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Δ9-tetrahydrocannabinol: Effects on EEG and behavior of rhesus monkeys
Lüe Sciences Vol . 11, Part I, pp . 843-851, 1972 . Printed in Cfreat Britain
Pergamon Press
~ 9 -TSTRAHYDROCANNABINOL : EFFECTS ON SSG AND BEHAVIOR OF RHESUS PlONRSYS~ Joe L . Martinet, Jr .s Stanley W . Stadnicki and Ulrich H . 3chaeppi Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts ; Mason Research Institute, Worcester, Massachusetts (Received 3 Jam~ary 1972 ; in ünal corm 22 May 1972) Summary Intravenous infusion of 09 -tetrahydrocannibinol (0 .05-12 .8 mg/kg) to awake rhesus monkeys with indwelling cortical and subcortical electrodes produced ptosis, sedation, immobility, muscle rigidity and hyper-reactivity to a noise stimulus . The ESG revealed a dose related increase in high voltage activity and epileptiform changes . A9-Tetrahydrocannabinol (D9-THC), the most important psychoactive constituent of marihuana (1), produced characteristic behavioral and SSG alterations in various animal species (2-5) .
The
cortical SSG of squirrel monkeys, cats, rabbits, and rats showed an increase in high voltage slow wave activity and cortical SSG changes such as high voltage spikes and waves in rabbits (3), polyapike discharge in rats
(5), and spikes in the frontal cortex of
squirrel monkeys (2) . Grunfeld and Sdery (6) observed among several species studied that the rhesus monkey was the most sensitive for evaluating psychoactive properties of cannabinoida .
Since McIsaac et al . (7)
demonstrated selective distribution of labelled A9 -THC in the brains of squirrel monkeys, it was of interest to investigate the effects of A9 -THC upon the ESG of particular brain areas in the rhesus monkey . ~Preaented in part at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, August, 1971, Burlington, Vermont. 843
844
EYfect ad D9 THC on EEG and Behavior
Vol. 11, No. 13
Methods in the present study one female and three male rhesus monkeys (3-4 kg) were operated under sodium pentobarbital anesthesia to prepare them for EEG récording .
For subcortical recording, bipolar
stainless steel rods insulated to within 1 mm of the tip were stereotaxically implanted in the basolateral amygdala, dorsal hippocampus,
superior cerebellar peduncle, and nucleus fastigü .
For cortical recording, stainless steel screws were bilaterally placed epidurally above the superior frontal, superior parietal and occipital gyri .
All implantations were made according to the
coordinates of Snider and Lee (8) .
Treatments and EEG recordings
were performed 10 days postoperatively .
The monkeys were restrainec
in a primate chair and kept in a sound attenuated room provided with a one-way glass .
The animals were observed continuously
during the treatment .
Pretreatment control recordings consisted
of at least one hour of EEG recording during three different recording sessions .
Vehicle control infusions were performed on
each monkey and demonstrated that volumes as large as 5 ml had no affect on the EEG even though the vehicle considerably reduced blood pressure (see Results) .
Each experimental session lasted
220 minutes ; the A9-THC was administered 30 minutes after the monkey had been restrained in a primate chair .
During the experimen-
tal session a bell was rung at half hour intervals .
~9-THC was
given in a counter-balanced order in doses of 0 .05 , 0 .4, 1 .6, 3 .2 and 12 .8 mq/kg such that two monkeys received increasing and two monkeys received decreasing doses . A9-THC was stored at 4oC under nitrogen .
The purity was
determined to be 968 by optical rotation and gas liquid chromatography . ment .
The formulations were prepared one hour prior to treat The drug was infused as an emulsion of 108 sesame oil, plus
Vol. 11, No. 13
Eüect od ~9 THC on EEG and Hehaviar
0 .48 Tween 80 in nofmal saline .
846
Total volumes ranged from 0 .2 -
3 .2 mls the concentration of ~ 9 -THC never exceeded 1 .5$ .
The drug
was infused via a polyethylene tubing inserted into the external jugular or saphenous vein and was flushed with salines the procedure was complete within 5 minutes .
Treatments were repeated
after an interval of at least 8 days .
The 8ßG was recorded on a
Grass model 7 polygraph . Indirect systolic blood pressure was measured by employing a sphygmomanometer and a plethysmographic pulse detector (C . H . Stoeltinq, Co ., Chicago, graph.
Ill .) connected to a Grass model 7 poly
Blood flow was impeded by occluding the vessels of the
upper arm with a cuff and eliminating the pulse .
Indirect systolic
blood pressure was obtained by gradually releasing the cuff pressure until the pulse was again evident .
Blood pressure values
were then read directly from the sphygmomanometer . The BBG was analyzed by sampling sixty second periods from each recording site at 2, 5, 10, 15, 25, 40, 60, 120 and 180 minutes after the onset of treatment .
Bach second of the 60-second
periods was scored for the presence ôf high voltage slow wave activity and/or high voltage burst activity (4) .
High voltage
activity was defined as at least a threefold increase in the amplitude of the pretreatment BBG during desynchronization .
For each
60-second period, the time occupied by high voltage activity was converted to a percent and averaged across periods .
Thus, the
mean of the periods was used as an indicator of high voltage activity . Results Administration of A9-THC in doses of 0 .05 to 1 .6 mq/kq elicited drowsiness and ptosis .
Two minutes after infusion of 3 .2 or
12 .8 mq/kq of D 9 -THC, lacrimination, slumped posture, immobility,
848
Effect ofO9 TSC on EEG and Behavior
Vol . 11, No. iS
muscle rigidity, and hyper-reactivity to an auditory stimulus were observed .
Treatment with the highest dose (12 .8 mg/kg)
led to clonic muscle spasms .
sometimes
All effects of the drug treatment
disappeared within 24 hours . Administration of D 9 -THC produced a dose-related increase in the amount of high voltage EEG activity (Figure 1) .
Analysis of
variance revealed a highly significant dose effect on the EEG (F4,2g ~ 15 .18, P < ,O1) but no significant differences between brain areas (amygdala,
cerebellar peduncle, frontal cortex, hippo-
campus, nucleus fastigü, occipital cortex, parietal cortex) .
W Q F -
m C w V W F-
DOSE n9THC (mp/kp) FIG. 1 Occurrence of dose-related high Volta EEG activity following i.v . infusion of D THC in 4 rhesus monkeys . Each curve represents a different area of the brain : frontal cortex (FC), nucleus fastigü (NF), occipital cortex (OC), superior cerebellar peduncle (CP), basolateral amygdala (A), parietal cortex (PC) and dorsal hippocampus (H) . Vehicle control is represented by V .C .
Vol . 11, No . 13
Effect od D9 THC on EEG and Behavior
847
The onset of BEG effects as measured by the appearance of rhythmic burst activity (12 to 16 cps) was dose related .
Two
minutes after infusion of 3 .2 or 12 .8 mq/kg of A 9 -THC bursts appeared in the amygdala and cerebellar peduncle .
Lower doses
(0 .05-1 .6 mg/kg) did not induce burst activity until 8-10 minutes after administration (Figure 2C) . not clearly dose-related .
The amount of burst activity was
Bursts occurred only rarely in the
hippocampus and were never seen in the frontal cortex .
The amyg-
dala and cerebellar peduncle exhibited burst activity at all doses (0 .05-12 .8 mq/kg) while the parietal cortex and nucleus fastigü only showed bursts at higher doses (1 .6-12 .8 mg/kg) .
High voltage
A OCCIlü'~I. L~7Q
Gt"YL 9IPIblypp~
!Aq"70AL üfmlL
QIRIO" ~~/4 ~CJi 'Y
`
V~
FIG . 2 The BEG record from a monkey given 1 .6 mq/kg ~9THC i .v . Panel (A), BBG desynchronization 2 minutes b®fore the administration of D9-THC (control) . Panel (B), SBG dissociation between brain areas 7 minutes after administration of A9-THC . Note the epileptiform slow waves in dorsal hippocampus, baaolateral amygdala aniï superior aerebellar peduncle during desynohronization in occipital and parietal cortex . Panel (C) rhythmic burst activity 9 minutes after the administration of A9-THC, The burst activity is most pronounced in the baaolateral amygdala and superior cerebellar peduncle .
848
Effect ad ~9 TSC on ELG and Behavior
Vol. 11, No. 19
in phase epi.leptiform activity occurred in all brain areas immediately following treatment with higher doses (1 .6-12 .8 mg/kq) . Within one hour after treatment the changes were less generalized and high voltage slow waves and low voltage fast waves were observed simultaneously in the EEG (EEG dissociation .
Figure 2B) .
These periods of EEG dissociation often lasted for several minutes . The monkeys exhibited hyper-reactivity to stimulation by a bell .
They responded with a grimace, often accompanied by jerky
body movements while attempting to turn away from the source of the noise .
Bell stimulation always elicited immediate EEG
desynchronization, frequently preceded by rhythmic burst activity . The time course and dose effect of A9-THC on the amount of high voltage EEG activity may be seen in the data presented in Table 1 .
It is evident that maximal EEG effects occurred about
fifteen minutes after administration of the drug and lasted from one to two hours depending on the dose . Administration of the vehicle alone or in combination with A9-THC induced a decrease in systolic blood pressure .
In the case
of the vehicle alone the blood pressure values fell to 53 .3 mm Hg and returned to normal levels within one hour .
This decrease was
somewhat greater following the administration of A9-TSC at doses of 0 .4-12 :8 mq/kq .
Following the administration of A 9 -THC the
blood pressure often fell to values as low as 35 .0 mm Hg and never returned to normal before two hours .
There was no apparent
relationship between the duration of the blood pressure decrease and the dose of A9 -TSC .
Eüect ad ~9 THC. on EEG and Behavior
Vol. 11, No. 13
849
TABLE 1 Time course of high wltage EBG activity in the amygdales following administration of A9-TSC to four rhesus monkeys
Time occupied by high voltage activity (mean percent) Dose A9-TBC mq/kq
-2
2
5
10
Vehicle Control
2 .8
0.
9 .5
4 .0
8 .7
0 .05
2 .6
1.3
2 .3
6 .0
0 .40
5 .0
3 .3
17 .0
1 .60
7 .0
8.0
3 .20
0.
12 .80
3 .3
Time (minutes) 15 25
40
60
120
180
3 .5
6 .5
0.
7 .1
0.
8 .6
3 .3
4 .6
0.
1 .3
0.
6 .6
8 .6
10 .6
6 .0
7 .6
0.
0.
5 .3
25 .3
38 .0
32 .0
32 .0
12 .6
6 .6
0.
1 .0
27 .0
21 .0
46 .3
45,3
27 .0
7 .0
4 .0
3 .3
11 .3
66 .3
47 .3
79 .0
53 .0
59 .3
45 .6
15 .3
1 .6
Discussion Other investigators have observed that A9 -THC administered i .p . or i .v . to monkeys produced an initial phase of increased psychomotor activity and hallucinations (7,9) .
Our findings agree
with Grunfeld and Edery (6) who observed that i .v . injection of A9-THC in the rhesus monkey elicited only sedation and inactivity . Our results also agree with earlier observations of cortical EEG activity in rat, rabbit and squirrel monkey (2,3,5) .
Moreover,
the EEG alterations observed in this study were consistent with EEG changes produced by the synthetic THC derivatives DMHP and MOP (10) , The EEG of monkeys treated with A9-THC differs from that seen in normal sleep, in several important ways .
First, the periods of
high voltage activity were interspersed with burst activity in several areas of the brain (Figure 2C) .
Secondly, the EEG
850
Effect od Os THC on EEG and Behavior
Vol. 11, No. 13
dissociation observed between brain areas was quite pronounced and would often last for minutes at a time .
Behavioral changes that
were inconsistent with sleep included muscle rigidity and the absence of complete eye closure (ptosis) .
None of these obser-
vations is characteristic of normal sleep in the monkey (11) . it could not be determined if blood pressure decreases contributed to the observed EEG changes .
However, the blood pressure
decreases probably did not affect the SEG since the changes per sisted after blood pressure returned to near normal (after two hours)
and no EEG changes were seen with the vehicle alone .
Infusion of large doses of D 9 -THC (3 .2-12 .8 mq/kg)
induced
changes in motor activity such as immobility, muscle rigidity, occasional clonic muscle spasms, and EEG .changes including burst activity in parietal cortex, cerebellur peduncle, and nucleus fastigü .
These observations of altered motor activity are even
more interesting when compared with the findings of Mcisaac et al . (7),who demonstrated that labelled D9-THC reached the greatest tissue levels in the cerebellum . Treatment with an extremely small dose of A9-THC (0 .05 mq/kg) produced epileptiform EEG activity in subcortical areas of the rhesus monkey .
This fact raises the intriguing question of whether
or not administration of D 9 -THC to man elicits similar subcortical effects that are not detectable with surface electrodes, since in man 0 .05 mg/kq D 9 -THC aäministered by the inhalation route was recognized as being similar to marihuana (12) . Acknowledgments Partial support of this research was provided by PBS Training Grant #TO1 MH-10625 to the Worcester Foundation for Experimental Biology .
Dr . M.C . Braude, Center for Studies of Narcotics and
Drug Abuse, NIMH supplied the A9-THC under contract HSM-42-70-95
Vol. 11, No. 13
Effect ad D9 THC on EEG and Hebavior
to Mason Research Institute .
851
Dr . H . Rosenkrantz, Director of
Biochemistry, Mason Research Institute, developed the formulation u4ed in this study .
The technical assistance of the New England
Regional Primate Research Center is gratefully acknowledged . References 1.
R. MECHOULAM, A SHAM , H . EDSRY and Y . GRUNFSLD, Science 169, 611(1970) .
2.
E .S . BOYD, S .H . BOYD, J .S . MUQiMORE and L .E . BRAWN, J . Pharmacol .- Exp . Ther~ . 176, 480(1971) .
3.
F . LIPPARINI, A. SCOTTI DeCAROLIS and V .G . LONGO, Physiol . Behav. 4, 527 G969) .
4.
C .H . HOCRMAN, R.G . PERIN and H . RALANT, Science 172, 968(1971)
5.
J . MASUR and N . RHAZAN, Life Sciences 9, 1275(1970) .
6.
Y . GRUNFELD and H . EDSRY, Psychopharmacologia 14, 200(1969) .
7.
W .M . MCISAAC, G .D . FRITCHIE, J .S . IDANPAAN-HEIRRILA, B .T . HO and L .F . ENGLSRT, Nature 230, 593(1971) .
8.
R.S . SNIDER and J .C . LSE, A Stereotaxic Atlas of the Monke Brain (Macaca mulatta) . Un v. cago Press, cago ) .
9.
C .L . SCHECREL, E . BOFF, P . DAHLSN and T . SMART, Science 160, 1467(1968) .
10 .
E .F . DOMINO, Ann. New York Acad . Sci . 191, 166(1971) .
11 .
M.L . REITE, J .M . RHODES, S . RAVAN and W .R . ADSY, Arch . Neurol . 12, 133(1965) .
12 .
H . ISBELL, C .W . GORODETZSRY, D. JASINSRI, U. CLAUSSSN, F.U . SPULAR and R. RORTE, Psychopharmacologia 11, 184(1967) .
Pergamon Press
~ 9 -TSTRAHYDROCANNABINOL : EFFECTS ON SSG AND BEHAVIOR OF RHESUS PlONRSYS~ Joe L . Martinet, Jr .s Stanley W . Stadnicki and Ulrich H . 3chaeppi Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts ; Mason Research Institute, Worcester, Massachusetts (Received 3 Jam~ary 1972 ; in ünal corm 22 May 1972) Summary Intravenous infusion of 09 -tetrahydrocannibinol (0 .05-12 .8 mg/kg) to awake rhesus monkeys with indwelling cortical and subcortical electrodes produced ptosis, sedation, immobility, muscle rigidity and hyper-reactivity to a noise stimulus . The ESG revealed a dose related increase in high voltage activity and epileptiform changes . A9-Tetrahydrocannabinol (D9-THC), the most important psychoactive constituent of marihuana (1), produced characteristic behavioral and SSG alterations in various animal species (2-5) .
The
cortical SSG of squirrel monkeys, cats, rabbits, and rats showed an increase in high voltage slow wave activity and cortical SSG changes such as high voltage spikes and waves in rabbits (3), polyapike discharge in rats
(5), and spikes in the frontal cortex of
squirrel monkeys (2) . Grunfeld and Sdery (6) observed among several species studied that the rhesus monkey was the most sensitive for evaluating psychoactive properties of cannabinoida .
Since McIsaac et al . (7)
demonstrated selective distribution of labelled A9 -THC in the brains of squirrel monkeys, it was of interest to investigate the effects of A9 -THC upon the ESG of particular brain areas in the rhesus monkey . ~Preaented in part at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, August, 1971, Burlington, Vermont. 843
844
EYfect ad D9 THC on EEG and Behavior
Vol. 11, No. 13
Methods in the present study one female and three male rhesus monkeys (3-4 kg) were operated under sodium pentobarbital anesthesia to prepare them for EEG récording .
For subcortical recording, bipolar
stainless steel rods insulated to within 1 mm of the tip were stereotaxically implanted in the basolateral amygdala, dorsal hippocampus,
superior cerebellar peduncle, and nucleus fastigü .
For cortical recording, stainless steel screws were bilaterally placed epidurally above the superior frontal, superior parietal and occipital gyri .
All implantations were made according to the
coordinates of Snider and Lee (8) .
Treatments and EEG recordings
were performed 10 days postoperatively .
The monkeys were restrainec
in a primate chair and kept in a sound attenuated room provided with a one-way glass .
The animals were observed continuously
during the treatment .
Pretreatment control recordings consisted
of at least one hour of EEG recording during three different recording sessions .
Vehicle control infusions were performed on
each monkey and demonstrated that volumes as large as 5 ml had no affect on the EEG even though the vehicle considerably reduced blood pressure (see Results) .
Each experimental session lasted
220 minutes ; the A9-THC was administered 30 minutes after the monkey had been restrained in a primate chair .
During the experimen-
tal session a bell was rung at half hour intervals .
~9-THC was
given in a counter-balanced order in doses of 0 .05 , 0 .4, 1 .6, 3 .2 and 12 .8 mq/kg such that two monkeys received increasing and two monkeys received decreasing doses . A9-THC was stored at 4oC under nitrogen .
The purity was
determined to be 968 by optical rotation and gas liquid chromatography . ment .
The formulations were prepared one hour prior to treat The drug was infused as an emulsion of 108 sesame oil, plus
Vol. 11, No. 13
Eüect od ~9 THC on EEG and Hehaviar
0 .48 Tween 80 in nofmal saline .
846
Total volumes ranged from 0 .2 -
3 .2 mls the concentration of ~ 9 -THC never exceeded 1 .5$ .
The drug
was infused via a polyethylene tubing inserted into the external jugular or saphenous vein and was flushed with salines the procedure was complete within 5 minutes .
Treatments were repeated
after an interval of at least 8 days .
The 8ßG was recorded on a
Grass model 7 polygraph . Indirect systolic blood pressure was measured by employing a sphygmomanometer and a plethysmographic pulse detector (C . H . Stoeltinq, Co ., Chicago, graph.
Ill .) connected to a Grass model 7 poly
Blood flow was impeded by occluding the vessels of the
upper arm with a cuff and eliminating the pulse .
Indirect systolic
blood pressure was obtained by gradually releasing the cuff pressure until the pulse was again evident .
Blood pressure values
were then read directly from the sphygmomanometer . The BBG was analyzed by sampling sixty second periods from each recording site at 2, 5, 10, 15, 25, 40, 60, 120 and 180 minutes after the onset of treatment .
Bach second of the 60-second
periods was scored for the presence ôf high voltage slow wave activity and/or high voltage burst activity (4) .
High voltage
activity was defined as at least a threefold increase in the amplitude of the pretreatment BBG during desynchronization .
For each
60-second period, the time occupied by high voltage activity was converted to a percent and averaged across periods .
Thus, the
mean of the periods was used as an indicator of high voltage activity . Results Administration of A9-THC in doses of 0 .05 to 1 .6 mq/kq elicited drowsiness and ptosis .
Two minutes after infusion of 3 .2 or
12 .8 mq/kq of D 9 -THC, lacrimination, slumped posture, immobility,
848
Effect ofO9 TSC on EEG and Behavior
Vol . 11, No. iS
muscle rigidity, and hyper-reactivity to an auditory stimulus were observed .
Treatment with the highest dose (12 .8 mg/kg)
led to clonic muscle spasms .
sometimes
All effects of the drug treatment
disappeared within 24 hours . Administration of D 9 -THC produced a dose-related increase in the amount of high voltage EEG activity (Figure 1) .
Analysis of
variance revealed a highly significant dose effect on the EEG (F4,2g ~ 15 .18, P < ,O1) but no significant differences between brain areas (amygdala,
cerebellar peduncle, frontal cortex, hippo-
campus, nucleus fastigü, occipital cortex, parietal cortex) .
W Q F -
m C w V W F-
DOSE n9THC (mp/kp) FIG. 1 Occurrence of dose-related high Volta EEG activity following i.v . infusion of D THC in 4 rhesus monkeys . Each curve represents a different area of the brain : frontal cortex (FC), nucleus fastigü (NF), occipital cortex (OC), superior cerebellar peduncle (CP), basolateral amygdala (A), parietal cortex (PC) and dorsal hippocampus (H) . Vehicle control is represented by V .C .
Vol . 11, No . 13
Effect od D9 THC on EEG and Behavior
847
The onset of BEG effects as measured by the appearance of rhythmic burst activity (12 to 16 cps) was dose related .
Two
minutes after infusion of 3 .2 or 12 .8 mq/kg of A 9 -THC bursts appeared in the amygdala and cerebellar peduncle .
Lower doses
(0 .05-1 .6 mg/kg) did not induce burst activity until 8-10 minutes after administration (Figure 2C) . not clearly dose-related .
The amount of burst activity was
Bursts occurred only rarely in the
hippocampus and were never seen in the frontal cortex .
The amyg-
dala and cerebellar peduncle exhibited burst activity at all doses (0 .05-12 .8 mq/kg) while the parietal cortex and nucleus fastigü only showed bursts at higher doses (1 .6-12 .8 mg/kg) .
High voltage
A OCCIlü'~I. L~7Q
Gt"YL 9IPIblypp~
!Aq"70AL üfmlL
QIRIO" ~~/4 ~CJi 'Y
`
V~
FIG . 2 The BEG record from a monkey given 1 .6 mq/kg ~9THC i .v . Panel (A), BBG desynchronization 2 minutes b®fore the administration of D9-THC (control) . Panel (B), SBG dissociation between brain areas 7 minutes after administration of A9-THC . Note the epileptiform slow waves in dorsal hippocampus, baaolateral amygdala aniï superior aerebellar peduncle during desynohronization in occipital and parietal cortex . Panel (C) rhythmic burst activity 9 minutes after the administration of A9-THC, The burst activity is most pronounced in the baaolateral amygdala and superior cerebellar peduncle .
848
Effect ad ~9 TSC on ELG and Behavior
Vol. 11, No. 19
in phase epi.leptiform activity occurred in all brain areas immediately following treatment with higher doses (1 .6-12 .8 mg/kq) . Within one hour after treatment the changes were less generalized and high voltage slow waves and low voltage fast waves were observed simultaneously in the EEG (EEG dissociation .
Figure 2B) .
These periods of EEG dissociation often lasted for several minutes . The monkeys exhibited hyper-reactivity to stimulation by a bell .
They responded with a grimace, often accompanied by jerky
body movements while attempting to turn away from the source of the noise .
Bell stimulation always elicited immediate EEG
desynchronization, frequently preceded by rhythmic burst activity . The time course and dose effect of A9-THC on the amount of high voltage EEG activity may be seen in the data presented in Table 1 .
It is evident that maximal EEG effects occurred about
fifteen minutes after administration of the drug and lasted from one to two hours depending on the dose . Administration of the vehicle alone or in combination with A9-THC induced a decrease in systolic blood pressure .
In the case
of the vehicle alone the blood pressure values fell to 53 .3 mm Hg and returned to normal levels within one hour .
This decrease was
somewhat greater following the administration of A9-TSC at doses of 0 .4-12 :8 mq/kq .
Following the administration of A 9 -THC the
blood pressure often fell to values as low as 35 .0 mm Hg and never returned to normal before two hours .
There was no apparent
relationship between the duration of the blood pressure decrease and the dose of A9 -TSC .
Eüect ad ~9 THC. on EEG and Behavior
Vol. 11, No. 13
849
TABLE 1 Time course of high wltage EBG activity in the amygdales following administration of A9-TSC to four rhesus monkeys
Time occupied by high voltage activity (mean percent) Dose A9-TBC mq/kq
-2
2
5
10
Vehicle Control
2 .8
0.
9 .5
4 .0
8 .7
0 .05
2 .6
1.3
2 .3
6 .0
0 .40
5 .0
3 .3
17 .0
1 .60
7 .0
8.0
3 .20
0.
12 .80
3 .3
Time (minutes) 15 25
40
60
120
180
3 .5
6 .5
0.
7 .1
0.
8 .6
3 .3
4 .6
0.
1 .3
0.
6 .6
8 .6
10 .6
6 .0
7 .6
0.
0.
5 .3
25 .3
38 .0
32 .0
32 .0
12 .6
6 .6
0.
1 .0
27 .0
21 .0
46 .3
45,3
27 .0
7 .0
4 .0
3 .3
11 .3
66 .3
47 .3
79 .0
53 .0
59 .3
45 .6
15 .3
1 .6
Discussion Other investigators have observed that A9 -THC administered i .p . or i .v . to monkeys produced an initial phase of increased psychomotor activity and hallucinations (7,9) .
Our findings agree
with Grunfeld and Edery (6) who observed that i .v . injection of A9-THC in the rhesus monkey elicited only sedation and inactivity . Our results also agree with earlier observations of cortical EEG activity in rat, rabbit and squirrel monkey (2,3,5) .
Moreover,
the EEG alterations observed in this study were consistent with EEG changes produced by the synthetic THC derivatives DMHP and MOP (10) , The EEG of monkeys treated with A9-THC differs from that seen in normal sleep, in several important ways .
First, the periods of
high voltage activity were interspersed with burst activity in several areas of the brain (Figure 2C) .
Secondly, the EEG
850
Effect od Os THC on EEG and Behavior
Vol. 11, No. 13
dissociation observed between brain areas was quite pronounced and would often last for minutes at a time .
Behavioral changes that
were inconsistent with sleep included muscle rigidity and the absence of complete eye closure (ptosis) .
None of these obser-
vations is characteristic of normal sleep in the monkey (11) . it could not be determined if blood pressure decreases contributed to the observed EEG changes .
However, the blood pressure
decreases probably did not affect the SEG since the changes per sisted after blood pressure returned to near normal (after two hours)
and no EEG changes were seen with the vehicle alone .
Infusion of large doses of D 9 -THC (3 .2-12 .8 mq/kg)
induced
changes in motor activity such as immobility, muscle rigidity, occasional clonic muscle spasms, and EEG .changes including burst activity in parietal cortex, cerebellur peduncle, and nucleus fastigü .
These observations of altered motor activity are even
more interesting when compared with the findings of Mcisaac et al . (7),who demonstrated that labelled D9-THC reached the greatest tissue levels in the cerebellum . Treatment with an extremely small dose of A9-THC (0 .05 mq/kg) produced epileptiform EEG activity in subcortical areas of the rhesus monkey .
This fact raises the intriguing question of whether
or not administration of D 9 -THC to man elicits similar subcortical effects that are not detectable with surface electrodes, since in man 0 .05 mg/kq D 9 -THC aäministered by the inhalation route was recognized as being similar to marihuana (12) . Acknowledgments Partial support of this research was provided by PBS Training Grant #TO1 MH-10625 to the Worcester Foundation for Experimental Biology .
Dr . M.C . Braude, Center for Studies of Narcotics and
Drug Abuse, NIMH supplied the A9-THC under contract HSM-42-70-95
Vol. 11, No. 13
Effect ad D9 THC on EEG and Hebavior
to Mason Research Institute .
851
Dr . H . Rosenkrantz, Director of
Biochemistry, Mason Research Institute, developed the formulation u4ed in this study .
The technical assistance of the New England
Regional Primate Research Center is gratefully acknowledged . References 1.
R. MECHOULAM, A SHAM , H . EDSRY and Y . GRUNFSLD, Science 169, 611(1970) .
2.
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