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Effects of monoamine reuptake blockade on ponto-geniculo-occipital wave activity
Neuropharmacology Vo1.29, No.10, pp.965968, Printed in Great Britain
1990
0028-3908/90 %3.00+0.00 Pergamon Press plc
EFFECTS OF MONOAMINE REUPTAKE BLOCKADE ON PONTO-GENICUM-OCCIPITAL
8.3, Ross'a2**,W.A. Ball', D.R. Levitt', P.J. Gresch2
WAVE ACTIVITY
and A.R. Morrison2.3
lphiladelphia Department of Veterans Affairs Medical Center, 2Department of Psychiatry, School of Medicine, University of Pennsylvania and 'Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104 U.S.A.
(AccepM
9 JuLy 19901 SUMMARY
Norepinephrine (NE) and serotonin (SHT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-f3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthylamine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features ofhyperarousal; PGOwave suppressionby antidepressant drugs may relate to clinical antidepressant actions. Key Words: PGO waves, monoamines, norepinephrine, serotonin, reuptake blockade, depression.
Biphasic electrical field potentials, termed ponto-geniculo-occipital (PGO) waves. occur spontaneously during REM sleep and the transition period preceding REM sleep in the cat (Jouvet, 1967). Norepinephrine or 5HT reupcake blockade, which increases monoaminergic transmission, reduces the frequency of PGO waves "released" into waking by chemical NE or 5HT depletion, respectively (Ruth-Monachon, Jalfre and Haefely, 1976). We hypothesized that NE or 5HT reuptake blockade with DMI or SER. respectively (Koe, Weissman, Welch and Browne, 1983). would diminish spontaneous PGO rates during REM sleep and the prior transition period in otherwise undrugged cats. METHODS. Using halothane anesthesia, 8 female cats (2.5-3.5 kg) were implanted aseptically with electrodes for recording EEG, EOG, EMG, and lateral geniculate body (LGB) PGO waves (Ross, Ball, Gresch and Morrison, 1990). Several weeks later, each cat was adapted to an illuminated, sound-attenuating recording chamber (1 meter3) between 10 AM and 4 PM for 1-2 days. On the following 2 days, a placebo capsule was administered at 9:45 AM, and sleep was recorded with a Grass 780 polygraph for 6 hours. The next day, the first dose of DMI or SER (0.75 mg/kg) was administered orally and sleep was again recorded (acute day). The same drug was then given repeatedly for approximately 2.5 weeks (range 17-21 days) while the cat remained in its home cage on a 12:12 light-dark schedule. The chronic oral dose of DMI was 1.0 mg/kg b.i.d. and that of SER was 2.0 mg/kg q.d. Pilot investigations had established that these produced steady state plasma levels similar to those in humans (Ross et al., 1990). Dosing schedules were devised from estimates of elimination half-lives. On weekend days, divided doses were combined into a single dose. Following re-adantation to the recording chamber, sleep was again recorded on 2 days (chronic days). Animals received a 1.0 mg/kg dose of drug immediately before recording on each of the 2 chronic days (and a 1.0 mg/kg dose following recording on the first chronic day). After "washout" periods of approximately 4 weeks, 6 cats received the alternative drug in a counter-balanced design. Due to deterioration of recording quality, 2 cats could be studied on only 1 drug. Another cat with a low PGO signal to noise ratio was excluded from the analysis. PGO activity was recorded on magnetic tape. An observer detected REM sleep episodes from the continuous polygraph record by standard criteria (Fig. 1) and signalled their start and finish on tape and polygraph. Computer files with times (in msec) of negative-going PGO-type events were created for all episodes. For each episode, events greater than or equal to 35% of the tenth largest were defined as PGO waves. Seventy-three episodes from 4 cats were also analyzed by human scoring of polygraph records. The product moment correlation between human and computer Q To whom correspondence should be addressed. 965
966
Preliminary
Notes
PGO wave tallies was 0.85. The PGO rate for each REM sleep episode longer than 2 min. was calculated by dividing the number of PGO waves in that episode by the episode duration. The frequency of PGO waves detected visually from the polygraph record was also calculated for the 2 min. period preceding each REM sleep episode (Fig. 2).
FIG. 1 EOG
1.0 MV
&A._.
EEG
.l
.02
LGB ~~ -i-SEC
Fig. 1. Representative REM sleep epoch in one cat, as indicated by rapid eye movements on the electrooculogram (EOG), desynchronous EEG activity, atonia on the electromyogram (EMG), and PGO waves recorded from the LGB.
FIG. 2 EOG
,*,‘p1”““1”“’
“,’ ,y EMG
2
SEC
Fig. 2. Transitional period prior to REM sleep onset, as indicated by an absence of eye movements on the EOG, sleep spindles on the EEG, low amplitude tonic activity on the EMG, and PGO waves recorded from the LGB.
For each cat, PGO rates of REM sleep episodes from the two placebo days were averaged, as were those from the two chronic days. For each drug, placebo PGO rate was compared with acute and chronic rates, using Student's t-test (2-tailed) for paired samples. RESULTS Examination the LGB.
of the 5 available
brains
revealed
that all PGO electrode
tips were
located
in
Drug effects on PGO rate during REM sleep are summarized in Table la. Acute doses had no significant effect. Chronic doses of either DMI or SER significantly reduced PGO rate. Drug effects on PGO rate in the transition period are presented in Table lb. There was no significant change after acute DMI, but a significant decline during chronic drug administration. Both acute and chronic SER significantly reduced PGO rate during the transition period.
Preliminary Notes
TABLE PGO PATES PLACEBO
vs.
967
la.
IN REM SLEEP
ACUTE
PLACEBO
vs.
CHRONIC
DMI
51.4 f 10.9
50.7 + 11.6
(n-5)
56.4 f. 6.0
38.7 + 15.2*
(n=5)
SER
59.1 + 9.9
55.3 + 10.9
(n-5)
56.1 + 7.9
48.8 f 11.3*
(n-7)
Values are numbers of PGO waves per minute * p
vs.
(mean + S.D.)
lb.
IN THE TRANSITION
ACUTE
PLACEBO
PERIOD vs.
CHRONIC
DMI
18.8 + 2.0
19.3 + 2.9
(n-5)
18.8 + 2.0
12.5 + 1.5***
(n=5)
SER
23.3 + 5.5
20.0 + 5.0* (n=5)
19.0 & 5.1
15.3 + 4.6**
(n=7)
Values are numbers of PGO waves per minute (mean k S.D.) * p
DISCUSSION. Contrary to expectations, acute administration of a dose of DMI or SER sufficient to reduce REM sleep profoundly (Ross et al., 1990) did not reduce the rate of PGO activity during REM sleep. The ineffectiveness of acute SER may have resulted from the activation of 2 populations of postsynaptic receptors, one inhibitory to PGO generation and the other excitatory (Kayama, Shimada, Hishikawa and Ogawa, 1989). Serotonin reuptake blockade might activate both inhibitory and excitatory postsynaptic serotonergic receptors, producing no net effect. The modest reduction of PGO activity by chronic SER, during REM sleep as well as transition, is consistent with evidence in the rat that repeated administration of another 5HT reuptake blocker, zimelidine, enhances net serotonergic function (Willner, 1985). Largely because chronic DMI augments postsynaptic responsiveness to 5HT, it has been suggested that even tricyclic antidepressants with predominant NE reuptake-blocking properties elevate serotonergic function (Willner, 1985). Consequently, PGO suppression by chronic DMI, like chronic SER, may have a serotonergic basis. DMI and drugs comparable to SER in inhibiting 5HT reuptake selectively act as antidepressants inhumans. The pharmacotherapy of depression generally requires several weeks before remission occurs. Because the PGO wave has been related to an alerting process that occurs almost continuously during REM sleep and because depression has been conceptualized as a disorder of hvuerarousal (Morrison, 1979; Gold, Goodwin and Chrousos, 1988), our demonstration that chronic DMI or SER reduces PGO rate assumes potential pathophysiological significance. Dampening of an alerting process by repeated antidepressant drug administration may be involved in the chain of CNS events that ameliorates depression (cf. Bert, Saier, Tognetti and Toure, 1977). REM sleep and PGO wave- generating systems can be uncoupled (Callaway, Lydic. Baghdoyan and Hobson, 1987). In contrast to the pattern of decline in PGO rate observed here, both acute DMI and SER markedly diminish REM sleep; after repeated administration of either drug in the cat, REM sleep structure normalizes (Ross et al., 1990). Thus, our results support the concept that distinct processes may initiate and maintain REM sleep as compared to PGO waves. While much speculation regarding the mechanism of action of antidepressants has focussed on REM sleep suppression (Vogel, Minter andwoolwine, 1986), analyses of PGO wave inhibition may offer additional insights into CNS mechanisms that malfunction in depression.
Preliminary
968
Notes
ACKNOWLEDGMENTS. We thank Ms. G. Mann and Mr. F. Mulvaney for their helpful comments and technical assistance. The desipramine was supplied by Merrell Dow Pharmaceuticals, Inc. Sertraline and sertraline plasma levels were provided by Pfizer, Inc. Supported by the Department of Veterans Affairs, Medical Research Service (R.J.R.), National Research Service Award F32-MH-09584-01 (W.A.B.), and ROl-MH42903 (A.R.M.). REFERENCES. Bert J., Saier J., Tognerti P. and Toure M.F. (1977) Effet de la chlorimipramine sur l'activite de pointes "Ponto-Geniculo-Occipitales" (PGO) du babouin Papio hamadryas. Psychopharmacology 51: 301-304. Callaway C.W., Lydic R., Baghdoyan H.A. and Hobson J.A. (1987) Pontogeniculooccipitalwaves spontaneous visual system activity during rapid eye movement sleep. Cell. Mol. Neurobiol. 7 105-149. Gold P.W., Goodwin F.K. and Chrousos G.P. (1988) Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. N. Engl. J. Med. 319: 413-420. Jouvet M. (1967) Neurophysiology of the states of sleep. Physiol. Rev. 47: 117-177. Kayama Y., Shimada S., Hishikawa Y. and Ogawa T. (1989) Effects of stimulating the dorsal raphe nucleus of the rat on neuronal activity in the dorsal lateral geniculate nucleus. Brain Res. 489:1-11. B.K., Weissman A., Welch W.M. and Browne R.G. (1983) Sertraline, 1S,4S-N-methyl-4-f3,4-dichlorophenylf-l,2,3,4-tetrahydro-l-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J. Pharmacol. Exp. Ther. 226: 686-700.
KOf2
Morrison A.R. (1979) Brainstem regulation of behavior during sleep and wakefulness. In: Psychobiology and Physiological Psychology (Sprague J.M., Epstein A.W., Eds.), pp. 91.131. Academic, New York. Ross R.J., Ball W.A.. Gresch P.J. and Morrison A.R. (1990) Acute and chronic effects of monoamine uptake blockade on paradoxical sleep in the cat. Biol. Psychiatry. In press. Ruth-Monachon M.A., Jalfre M. and Haefely W. (1976) Drugs and PGO waves in the Lateral geniculate body of the curarized cat. V. Miscellaneous compounds. Synopsis of the role of central neurotransmitters on PC0 wave activity. Arch. Int. Pharmacodyn. Ther. 219: 326-346. Vogel G.W., Minter K. and Woolwine B. (1986) Effects of chronically antidepressant drugs on animal behavior. Physiol. Behav. 36: 659-666. Willner P. (1985)Antidepressants 387-404.
administered
and serotonergic neuro-transmission. Psychopharmacology 85:
1990
0028-3908/90 %3.00+0.00 Pergamon Press plc
EFFECTS OF MONOAMINE REUPTAKE BLOCKADE ON PONTO-GENICUM-OCCIPITAL
8.3, Ross'a2**,W.A. Ball', D.R. Levitt', P.J. Gresch2
WAVE ACTIVITY
and A.R. Morrison2.3
lphiladelphia Department of Veterans Affairs Medical Center, 2Department of Psychiatry, School of Medicine, University of Pennsylvania and 'Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104 U.S.A.
(AccepM
9 JuLy 19901 SUMMARY
Norepinephrine (NE) and serotonin (SHT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-f3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthylamine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features ofhyperarousal; PGOwave suppressionby antidepressant drugs may relate to clinical antidepressant actions. Key Words: PGO waves, monoamines, norepinephrine, serotonin, reuptake blockade, depression.
Biphasic electrical field potentials, termed ponto-geniculo-occipital (PGO) waves. occur spontaneously during REM sleep and the transition period preceding REM sleep in the cat (Jouvet, 1967). Norepinephrine or 5HT reupcake blockade, which increases monoaminergic transmission, reduces the frequency of PGO waves "released" into waking by chemical NE or 5HT depletion, respectively (Ruth-Monachon, Jalfre and Haefely, 1976). We hypothesized that NE or 5HT reuptake blockade with DMI or SER. respectively (Koe, Weissman, Welch and Browne, 1983). would diminish spontaneous PGO rates during REM sleep and the prior transition period in otherwise undrugged cats. METHODS. Using halothane anesthesia, 8 female cats (2.5-3.5 kg) were implanted aseptically with electrodes for recording EEG, EOG, EMG, and lateral geniculate body (LGB) PGO waves (Ross, Ball, Gresch and Morrison, 1990). Several weeks later, each cat was adapted to an illuminated, sound-attenuating recording chamber (1 meter3) between 10 AM and 4 PM for 1-2 days. On the following 2 days, a placebo capsule was administered at 9:45 AM, and sleep was recorded with a Grass 780 polygraph for 6 hours. The next day, the first dose of DMI or SER (0.75 mg/kg) was administered orally and sleep was again recorded (acute day). The same drug was then given repeatedly for approximately 2.5 weeks (range 17-21 days) while the cat remained in its home cage on a 12:12 light-dark schedule. The chronic oral dose of DMI was 1.0 mg/kg b.i.d. and that of SER was 2.0 mg/kg q.d. Pilot investigations had established that these produced steady state plasma levels similar to those in humans (Ross et al., 1990). Dosing schedules were devised from estimates of elimination half-lives. On weekend days, divided doses were combined into a single dose. Following re-adantation to the recording chamber, sleep was again recorded on 2 days (chronic days). Animals received a 1.0 mg/kg dose of drug immediately before recording on each of the 2 chronic days (and a 1.0 mg/kg dose following recording on the first chronic day). After "washout" periods of approximately 4 weeks, 6 cats received the alternative drug in a counter-balanced design. Due to deterioration of recording quality, 2 cats could be studied on only 1 drug. Another cat with a low PGO signal to noise ratio was excluded from the analysis. PGO activity was recorded on magnetic tape. An observer detected REM sleep episodes from the continuous polygraph record by standard criteria (Fig. 1) and signalled their start and finish on tape and polygraph. Computer files with times (in msec) of negative-going PGO-type events were created for all episodes. For each episode, events greater than or equal to 35% of the tenth largest were defined as PGO waves. Seventy-three episodes from 4 cats were also analyzed by human scoring of polygraph records. The product moment correlation between human and computer Q To whom correspondence should be addressed. 965
966
Preliminary
Notes
PGO wave tallies was 0.85. The PGO rate for each REM sleep episode longer than 2 min. was calculated by dividing the number of PGO waves in that episode by the episode duration. The frequency of PGO waves detected visually from the polygraph record was also calculated for the 2 min. period preceding each REM sleep episode (Fig. 2).
FIG. 1 EOG
1.0 MV
&A._.
EEG
.l
.02
LGB ~~ -i-SEC
Fig. 1. Representative REM sleep epoch in one cat, as indicated by rapid eye movements on the electrooculogram (EOG), desynchronous EEG activity, atonia on the electromyogram (EMG), and PGO waves recorded from the LGB.
FIG. 2 EOG
,*,‘p1”““1”“’
“,’ ,y EMG
2
SEC
Fig. 2. Transitional period prior to REM sleep onset, as indicated by an absence of eye movements on the EOG, sleep spindles on the EEG, low amplitude tonic activity on the EMG, and PGO waves recorded from the LGB.
For each cat, PGO rates of REM sleep episodes from the two placebo days were averaged, as were those from the two chronic days. For each drug, placebo PGO rate was compared with acute and chronic rates, using Student's t-test (2-tailed) for paired samples. RESULTS Examination the LGB.
of the 5 available
brains
revealed
that all PGO electrode
tips were
located
in
Drug effects on PGO rate during REM sleep are summarized in Table la. Acute doses had no significant effect. Chronic doses of either DMI or SER significantly reduced PGO rate. Drug effects on PGO rate in the transition period are presented in Table lb. There was no significant change after acute DMI, but a significant decline during chronic drug administration. Both acute and chronic SER significantly reduced PGO rate during the transition period.
Preliminary Notes
TABLE PGO PATES PLACEBO
vs.
967
la.
IN REM SLEEP
ACUTE
PLACEBO
vs.
CHRONIC
DMI
51.4 f 10.9
50.7 + 11.6
(n-5)
56.4 f. 6.0
38.7 + 15.2*
(n=5)
SER
59.1 + 9.9
55.3 + 10.9
(n-5)
56.1 + 7.9
48.8 f 11.3*
(n-7)
Values are numbers of PGO waves per minute * p
vs.
(mean + S.D.)
lb.
IN THE TRANSITION
ACUTE
PLACEBO
PERIOD vs.
CHRONIC
DMI
18.8 + 2.0
19.3 + 2.9
(n-5)
18.8 + 2.0
12.5 + 1.5***
(n=5)
SER
23.3 + 5.5
20.0 + 5.0* (n=5)
19.0 & 5.1
15.3 + 4.6**
(n=7)
Values are numbers of PGO waves per minute (mean k S.D.) * p
DISCUSSION. Contrary to expectations, acute administration of a dose of DMI or SER sufficient to reduce REM sleep profoundly (Ross et al., 1990) did not reduce the rate of PGO activity during REM sleep. The ineffectiveness of acute SER may have resulted from the activation of 2 populations of postsynaptic receptors, one inhibitory to PGO generation and the other excitatory (Kayama, Shimada, Hishikawa and Ogawa, 1989). Serotonin reuptake blockade might activate both inhibitory and excitatory postsynaptic serotonergic receptors, producing no net effect. The modest reduction of PGO activity by chronic SER, during REM sleep as well as transition, is consistent with evidence in the rat that repeated administration of another 5HT reuptake blocker, zimelidine, enhances net serotonergic function (Willner, 1985). Largely because chronic DMI augments postsynaptic responsiveness to 5HT, it has been suggested that even tricyclic antidepressants with predominant NE reuptake-blocking properties elevate serotonergic function (Willner, 1985). Consequently, PGO suppression by chronic DMI, like chronic SER, may have a serotonergic basis. DMI and drugs comparable to SER in inhibiting 5HT reuptake selectively act as antidepressants inhumans. The pharmacotherapy of depression generally requires several weeks before remission occurs. Because the PGO wave has been related to an alerting process that occurs almost continuously during REM sleep and because depression has been conceptualized as a disorder of hvuerarousal (Morrison, 1979; Gold, Goodwin and Chrousos, 1988), our demonstration that chronic DMI or SER reduces PGO rate assumes potential pathophysiological significance. Dampening of an alerting process by repeated antidepressant drug administration may be involved in the chain of CNS events that ameliorates depression (cf. Bert, Saier, Tognetti and Toure, 1977). REM sleep and PGO wave- generating systems can be uncoupled (Callaway, Lydic. Baghdoyan and Hobson, 1987). In contrast to the pattern of decline in PGO rate observed here, both acute DMI and SER markedly diminish REM sleep; after repeated administration of either drug in the cat, REM sleep structure normalizes (Ross et al., 1990). Thus, our results support the concept that distinct processes may initiate and maintain REM sleep as compared to PGO waves. While much speculation regarding the mechanism of action of antidepressants has focussed on REM sleep suppression (Vogel, Minter andwoolwine, 1986), analyses of PGO wave inhibition may offer additional insights into CNS mechanisms that malfunction in depression.
Preliminary
968
Notes
ACKNOWLEDGMENTS. We thank Ms. G. Mann and Mr. F. Mulvaney for their helpful comments and technical assistance. The desipramine was supplied by Merrell Dow Pharmaceuticals, Inc. Sertraline and sertraline plasma levels were provided by Pfizer, Inc. Supported by the Department of Veterans Affairs, Medical Research Service (R.J.R.), National Research Service Award F32-MH-09584-01 (W.A.B.), and ROl-MH42903 (A.R.M.). REFERENCES. Bert J., Saier J., Tognerti P. and Toure M.F. (1977) Effet de la chlorimipramine sur l'activite de pointes "Ponto-Geniculo-Occipitales" (PGO) du babouin Papio hamadryas. Psychopharmacology 51: 301-304. Callaway C.W., Lydic R., Baghdoyan H.A. and Hobson J.A. (1987) Pontogeniculooccipitalwaves spontaneous visual system activity during rapid eye movement sleep. Cell. Mol. Neurobiol. 7 105-149. Gold P.W., Goodwin F.K. and Chrousos G.P. (1988) Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. N. Engl. J. Med. 319: 413-420. Jouvet M. (1967) Neurophysiology of the states of sleep. Physiol. Rev. 47: 117-177. Kayama Y., Shimada S., Hishikawa Y. and Ogawa T. (1989) Effects of stimulating the dorsal raphe nucleus of the rat on neuronal activity in the dorsal lateral geniculate nucleus. Brain Res. 489:1-11. B.K., Weissman A., Welch W.M. and Browne R.G. (1983) Sertraline, 1S,4S-N-methyl-4-f3,4-dichlorophenylf-l,2,3,4-tetrahydro-l-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J. Pharmacol. Exp. Ther. 226: 686-700.
KOf2
Morrison A.R. (1979) Brainstem regulation of behavior during sleep and wakefulness. In: Psychobiology and Physiological Psychology (Sprague J.M., Epstein A.W., Eds.), pp. 91.131. Academic, New York. Ross R.J., Ball W.A.. Gresch P.J. and Morrison A.R. (1990) Acute and chronic effects of monoamine uptake blockade on paradoxical sleep in the cat. Biol. Psychiatry. In press. Ruth-Monachon M.A., Jalfre M. and Haefely W. (1976) Drugs and PGO waves in the Lateral geniculate body of the curarized cat. V. Miscellaneous compounds. Synopsis of the role of central neurotransmitters on PC0 wave activity. Arch. Int. Pharmacodyn. Ther. 219: 326-346. Vogel G.W., Minter K. and Woolwine B. (1986) Effects of chronically antidepressant drugs on animal behavior. Physiol. Behav. 36: 659-666. Willner P. (1985)Antidepressants 387-404.
administered
and serotonergic neuro-transmission. Psychopharmacology 85: