were determined for each rat by monitoring the electrical activity of single neurons in and near the LC via a microelectrode. The bipolar electrode consisted of 100 um tungsten wire carried within the lumen of a 350 um stainless steel tube with the wire protruding about 300 um from the tube . Both the wire and the tube were insulated except at the cut ends . The stimulus current was biphasic with a phase duration of 0 .05 - 0.2 meet, an intensity of 0 .05 - 0 .2 mA, sad a frequency of 5 - 30 Hz . The stimulus train was usually applied for 30 sec . Recording CA1 pyramidal cell activity Unit activity is the hippocampal CA1 area, ipsilateral to the side of LC stimulation, was monitored via micropipettes filled with a Fast Greeasaturated, 2 M NaCl solution . Each unit was monitored for at least 20 min so that a representative discharge level could be obtained . This was required because some hippocampal cells showed a large variation is their activity . Amplified unit activity was led to a stimulus artifact auppreasor which allowed quantitative analyses of unit activity during high frequency stimulation (10) . The output from the artifact suppreesor was in turn fed to a storage oscilloscope, an audio monitor, and a Schmitt circuit for amplitude and duration discrimination . The output from the circuit, integrated over 1 or 10 sec intervals, was recorded on both a Gould event recorder and a Datel digital printer. Histology At the conclusion of the recording experiments, a discrete electrolytic lesion was made at the stimulation site by passing a negative 20 uA current for 7 sec and Fast Green was deposited at the recording site by passing a negative 20 uA current for 12 min. These sites were later identified hietologically by examining 50 Um sections stained with cresyl violet . Data were analyzed only from the animals with correct placements of the stimulating electrode is the LC (Fig . lA) and recording electrodes is the stratum pyramidale of CA1 (Fig . 1B) . Drug used Rate were given daily intraperitoaeal injections of deaipramine HC1 (Geigy) 5 mg/kg or 10 mg/kg. Control animals received daily intraperitoaeal injections of saline is amounts equivalent to that of the DMI solution . The injections were continued for 21 days and~aubaequently the recording experiment was performed on the 22nd day .
Vol . 25, No . 8, 1979
Desipramine and Hippocampal Cells
711
Data analyses Each CA1 pyramidal cell encountered was tested to determine whether it was first inhibited by LC stimulation . The magnitude of inhibition, referred to as overall inhibition, waa calculated from : 1 - the firing rate during the stimulation/prestimulation rate, where the prestimulation rate was derived from a 60 sec record immediately preceding stimulation . Only those unite which showed at least a 30Z overall inhibition (Fig . 1C) and whose activity was recorded for at least 20 min were used to assess baseline firing rates .
LC
Lc
FIG . 1 _A and B : Photographs taken from sections of brain tissues stained with cresyl violet . _A shows a stimulated site is the locus coeruleus (LC), which was marked by a small electrolytic lesion . _B shows a recorded site, deposited with Fast Green, in the stratum pyramidale of CA1 of the hippocampus . _C and _D : Photographic records of electrical activity of a CA1. pyramidal cell taken from a storage oscilloscope . A current applied to the LC of 0 .1 mast pulse duration, 0 .1 mA, and repeated at 10 Hz (~ or 30 Hz D(, produced a marked decrease of hippocampal cell activity . _E and F show another example of LC-induced inhibition ; the stimulus current was 0 .1 meet pulse duration, 0,1 mA, and repeated at 30 Hz . The calibration at F are 2 sec .4 mV for C-D, and 10 sec 1 mV for E-F .
71 2
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
Results This report was based on 52 CA1 pyramidal cells in 11 saline-injected rate, 60 in 13 rats chronically treated with 5 mg/kg DMI, and 53 in 9 rate chronically given 10 mg/kg DMI . The effects of LC stimulation on hippocampal pyramidal cells is DMI-treated rats . Since each hippocampal pyramidal cell encountered was studied for its responses to LC stimulation, it was possible to compare the responses among the three groups of animals . Activation of the LC suppressed similar per ceatages of hippocampal pyramidal cells in the three groups : 81X of cells in the saline group, 75X in the 5 mg/kg DMI group, and S1X in the 10 mg/kg DMI group . LC stimulation produced a similar magnitude of inhibition among the three groups . At the current of a 0.15 msec pulse duration, 0.15 mA and 10 Hz for 30 sec, the overall inhibition was 59 .1X (+_ 9 .2, N ~ 42) for the control group, 58 .2X ~ 8 .7, N ~ 45) for the 5 mg/kg DMI group, and 54 .7X 8 .3, N 43) for the 10 mg/kg DMI group. Although the drug-treated animals showed leas inhibition than did the control, the difference was not significant .
L
The baseline firing rates of LC-responsive hippocampal pyramidal cells follow chron ic DMI treatment.
ing
Figure 2A compares the mean firing rates of LC-responsive hippocampal pyramidal cells recorded from the three groups . The mean baseline rate for saline-injected rats was 5 .88 Hz ~± 1.01, N ~ 34). . The mean firing rate for 5 mg/kg DMI rata was 8 .11 Hz (+_ 1.16, N ~ 40), 32X faster than the control, but this difference was not significant statistically. The mean rate for 10 mg/kg DMI animals was 9 .19 Hz ~± 0.88, N - 34), 49X faster than the control and the difference was significant (t ~ 2.03, d .f . ~ 68, p < .05) . The difference between the two drug-treated groups was not significant. Figure 2B shows the percentages of units plotted against three ranges of firing rates, 0 - 4 .9, 5 .0 - 9 .9, and 10 Hz or more . The majority of units in the control rats fired at the lowest range while the opposite wse itos with 10 mg/kg DMI animals . The results with the 5 mg/kg DMI group appears to lie between the saline and the 10 mg/kg DMI groups . The Chi square test indicates that the difference between the saline and the 10 mg/kg DMI groups was significant (X 2 - 7 .03, d .f . ~ 2, p < .05), but that the differences between the saline and the 5 mg/kg DMI groups or between the two drug groups were not .
Diacuasion Chronic treatment with DMI altered neither the percentages of units affected nor the magnitude of inhibition produced by LC stimulation . This is of interest is view of the data on the sensitivity of noradrenergic postsynaptic neurone . If poatsynaptic sensitivity is indeed reduced by chronic DMI, as suggested by biochemical studies (6-9), the similar efficacy of LC stimulation to induce hippocampal inhibition would indicate that the amount of NE released per nerve impulse sad then made available to hippocampal cell receptors is greater in DMI-treated preparations than in controls . This interpretation is consistent with the currentlq available data concerning the effects of chronic
Desipramine and Hippocampal Cells
Vol . 25, No . 8, 1979
A
10
N W H
5
0
B
SALI NE
D~A I 5 Mß/KG
SALINE
DMI 5MG/KG
D1A I 10 MO/KG
60
40
Z
~ 20
0
DMI 10 MG/KG
FIG . 2 A shows the~mean firing rates of locus coeruleue-responsive hippocampal pyramidal cells recorded from different groups of rata . B shows the percentages of unite firing at 0 - 4 .9, 5 .0 - 9 .9 or faster Hz . The difference between the saline and the 10 mg/kg DMI groups was significant ~ 2 .03, d .f . ~ 68, p < .05 for A ; Xz 7. .03, d .f . ~ 2, p < .05 for ~ . See the tent for details .
L
713
71 4
Desipramine and Hippocampal Cells
Vol . 25, No . 8,
1979
DMI on noradrenergic systems . Long-term DMI treatment has been shown to block amine reuptake (3), decrease S-adenosyl-l-methioaine levels (4), and inhibit presynaptic a-receptors (5), all of which should enhance the effect of LC stimulation by increasing the amount of NE in the synapse . Other drug effects such as decreases in noradrenergic cell activity (2) or tyrosine hydroxylase activity (1), which should reduce the amount of synaptic NE, are counteracted by LC activation . Thus each nerve impulse in noradrenergic neurons may result in more NE available to postaynaptic cells in DMI-treated rata than in controls . However, this increased efficacy of presynaptic nerve impulses appears to be almost completely offset by decreased sensitivity of postaynaptic neurons, as suggested by the present finding that LC stimulation elicited similar degrees of inhibition in similar percentages of hippocampal pyramidal cells . The present study also found that the baseline firing rate of hippocampal pyramidal cells was significantly enhanced by long-term administration of 10 mg/kg DMI . Chronic administration with 5 mg/kg DMI produced only a slight increase in hippocampal cell activity . These results suggest that chronic deaipramine treatment is antagonistic to noradrenergic functions. A single dose of DMI given either i .p . (5 or 10 mg/kg) or i .v . (0 .3 or 0.6 mg/kg) produced an immediate but transient decrease in hippocampal cell firing (submitted for publication) suggesting that acute administration of DMI is facilitatory to noradrenergic functions . Thus, the antagonistic effect seen after chronic treatment does not occur after a single dose . Experiments are under way to determine the time course of the change from acute facilitatory to chronic inhibitory effect . The effects of TADs on different noradrenergic mechanisms have been used to generate differing or opposing hypotheses . For instance, the increase in NE turnover following chronic imipramine administration has been used as supportive evidence that the clinical efficacy of this sad other related drugs is due to their ability to increase noradrenergic functions (3) . On the other hand, the decrease in tyrosine hydroaylase activity after chronic treatment with desipramine has suggested to some investigators (1) that the antidepressant actions of this drug are mediated by its ability to decrease noradrenergic functions. Recent data on the sensitivity of postsyaaptic neuron receptors have also been mentioned as potential mechanisms related to the beneficial effects of these drugs (7) . Perhaps the overall evaluation of net TAD effect on noradrenergic functions will help to avoid or resolve these conflicting interpretations . Ackaowledgemeata The author is grateful to Drs . D. R. Snyder and J . W. Maae for their helpful advice and to G. Hu for technical assistance . This work was supported by MH 31104.
References 1. 2. 3. 4.
D .S . SEGAL, R. RUCZENSRI, sad A.J . MANDELL, Biol . Paychiat . 9, 147-159 (1974) . T .H . SVENSSON and T . USDIN, Science _202, 1089-1091 (1978) . J .J . SCHILDRRAUT, A . WINORUR, and C.W . APPLEGoATE, Science 168, 867-869 (1970) . R.M . TAYLOR and P.R . RANDALL, J . Pharmacol. Ex~. Therap . 194, 303-310 (1975) .
Vol . 25, No . 8, 1979 5. 6. 7. 8. 9. 10 .
Desipramine and Hippocampal Cells
715
F .T . CREWS and C .B . SMITH, Science 202, 322-324 (1978) . G . VETQLANI, R .J . STAWARZ, J .V . DINGELL and F . SULSER, Naunyn SchmiedeberA's Arch . Pharmacol . 293, 109-114 (1976) . B .B . F~OLFE, T .R . HARDEN, J .R . SPORN aad P .B . MOLINOFF, _J . Pharmacol . EEC. Ther . 207, 446-457 (1978) . S .R . BAREGGI, R . MARREY and E . GENOVESE, Europ . J . Pharmacol . 50, 301-306 (1978) . J .E . ROSENBLATT, C .B . PERT, J .F . TALLMAN, A . PERT and W .E . BUNNEY JR ., Brain Res . 160, 186-191 (1979) . Y .H . HÛANG and J .P . FLYNN, Brain Res . 93, 419-440 (1975) .