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Reduction in paradoxical sleep after l -dopa administration in rats
BEHAVIORALAND NEURALBIOLOGY46, 249--256 (1986)
Reduction in Paradoxical Sleep after L-DOpa Administration in Rats E . GALARRAGA, M . CORsI-CABRERA, AND M . SANGRI 1
Laboratorio de Psicofisiologia, Facultad de Psicologia, Universidad An~huac, Mdxico lO D. F., M~xico The EEG and EMG activity of two groups of rats (N = 8 each) was recorded during one experimental and 5 control days. On the experimental day, one group received 125.0 mg/kg L-dopa preceded by 50.0 mg/kg benserazide hydrochloride. The other group received 1.0 mg/kg haloperidol, immediately before the recording session. After e-dopa plus benserazide administration the total time and the number of episodes of paradoxical sleep and slow wave sleep decreased significantly compared to control sessions. © 1986AcademicPress, Inc.
Evidence for an influence of L-dopa on sleep has been reported during the past few years, but despite its use in the treatment of Parkinson's disease, its effects on sleep are not yet clear. Although its action seems more evident on paradoxical sleep (PS), reports differ on the direction of its effects, probably because most studies have been carded on patients, mainly Parkinsonian, while the number of studies which employed normal subjects are very few, rendering interpretation difficult. In Parkinsonian patients treated with L-dopa, increased PS has been reported (Bricolo, Turella, Mazza, Buffatti, & Grosslercher, 1970); however, in other studies no consistent changes in sleep patterns have been found using similar doses (Bassi, Albizzata, Frattola, Passerini, & Trabucchi, 1979; Greenberg & Pearlman, 1970). Further, the effect may be related to the degree of clinical improvement: patients who improved, showed an increase in PS after L-dopa administration, whereas those who showed no improvement showed no consistent changes (Kendel, Beck, Wita, Hohneck, & Zimmerman, 1972). Similar contradictory results have been found with depressed patients: PS increment (Zarcone, Hollister, & Dement, 1970), as well as decrement (Fram, Murphy, Goodwin, Brodie, Bunney, & Snyder, 1970) have both been reported following treatment with L-dopa. i We are grateful to the pharmaceutical companies, La Roche de Mrxico and Johnson and Johnson de Mrxico, for providing the drugs used. Address requests for reprints to M. Corsi-Cabrera. 249 0163-1047/86 $3.00 Copyright© 1986by AcademicPress, Inc. All rightsof reproductionin any formreserved.
250
GALARRAGA, CORSI-CABRERA, AND SANGRI
Studies of normal subjects with acute oral doses of L-dopa have revealed no statistically significant changes in PS (Castaldo, Krynicki, & Crade, 1973) but, in these studies, no peripheral decarboxylase inhibitor was used. In contrast, intravenous L-dopa administration plus a peripheral decarboxylase inhibitor, when infused 25 min after sleep onset, significantly delays the first PS episode and, when infused after PS onset, the duration of the episode is reduced (Gillin, Post, Wyatt, Goodwin, Snyder, & Bunney, 1973). However, subjects in that study were patients with affective disorders in partial remission. In order to further explore the effects of L-dopa on sleep, L-dopa was intraperitoneally administered to one group of rats after a prior injection of a peripheral decarboxylase inhibitor in order to allow the L-dopa to be converted to dopamine (DA) only in the central nervous system. Haloperidol (HAL) was injected to another group of rats to assess the effect of dopamine receptor blockade. METHOD A total of 16 male Wistar rats, weighing between 150 and 350 g were used. All rats were maintained in individual cages with ad lib food and water in a room with a 12-hr light-dark cycle. The rats were randomly divided into two groups according to the drug received: an L-dopa group (N = 8) and H A L group (N = 8). Under conventional stereotaxic techniques bipolar cortical electrodes were ipsilaterally implanted 2.0 mm from the median fine, 2.0 mm posterior to bregma and on the surface of the dura mater for electroencephalographic (EEG) recording. For electromyographic (EMG) recording two additional electrodes were attached to neck muscles. At least 5 to 8 days were allowed for complete recovery. EEG and EMG were recorded during 4 hr (8-12 A~) on 6 consecutive days. The first 2 days of recording were considered as base line (BL) and no injections were given. On the third day, immediately before the beginning of the recording session, the vehicle of the drug was intraperitoneally (ip) injected as a solvent injection control (SIC), the L-dopa group received isotonic saline solution (ip), preceded by 30 min by the peripheral decarboxylase inhibitor benserazide (ip). The H A L group received an injection of the same solvent used for haloperidol (ip), supplied by Johnson and Johnson de Mrxico. Next day was considered as a postsolvent control (PSC). On the fifth day or drug injection day (DI) L-dopa group received 125.0 mg/kg L-dopa (ip) and HAL Group 1.0 mg/kg haloperidol (ip). All rats of L-dopa group received 30 rain before L-dopa, 50.0 mg/kg benserazide hydrochloride (ip) (RO 4-4602). Last day was a post-injection control (PDC). The volume of all injections was 0.5 ml/kg in all cases.
PARADOXICAL SLEEP AND L-DOPA IN RATS
251
Three EEG and EMG stages were identified according to the usual criteria for the rat: wakefulness (W) was characterized by low voltage fast EEG activity intermingled with theta rhythm and high EMG amplitude. Slow wave sleep (SWS) was identified by high amplitude slow waves in the EEG. PS was signaled by the adoption of the typical posture of the rat, nodded head and curled up, at the same time EMG activity disappears becoming an isopotential line and in the EEG a more regular theta rhythm than that of W is observed. The total time in seconds as well as the number of episodes and mean duration of PS, SWS, and W episodes was calculated for each session and group. The differences between sessions of the same group were compared with an analysis of variance for repeated measures. The number of episodes was converted to proportion (number of episodes of one session/total episodes). A Student t test for uncorrelated samples was used for the comparison between groups.
RESULTS The comparison between the first 2 days (BL) rendered no significant differences in either group or sleep stage; accordingly the mean of the two sessions was used for the remaining comparisons. Since the comparison of the BL between groups did not show significant differences, all of the rats were considered as belonging to the same population.
L-Dopa Group The comparison of the time spent in PS across sessions, showed significant differences IF(4, 28) -- 8.69, p < .01]. As can be seen in Fig. la, PS is reduced after L-dopa injection as compared to all control conditions. The decrease of PS was due to a significant reduction of the episodes [F(4, 28) = 9.49, p < .01] and not to the mean duration [F(4, 28) = 1, p > .05; see Figs. l b a n d c ] . The time spent in SWS was significantly different across sessions too [F(4, 28) = 9.14, p < .01], being lower after L-dopa injection. As in the case of PS, the mean duration did not show significant changes [F(4, 28) = 1, p > .05], but the number of episodes was significantly reduced [F(4, 28) = 13.45, p < .01; see Figs. 2a-c]. In order to evaluate the reduction of PS and SWS, the ratio of PS/SWS was calculated and, as it c~n be seen in Fig. 4, the reduction of PS was greater than that of SWS. The time spent in W was not significantly different [F(4, 28) = 1.49, p > .05], but the mean duration of W was increased after L-dopa injection [F(4, 28) = 4.26, p < .01]. The number of episodes showed significant differences, being lower after L-dopa injection and higher after solvent injection control [F(4, 28) = 3.75, p < .05; see Figs. 3a-c].
252
GALARRAGA CORSI-CABRERA, , AND SANGRI • ~'~
L-DOPA
[ ] HALOPERIOOL
2000"1
T
a
1000 o
'*
30
~
ao
z
--
= ~
200]
c
I00
o~
BL
SIC
PSC
DI
PDC
FIG. 1. Total time spent in paradoxical sleep (PS) (a), number of PS episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-druk control (PDC). Each bar represents mean value and standard error of the two experimental groups. Observe PS reduction after L-dopa injection as compared to all control sessions.
HAL Group There were no significant changes in any of the parameters measured in this group (see Figs. 1-3). The total time spent in PS, SWS, and W, in the drug injection day was significantly different between L-dopa and H A L group. PS and SWS were lower in L-dopa group (t(14) = 4.16, and t = 3.37, p < .01, respectively) and W was lower in H A L group (t(14) = 3.66, p < .01). There were no significant differences between both groups in any of the other sessions.
DISCUSSION L-dopa injection p r o d u c e d a significant decrease in the total time and n u m b e r o f episodes of PS and SWS compared to all control conditions.
PARADOXICAL SLEEP AND L-DOPA IN RATS
"~ 15000
253
• L-DOPA
O~'~m ] []HALOPERIDOL
.
~
"6c°_I0000
a
i 5000o o
40 " -
~
"
~
5o-
20+ io-
I000
-
¢
c ~-
.o ~ 500~=
BL
SIC
PSC
DI
PDC
FIG. 2. Total time spent in slow wave sleep (SWS) (a), number of SWS episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Each bar represents mean value and standard error of the two exper~nental groups. Observe SWS reduction after L-dopa injection as compared to all control sessions.
This effect on sleep can not be attributed to the solvent of the drugs or in the case of PS to the peripheral decarboxylase inhibitor benserazide, since injection of benserazide alone in the solvent injection session did not p r o d u c e a significant change. Therefore, the decrease in PS and SWS seems to be due to the action of L-dopa. In the past few years two major hypotheses concerning PS triggering m e c h a n i s m s h a v e b e e n developed. One hypothesis considers PS as a sleep-independent p h e n o m e n o n triggered by a periodic driving force (Czeisler, Z i m m e r m a n n , Ronda, M o o r e - E d e , & Weitzman, 1980; Weitzman, Czeisler, Z i m m e r m a n n , & Ronda, 1980), while the other considers PS as a sleep-dependent p h e n o m e n o n , that is, the onset and duration of PS being determined b y the previous amount of SWS (Johnson, 1980; Moses, Lubin, Johnson, & Naitoh, 1977). The significant reduction of
254
GALARRAGA, CORSI-CABRERA, AND SANGRI
•
15000.
o c
L-DOPA
I0000"
i 5000. o
oo 40.~ 50 -
g
20-
"6
Jo-
~=I000 ~i
~
g ==
=~~ 5oo
~.~ =E
BL
SIC
PSC
DI
PDC
FIG. 3. Total time spent in wakefulness (W) (a), number of W episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Each bar represents mean value and standard error of the two experimental groups. Observe the increase in the mean duration of the episodes after L-dopa injection as compared to all control sessions. L - DOPA
group
0,20. oa) 0.15'
~'~
0.10'
E 0.05.
o
B'L
S;C
PSC
D'I
PE)C
FIG.4. PS/SWS ratio of the total time spent by L-dopa group in base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Observe the greater reduction of PS compared to SWS after L-dopa injection.
PARADOXICAL SLEEP AND L-DOPA IN RATS
255
PS after L-dopa injection could be attributed to changes in SWS. However, the ratio of PS/SWS showed a greater decrease of PS suggesting a more powerful action of L-dopa on PS than on sleep in general. e-dopa influences not only DA, but also other neurotransmitters such as N E and 5-HT. The decrease in PS and SWS seen after L-dopa administration could be due to unspecific changes in brain concentration of one or more of these amines. However, a single ip injection of Ldopa preceded by benserazide (the same doses as used in this study) significantly increases DA concentration but does not alter brain NE concentration and produces only a slight but nonsignificant reduction of 5-HT (Pletscher & Bartholini, 1971). These data lead us to assume that the reduction in PS and SWS observed in the present experiment is more likely to be attributed to an increase in brain DA and not to unspecific changes in other neurotransmitters. However, in order to support this idea the opposite effect should have been obtained after injection of the DA receptor blocker haloperidol and HAL injection failed to produce significant changes from baseline. However, the total time spent in PS, SWS, and W by the group treated with HAL was significantly different from the group treated with L-dopa. Although a suppressive effect of L-dopa on SWS and PS is apparent, the exact mechanism of L-dopa action on sleep remains to be determined. REFERENCES Bassi, S., Albizzata, M. G., Frattola, L., Passerini, D., & Trabucchi, M. (1979). Dopamine receptors and sleep induction in man. Journal of Neurology Neurosurgery and Psychiatry, 42, 458-460. Bricolo, A., Turella, G., Mazza, C. A., Buffatti, P., & Grosslercher, J. C. (1970). Modification del sonno noturno in parkinsoniani trattati con L-DOPA. Sistema Nervoso, 2, 181190. Castaldo, V., Krynicki, V. E., & Crade, M. (1973). L-DOPA and REM sleep in normal subjects and mentally retarded subjects. Biological Psychiatry, 6, 295-299. Czeisler, Ch. A., Zimmermann, J. C., Ronda, J. M., Moore-Ede, M. C., & Weitzman, D. (1980). Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep, 2, 329-346. Fram, D. H., Murphy, D. L., Goodwin, F. K., Brodie, H. K., Bunney, W. E., & Snyder, F. (1970). L-DOPA and sleep in depressed patients. Psychophysiology, 7, 316-317. Gillin, J. C., Post, R. M., Wyatt, R. J., Goodwin, F. K., Snyder, F., & Bunney, W. E. (1973). REM inhibitory effect of L-DOPA infusion during human sleep. Electroencephalography and Clinical Neurophy siology , 35, 181-186. Greenberg, R., & Pearlman, Ch. (1970), L-DOPA, Parkinsonism and sleep. Psychophysiology, 7, 314. Johnson, L. C. (1980). The REM cycle is a sleep-dependent rhythm. Sleep, 2, 299-307. Kendel, K., Beck, U., Wita, C., Hohneck, E., & Zimmermann, H. (1972). Der Einfluss von L-DOPA auf den Nachtschlaff bei Patienten mit Parkinson-Syndrom. Archiv der Psychiatrie und der Nervenkrankheiten, 216, 82-100. Moses, L., Lubin, A,, Johnson, L. C., & Naitoh, P. (1977). Rapid eye movement sleep is a sleep-dependent rhythm. N a t u r e (London), 265, 360-361.
256
GALARRAGA, CORSI-CABRERA, AND SANGRI
Pletscher, A., & Bartholini, G. (1971). Selective rise in brain dopamine by inhibition of extracerebral levodopa decarboxilation. Clinical Pharmacology and Therapeutics, 12, 244-452. Weitzman, E. D., Czeisler, Ch. A., Zimmermann, J. C., & Ronda, J. M. (1980). Timing of REM And stages 3 + 4 sleep during temporal isolation in man. Sleep, 2, 391-408. Zarcone, V., Hollister, M., & Dement, W. C. (1970). The effect of L-dihidroxyphenylalanine (L-DOPA) on the sleep of two depressed patients. Psychophysiology, 7, 314-315.
Reduction in Paradoxical Sleep after L-DOpa Administration in Rats E . GALARRAGA, M . CORsI-CABRERA, AND M . SANGRI 1
Laboratorio de Psicofisiologia, Facultad de Psicologia, Universidad An~huac, Mdxico lO D. F., M~xico The EEG and EMG activity of two groups of rats (N = 8 each) was recorded during one experimental and 5 control days. On the experimental day, one group received 125.0 mg/kg L-dopa preceded by 50.0 mg/kg benserazide hydrochloride. The other group received 1.0 mg/kg haloperidol, immediately before the recording session. After e-dopa plus benserazide administration the total time and the number of episodes of paradoxical sleep and slow wave sleep decreased significantly compared to control sessions. © 1986AcademicPress, Inc.
Evidence for an influence of L-dopa on sleep has been reported during the past few years, but despite its use in the treatment of Parkinson's disease, its effects on sleep are not yet clear. Although its action seems more evident on paradoxical sleep (PS), reports differ on the direction of its effects, probably because most studies have been carded on patients, mainly Parkinsonian, while the number of studies which employed normal subjects are very few, rendering interpretation difficult. In Parkinsonian patients treated with L-dopa, increased PS has been reported (Bricolo, Turella, Mazza, Buffatti, & Grosslercher, 1970); however, in other studies no consistent changes in sleep patterns have been found using similar doses (Bassi, Albizzata, Frattola, Passerini, & Trabucchi, 1979; Greenberg & Pearlman, 1970). Further, the effect may be related to the degree of clinical improvement: patients who improved, showed an increase in PS after L-dopa administration, whereas those who showed no improvement showed no consistent changes (Kendel, Beck, Wita, Hohneck, & Zimmerman, 1972). Similar contradictory results have been found with depressed patients: PS increment (Zarcone, Hollister, & Dement, 1970), as well as decrement (Fram, Murphy, Goodwin, Brodie, Bunney, & Snyder, 1970) have both been reported following treatment with L-dopa. i We are grateful to the pharmaceutical companies, La Roche de Mrxico and Johnson and Johnson de Mrxico, for providing the drugs used. Address requests for reprints to M. Corsi-Cabrera. 249 0163-1047/86 $3.00 Copyright© 1986by AcademicPress, Inc. All rightsof reproductionin any formreserved.
250
GALARRAGA, CORSI-CABRERA, AND SANGRI
Studies of normal subjects with acute oral doses of L-dopa have revealed no statistically significant changes in PS (Castaldo, Krynicki, & Crade, 1973) but, in these studies, no peripheral decarboxylase inhibitor was used. In contrast, intravenous L-dopa administration plus a peripheral decarboxylase inhibitor, when infused 25 min after sleep onset, significantly delays the first PS episode and, when infused after PS onset, the duration of the episode is reduced (Gillin, Post, Wyatt, Goodwin, Snyder, & Bunney, 1973). However, subjects in that study were patients with affective disorders in partial remission. In order to further explore the effects of L-dopa on sleep, L-dopa was intraperitoneally administered to one group of rats after a prior injection of a peripheral decarboxylase inhibitor in order to allow the L-dopa to be converted to dopamine (DA) only in the central nervous system. Haloperidol (HAL) was injected to another group of rats to assess the effect of dopamine receptor blockade. METHOD A total of 16 male Wistar rats, weighing between 150 and 350 g were used. All rats were maintained in individual cages with ad lib food and water in a room with a 12-hr light-dark cycle. The rats were randomly divided into two groups according to the drug received: an L-dopa group (N = 8) and H A L group (N = 8). Under conventional stereotaxic techniques bipolar cortical electrodes were ipsilaterally implanted 2.0 mm from the median fine, 2.0 mm posterior to bregma and on the surface of the dura mater for electroencephalographic (EEG) recording. For electromyographic (EMG) recording two additional electrodes were attached to neck muscles. At least 5 to 8 days were allowed for complete recovery. EEG and EMG were recorded during 4 hr (8-12 A~) on 6 consecutive days. The first 2 days of recording were considered as base line (BL) and no injections were given. On the third day, immediately before the beginning of the recording session, the vehicle of the drug was intraperitoneally (ip) injected as a solvent injection control (SIC), the L-dopa group received isotonic saline solution (ip), preceded by 30 min by the peripheral decarboxylase inhibitor benserazide (ip). The H A L group received an injection of the same solvent used for haloperidol (ip), supplied by Johnson and Johnson de Mrxico. Next day was considered as a postsolvent control (PSC). On the fifth day or drug injection day (DI) L-dopa group received 125.0 mg/kg L-dopa (ip) and HAL Group 1.0 mg/kg haloperidol (ip). All rats of L-dopa group received 30 rain before L-dopa, 50.0 mg/kg benserazide hydrochloride (ip) (RO 4-4602). Last day was a post-injection control (PDC). The volume of all injections was 0.5 ml/kg in all cases.
PARADOXICAL SLEEP AND L-DOPA IN RATS
251
Three EEG and EMG stages were identified according to the usual criteria for the rat: wakefulness (W) was characterized by low voltage fast EEG activity intermingled with theta rhythm and high EMG amplitude. Slow wave sleep (SWS) was identified by high amplitude slow waves in the EEG. PS was signaled by the adoption of the typical posture of the rat, nodded head and curled up, at the same time EMG activity disappears becoming an isopotential line and in the EEG a more regular theta rhythm than that of W is observed. The total time in seconds as well as the number of episodes and mean duration of PS, SWS, and W episodes was calculated for each session and group. The differences between sessions of the same group were compared with an analysis of variance for repeated measures. The number of episodes was converted to proportion (number of episodes of one session/total episodes). A Student t test for uncorrelated samples was used for the comparison between groups.
RESULTS The comparison between the first 2 days (BL) rendered no significant differences in either group or sleep stage; accordingly the mean of the two sessions was used for the remaining comparisons. Since the comparison of the BL between groups did not show significant differences, all of the rats were considered as belonging to the same population.
L-Dopa Group The comparison of the time spent in PS across sessions, showed significant differences IF(4, 28) -- 8.69, p < .01]. As can be seen in Fig. la, PS is reduced after L-dopa injection as compared to all control conditions. The decrease of PS was due to a significant reduction of the episodes [F(4, 28) = 9.49, p < .01] and not to the mean duration [F(4, 28) = 1, p > .05; see Figs. l b a n d c ] . The time spent in SWS was significantly different across sessions too [F(4, 28) = 9.14, p < .01], being lower after L-dopa injection. As in the case of PS, the mean duration did not show significant changes [F(4, 28) = 1, p > .05], but the number of episodes was significantly reduced [F(4, 28) = 13.45, p < .01; see Figs. 2a-c]. In order to evaluate the reduction of PS and SWS, the ratio of PS/SWS was calculated and, as it c~n be seen in Fig. 4, the reduction of PS was greater than that of SWS. The time spent in W was not significantly different [F(4, 28) = 1.49, p > .05], but the mean duration of W was increased after L-dopa injection [F(4, 28) = 4.26, p < .01]. The number of episodes showed significant differences, being lower after L-dopa injection and higher after solvent injection control [F(4, 28) = 3.75, p < .05; see Figs. 3a-c].
252
GALARRAGA CORSI-CABRERA, , AND SANGRI • ~'~
L-DOPA
[ ] HALOPERIOOL
2000"1
T
a
1000 o
'*
30
~
ao
z
--
= ~
200]
c
I00
o~
BL
SIC
PSC
DI
PDC
FIG. 1. Total time spent in paradoxical sleep (PS) (a), number of PS episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-druk control (PDC). Each bar represents mean value and standard error of the two experimental groups. Observe PS reduction after L-dopa injection as compared to all control sessions.
HAL Group There were no significant changes in any of the parameters measured in this group (see Figs. 1-3). The total time spent in PS, SWS, and W, in the drug injection day was significantly different between L-dopa and H A L group. PS and SWS were lower in L-dopa group (t(14) = 4.16, and t = 3.37, p < .01, respectively) and W was lower in H A L group (t(14) = 3.66, p < .01). There were no significant differences between both groups in any of the other sessions.
DISCUSSION L-dopa injection p r o d u c e d a significant decrease in the total time and n u m b e r o f episodes of PS and SWS compared to all control conditions.
PARADOXICAL SLEEP AND L-DOPA IN RATS
"~ 15000
253
• L-DOPA
O~'~m ] []HALOPERIDOL
.
~
"6c°_I0000
a
i 5000o o
40 " -
~
"
~
5o-
20+ io-
I000
-
¢
c ~-
.o ~ 500~=
BL
SIC
PSC
DI
PDC
FIG. 2. Total time spent in slow wave sleep (SWS) (a), number of SWS episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Each bar represents mean value and standard error of the two exper~nental groups. Observe SWS reduction after L-dopa injection as compared to all control sessions.
This effect on sleep can not be attributed to the solvent of the drugs or in the case of PS to the peripheral decarboxylase inhibitor benserazide, since injection of benserazide alone in the solvent injection session did not p r o d u c e a significant change. Therefore, the decrease in PS and SWS seems to be due to the action of L-dopa. In the past few years two major hypotheses concerning PS triggering m e c h a n i s m s h a v e b e e n developed. One hypothesis considers PS as a sleep-independent p h e n o m e n o n triggered by a periodic driving force (Czeisler, Z i m m e r m a n n , Ronda, M o o r e - E d e , & Weitzman, 1980; Weitzman, Czeisler, Z i m m e r m a n n , & Ronda, 1980), while the other considers PS as a sleep-dependent p h e n o m e n o n , that is, the onset and duration of PS being determined b y the previous amount of SWS (Johnson, 1980; Moses, Lubin, Johnson, & Naitoh, 1977). The significant reduction of
254
GALARRAGA, CORSI-CABRERA, AND SANGRI
•
15000.
o c
L-DOPA
I0000"
i 5000. o
oo 40.~ 50 -
g
20-
"6
Jo-
~=I000 ~i
~
g ==
=~~ 5oo
~.~ =E
BL
SIC
PSC
DI
PDC
FIG. 3. Total time spent in wakefulness (W) (a), number of W episodes (b), and mean duration of the episodes (c) obtained on base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Each bar represents mean value and standard error of the two experimental groups. Observe the increase in the mean duration of the episodes after L-dopa injection as compared to all control sessions. L - DOPA
group
0,20. oa) 0.15'
~'~
0.10'
E 0.05.
o
B'L
S;C
PSC
D'I
PE)C
FIG.4. PS/SWS ratio of the total time spent by L-dopa group in base line (BL), solvent injection control (SIC), post-solvent control (PSC), drug injection (DI), and post-drug control (PDC). Observe the greater reduction of PS compared to SWS after L-dopa injection.
PARADOXICAL SLEEP AND L-DOPA IN RATS
255
PS after L-dopa injection could be attributed to changes in SWS. However, the ratio of PS/SWS showed a greater decrease of PS suggesting a more powerful action of L-dopa on PS than on sleep in general. e-dopa influences not only DA, but also other neurotransmitters such as N E and 5-HT. The decrease in PS and SWS seen after L-dopa administration could be due to unspecific changes in brain concentration of one or more of these amines. However, a single ip injection of Ldopa preceded by benserazide (the same doses as used in this study) significantly increases DA concentration but does not alter brain NE concentration and produces only a slight but nonsignificant reduction of 5-HT (Pletscher & Bartholini, 1971). These data lead us to assume that the reduction in PS and SWS observed in the present experiment is more likely to be attributed to an increase in brain DA and not to unspecific changes in other neurotransmitters. However, in order to support this idea the opposite effect should have been obtained after injection of the DA receptor blocker haloperidol and HAL injection failed to produce significant changes from baseline. However, the total time spent in PS, SWS, and W by the group treated with HAL was significantly different from the group treated with L-dopa. Although a suppressive effect of L-dopa on SWS and PS is apparent, the exact mechanism of L-dopa action on sleep remains to be determined. REFERENCES Bassi, S., Albizzata, M. G., Frattola, L., Passerini, D., & Trabucchi, M. (1979). Dopamine receptors and sleep induction in man. Journal of Neurology Neurosurgery and Psychiatry, 42, 458-460. Bricolo, A., Turella, G., Mazza, C. A., Buffatti, P., & Grosslercher, J. C. (1970). Modification del sonno noturno in parkinsoniani trattati con L-DOPA. Sistema Nervoso, 2, 181190. Castaldo, V., Krynicki, V. E., & Crade, M. (1973). L-DOPA and REM sleep in normal subjects and mentally retarded subjects. Biological Psychiatry, 6, 295-299. Czeisler, Ch. A., Zimmermann, J. C., Ronda, J. M., Moore-Ede, M. C., & Weitzman, D. (1980). Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep, 2, 329-346. Fram, D. H., Murphy, D. L., Goodwin, F. K., Brodie, H. K., Bunney, W. E., & Snyder, F. (1970). L-DOPA and sleep in depressed patients. Psychophysiology, 7, 316-317. Gillin, J. C., Post, R. M., Wyatt, R. J., Goodwin, F. K., Snyder, F., & Bunney, W. E. (1973). REM inhibitory effect of L-DOPA infusion during human sleep. Electroencephalography and Clinical Neurophy siology , 35, 181-186. Greenberg, R., & Pearlman, Ch. (1970), L-DOPA, Parkinsonism and sleep. Psychophysiology, 7, 314. Johnson, L. C. (1980). The REM cycle is a sleep-dependent rhythm. Sleep, 2, 299-307. Kendel, K., Beck, U., Wita, C., Hohneck, E., & Zimmermann, H. (1972). Der Einfluss von L-DOPA auf den Nachtschlaff bei Patienten mit Parkinson-Syndrom. Archiv der Psychiatrie und der Nervenkrankheiten, 216, 82-100. Moses, L., Lubin, A,, Johnson, L. C., & Naitoh, P. (1977). Rapid eye movement sleep is a sleep-dependent rhythm. N a t u r e (London), 265, 360-361.
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Pletscher, A., & Bartholini, G. (1971). Selective rise in brain dopamine by inhibition of extracerebral levodopa decarboxilation. Clinical Pharmacology and Therapeutics, 12, 244-452. Weitzman, E. D., Czeisler, Ch. A., Zimmermann, J. C., & Ronda, J. M. (1980). Timing of REM And stages 3 + 4 sleep during temporal isolation in man. Sleep, 2, 391-408. Zarcone, V., Hollister, M., & Dement, W. C. (1970). The effect of L-dihidroxyphenylalanine (L-DOPA) on the sleep of two depressed patients. Psychophysiology, 7, 314-315.