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Ketamine catalepsy and anesthesia in dogs pretreated with antiserotonergic or antidopaminergic neuroleptics or with anticholinergic agents
Pharmacological Research Commun[cations, VoL 6, No. 3, 1974
289
KETAMINE CATALEPSY AND ANESTHESIA IN DOGS PRETREATED WITH ANTISEROTONERGIC OR ANTIDOPAMINERGIC NEUROLEPTICS OR WITH ANTICHOLINERGIC AGENTS
Roger C. Hatch 1 Department of Biomedical Sciences University of Guelph, Guelph, Ontario, Canada NIG 2WI /eceiv~d 6 iJcvenber I c~'~,~
SUMMARY
Pretreatment with methlothepin or chlorpromazi~e prevents catalepsy,
prolongs duration of anesthesia and recovery, ~revents apneustic respiration, and favors disappearance of llmb-withdrawal and jaw reflexes in dogs injected intramuscularly with a minimum anesthetic dose of ketamlne.
These effects re-
late to degree of sedation produced by the neuroleptics, and therefore may be nonspeclfic.
A subsedative dose of plmozlde antagonizes ketamlne anesthesia
and potentiates catalepsy, respiratory apneusis, and emergent delirium. tive doses of plmozide are less effective in these regards.
Seda-
Mecamylamine en-
hances ketamlne catalepsy and respiratory apneusls, and lightens (but does not shorten) anesthesia.
Atropine prevents ketamlne catalepsy and antagonizes re-
spiratory apneusls, but potentiates muscle jerking, prolongs recovery time, and greatly prolongs emergent delirium.
The results seem to implicate dopaminer-
glc, nicotinic cholinoceptive, and muscarinlc chollnoceptive mechanisms in a complex system of mediation and modulation of canine responses to ketamlne. This system is different from one previously proposed for the cat.
Ipresent address: Diagnostic Assistance Laboratory, College of Veterinary Medicine, The University of Georgia, Athens, Georgla, 30602, U.S.A.
Pharmaco/ogica/ Research Communications, Vol. 6, No. 3, 1974
290
Weingarten (1972) postulated that ketamine catalepsy might be due to stimulation.of the monoaminergic component of a balanced cholinergic-monoaminergic system in the brain.
In rabbits, the anticholinergic agent procyclidine en-
hanced ketamine catalepsy (Authier & others, 1972).
In cats, the antiserotonergic
neuroleptic agent methiothepin (Monach0n &rothers, 1972) prevented ketamine catalepsy, but plmozide (an antidopaminergic neuroleptic, And~n & others, 1970) and chlorpromazine (a neurolepticof mixed antlmonoamine activity) did not affect ketamine catalepsy (Hatch, 1973).
Thus, it appeared that ketamine catalepsy may
indeed relate to a cholinergic-monoaminergic imbalanc~,land that the monoamine of interest in this regard might be serotonin. The purpose of the present study was to examine the validity of the proposed cholinergic-serotonergic mechanism of ketamine catalepsy in dogs.
This species
is particularly susceptible uo the cataleptic and deliriant effects of ketamine.
METHODS
Eighteen 8.5 - 12.0 kg Beagle dogs of both sexes were allotted to 3
groups of 6 dogs each.
Group I dogs were given an intramuscular (i.m,) injec-
tion of methlothepin vehicle (30% v/v propyleneglycol in water).
Group 2 and
3 dogs were given an i.m. injection of 0.03 and 0.I mg/kg methlothepin maleate respectively.
Thirty minutes later, overt signs and behavior were noted and
then the dogs were given a minimum anesthetic dose (20 mg/kg i.m.) of ketamlne HC1.
With this dose of ketamlne, muscle tonus is pronounced in neck, limbs,
and abdomen.
There is usually foreleg extensor rigidity and jerking of the
limbs or faclal or neck muscles during onset of anesthesia.
Respiration is
irregular and apneustlc, reflexes are well preserved, and anesthesia is brief. About half of a given group of dogs will manifest emergent delirium (whining or loud crying, constant limb and head movements, wide open but apparently unseeing eyes, and semi-conscious attempts to remain upright).
The delirium
Pharmacological Research Communications, VoL 6, No. 3, 1974
291
is reminiscent of the delirium induced by atropine in dogs (see White & others, 1961; Albanus & others, 1969; Albanus, 1970). Measured data included onset of anesthesia (to loss of righting reflex), duration of anesthesia (to ability to hold up the head and follow gross movements with the eyes), ambulation time (from awakening to ability to walk when assisted), and recovery time (anesthesia plus ambulation time). Observations made at onset of anesthesia and at i0 minute intervals thereafter included presence of foreleg extensor rigidity and muscle Jerking, presence of tonus in neck, limb, and abdominal muscles, character of respiration, and presence of limb-withdrawal and Jaw reflexes.
Signs of emergent delirium
were noted when they occurred. The following week, the experiment was repeated using saline instead of methlothepln vehicle in group i. i.m.) of methlothepln.
Group 2 dogs were given a large dose (i mg/kg
A small dose (i mg/kg i.m.) of ch!orpromazine was given
to group 3 dogs. In subsequent biweekly experiments, the principals received a large dose (5 mg/kg i.m.) of chlorpromazlne HC!, small and large doses of plmozide (0.2, 0.5, 5.0 mg/kg i.m.), or a single dose of either mecamylamlne HCI (I.0 mg/kg i.m.) or atropine sulfate (0.5 mg/kg i.m.).
In plmozlde-treated dogs, 45 - 60
minutes elapsed before administration of ketamine. Measured data were analyzed using Student's t_-test for unpaired observations (Steel & Torrie, 1960).
RESULTS
A subsedatlve dose (0.I mg/kg) of methiothepin had little effect on
measured indices of ketamlne anesthesia (Table i).
Muscle tonus and respira-
tory apneusis were gradually abolished by this dose in some of the dogs. Extensor rigidity, reflex activity, muscle jerking, and emergent delirlumwere
Pharmacological Research Communications, VoL 6, No. 3, 1974
292
Effect of Methiothepin, Chlorpromazine, Pimozide, Mecamylamine, or Atropine Pretreatment on Mean (~ SEM) Onset and Duration of Anesthesia, Ambulation Time, and Recovery Time in Dogs Given Ketamine HCI
Table I.
Effects of Ketamine HCl, 20 mg/kg i.m.
Group a
Onset of
Duration
Ambulation
Recovery
Anesthesia c
Anesthesia d
Time e
Time f
(mln)
(min)
(rain)
(rain)
(N = 6)
Pretreatment b
1
Vehicle, i ml
4.4 ~0.5
22.1 ±1.4
21.2 ±2.8
43.3 2 3.1
Methlothepin, 0.i
4.3 ±0.3
26.2 ±2.3
25.8 ±7.0
51.9 ± 6.5
Methlothepln, 0.3
3.5 ~Q.5
33.7±5.0
30.2 ±3.1
63.8 ± 3.8*
3 -
i
3
f
.
.
.
.
.
.
.
.
.
.
,i
•
.
.
.
.
.
.
.
-
.
.
.
.
.
.
Saline, i ml
3.6 ±0.5
21.8 ±2.3
19.0 ±2.4
40.8 ± 3.2
Methiothepln, l.O
2;6 ±0.4
34.3 ±2.4*
56.1±5.4"
90.4 ±10.4'
Chlorpromazine, 1.0
2.4 _+0.4
22.4 _+I.I
16.5 ±1.8
38.9 ± 2.5 24.0 2 3.8
,
,
,
i
Saline, I ml
5.1 ~0.8
16.1 23.1
7.9 ±I.I
2
Chlorpromazlne, 5.0
2.8 ~0.3,*
32.8 ,2.2"
62.5 ~8.1"*
3
Pimozfde, 0.2
glO.0 ~0.0"*
g2.1 21.5"
1
Sallne, 1 ml
5.6 ~1.2
14.5 ~2.1
11.9 ~1.7
26.4 ~ 3.2
2
Pimozlde, D.5
h5.3 ±1.3
h7.9 ±2.9
hlg.0 ±3.9
h26.9 ± 4.2
3
Pimozide, 5.0
2.1 ~0.2"
19.3 ±1.5
16.5 ±2.7
35.8 ± 3.0
I
Saline, 1 ml
3.1 _+0.4
13.5 +1.6
18.6 +3.4
32.1 + 4.0 !
2
Mecam~!amine, I.O
i2.3 _+O.2
i16.1 _+0.6
21.6 ±2.8
37~7 ± 3.0
3
Atropine, 0.5
J49.6 ±5.3**
17.7 ±3.1
J67.4 ~ 6.7*
2.4 _~0.4
95.2 ± 8.1**
g25.2 ~3.1"* g27.2 2 2.9 i
aGroups reused at weekly or biweekly intervals (see text), bDoses in mg/kg as the salt, given ~i.m; 3Ominutes before ketamine (45 - 60 minutes allowed for
Pharmacologicat Research Communications, Vol. 6; No. 3, 1974
293
.
imozide) ' ~ e a s u r e d from i n j e c t i o n of ketamine t o l o s s of r i g h t i n g r e f l e x . 'Measured from l o s s of r i g h t i n g r e f l e x t o a b i l i t y t o hold up t h e head and follow gross 'movem n t a with t h e eyes. e ~ e a s u r e dfrom awakening t o a b i l i t y t o walk when a s s i s t e d . 'Anesthesia p l u s ambulstion t i m e . g ~ n l y2 dogs l o s t t h e r i g h t i n g r e f l e x . The o t h e r 4 dogs were not included i n c a l c u l a t i o n of mean onset and d u r a t i o n of ane s t h e s i a . A l l 6 dogs 1 ~ s fthe a b i l i t y t o stand and walk, however. dog d i d not l o s e t h e r i g h t i n g r e f l e x and was not included i n c a l c u l a t i o n of mean onset and duration of anesthesia. iAnesthesia very l i g h t in a l l 6 dogs (heads were r a i s e d and r e f l e x e s were sharp). j ~ r o l o n ~ eadn e s t h e s i a and recovery due mainly t o a prolonged emergent delirium i n a l l 6 dogs. *Difference from c o n t r o l group s i g n i f i c a n t (P(0.05). **Difference frbm c o n t r o l group highly s i g n i f i c a n t (Pe0.001) , Expected week t o week v a r i a t i o n i n ,"normal" response t o ketamine (due t o t o l e r a n c e lnecbanisms and i n d i v i d u a l ' v a r i a t i o n ) n e c e s s i t a t e d the group of p a r a l l e l c o n t r o l dogs.
not ,diminished (Table 2). Sedative doses (0.3,
1.0 mg/kg) of methiothepin prolonged d u r a t i o n of
anesthesia, amburation time, and recovery time i n s dose dependent manner (Table 1 ) .
These doses, a l s o reduced o r abolished extensor r i g i d i t y , muscle
tonus, r e s p i r a t o r y apneusis, limb-withdrawal and jaw r e f l e x e s , sporadic muscle jerking, and emergent delirium (Table. 2). A mildly s e d a t i v e dos,e (1.0 mg/kg) of chlorprornazine had no e f f e c t on
measured i n d i c e s of ketamine a n e s t h e s i a (Tab1.e I).
Muscle tonus, r e s p i r a t o r y
apneusis, and reflex a c t i v S t y gradually disappeared i n some of t h e dogs, but muscle j e r k i n g and emergent*d e i i r i m weye Lncreased in.incidence (Table 2). '
The l a r g e r dose (5.0 mg/kg) of chlorpromazfne was markedly sedative.
Onset
of a n e s t h e s i a was shortened and o t h e r measured i n d i c e s of a n e ~ t h e s i awere prolonged (Table
I).
Extensor r i g i d i t y was prevented i n 5 dogs, while muscle
tonus and r e s p i r a t o r y apneusis w e r e abolished i n a l l 6 dogs.
Reflex a c t i v i t y
and muscle j e r k i n g disappeared i n some dogs, b u t emergent delirium was s t i l l a prominent f e a t u r e of recovery (Table 2). After pretreatment with a subsedative dose (0.2 mg/kg) of pimozide, 4 dogs did n o t l o s e t h e r i g h t i n g r e f l e x .
Onset of a n e s t h e s i a w a s prolonged to 10 minutes
i n each of t h e 2 dogs t h a t did l o s e the r i g h t i n g r e f l e x , and d u r a t i o n of a n e s t h e s i a i n
2 0
6
0 3
5 1
4
0 6
5
Methiothepin, 0.i
Methiothepin, 0.3
Saline, i ml
Methiothepln, 1.0
Chlorpromazine, 1.0
Saline, i ml
Chlorpromazlne, 5.0
2
3
i
2
3
i
Pimozide, 0.2
3
6
6
Vehicle, i ml
1
3
0
tonus c
rigidityb
Pretreatment a
(N = 6)
0
0
6f
1 6f
6
6
6
5
0
3
6
Muscle
Extensor
Apneustic, irregular respiration
6g
z
6
~
0
6
2
6
6
Limbwithdrawal reflex
6g
4
6
4
I
6
3
6
6
reflex
Jaw
5h
2
4
5i
4
3
5
0
2 6
3
3
3
4
4
4
3
delirium e
jerking d
4
Emergent
Muscle
After Ketamlne HCI (20 mg/kg i.m.), Number of Dogs Mmnifesting:
Effect of Methiothepin, Chlorpromazine, Pimozide, Mecamylamine, or Atropine Pretreatment on Extensor Rigidity, Tonus in Neck, Limb, and Abdominal Muscles, Character of Respiration, Limb-Withdrawal and Jaw Reflexes, Muscle Jerking, and Emergent Delirium in Dogs Given Ketamine HCI
Group a
Table 2.
5"
O
~O CO
Saline, i ml
Pimozlde, 0.5
Pimozide, 5.0
Saline, i ml
Mecamylamlne, 1.0
Atropine, 0.5
i
2
3
1
2
3
01
6k
6
6J
6
5
tonus c
21
6k
6
6 6
6
6
6
6
6
5 6
6
6
5
i
6
6
5
reflex
Jaw
Limbwithdrawal reflex
Apneustic, irregular respiration
6TM
3
4
61
3
5
3
3
delirium e
Emergent
4
2
1
3
Jerking
Muscle
~pp
asee Table;l. bStlffenlng of forelegs at onset of anesthesia. CResistance in neck, llmb, and abdominal muscles. ~Sporadlc jerking of limbs, neck, or facial muscles at onset of anesthesia, eVocallzation, arently unseeing eyes, and semiconscious struggling to rise or maintain equilibrium during recovery. ~e" dog manifested 2 stlmulus-induced tonic seizures during onset of anesthesia. The seizures lasted less than 1 minute and were confined to the forelimbs, neck, and facial musculature, and app@rently to the intercostal muscles and diaphragm, gReflexes were very brisk compared to control an£mals, nMuscle Jerking was more frequent and more pronounced than in control animals. ~Delirium was ~ r e severe. ~ocaiization was very loud and Body movements were more vigorous than in control animals. One dog manifested_l seizure as described above, kcatalepsy and respiratory apneusls more intense than in control animals, iSkeletal muscles completely flaccid I - 5 minutes after onset of anesthesia, but sporadic Jerking of limbs and head was much more intense than in control animals. The Jerking was seen in all 6 dogs and occurred continuously throughout anesthesia. Respiratory apneusls was prevented in 4 dogs, but respiration was irregular in all 6 dogs due to the intensity of muscle jerking, mEmergent delirium was no more severe than that seen in control animals, but it occurred in all 6 dogs and it was markedly prolonged (Table 1).
01
5k
5
6J
6
6
rlgldity b
Pretreatment a
(N = 6)
Muscle
After Ketamine RCI (20 mg/kg i.m.), Number of Dogs Manifesting:
Extensor
(Continued)
Groupa
Table 2.
~O CP On
9
-'~"
O
296
Pharmacological Research Communications, VoL 6, No. 3, 1974
these 2 dogs was drastically shortened.
All 6 dogs lost the ability to stand,
Ambulation time was prolonged but total recovery time was not affected (Table i). This apparent antagonism of ketamlne anesthesia was further characterized by maintenance of extensor riEidity and muscle tonus, occurrence of 2 touch-induced seizures in i dog (see legend, Table 2), apneustic, irregular respiration, brisk llmb-wlthdrawal reflexes and tight closure of the Jaw, muscle jerking in l~mbs and headwhich was less sporadic and more intense than in control dogs, and dellriumwhich was of higher incidence and greater severity than in control dogs (Table 2). Sedative doses (0.5, 5.0 mg/kg) of plmozlde were less effective than the subseda=Ive dose in antagonizing ketam/ne anesthesia and enhancing vaYious
"slde effects" of ketamlne. M~camylamine pretreatment caused a much lighter ketamine anesthesia than in control dogs, but none Of the measured indices of anesthesia was shortened or prolonged (Table I).
This drug also intensified extensor rigidity, muscle
tonus, and respiratory apneusis (Table 2). Atropine prolonged ke~amine anesthesia and recovery time (Table I).
These
effects were largely due to prolonged emergent dellrlumwhlch occurred in all 6 dogs (Table 2).
Atropine also prevented ketamine catalepsy and reduced the
incidence of respiratory apneusis.
Muscle jerking occurred throughout anes-
thesla in all 6 dogs and was less sporadic and more intense than In control dogs.
DZSCUSSION
I/hen drugs that probably have numerous biochemical effects are used
as tools to Investlgate how another drug acts, ewper~mental results can only give suggestive evidence of mechanism of drug action.
In the present study,
ketamlne anesthesia was antagonized by a subsedative dose of the antidopaminerglc neuroleptlc pimozlde, and partly antagonized by the nicotinic chollnoceptor
297
Pharmacological Research Communications, VoL 6, No. 3, 1974 blocking agent mecamylamine.
These results suggest dopaminergic and nicotinic
cholinoceptive receptors could be involved in mediation of ketamine anesthesia in the dog. Ketam~ne catalepsy (extensor rigidity and increased muscle tonus) and respiratory apneusis were enhanced by mecamylamine and prevented by the muscarinic cholinoceptor
antagonist atropine.
These observations suggest that ketamine
catalepsy and respiratory apneusls in dogs could be mediated by muscarinic cholinoceptive mechanisms, and that adaptation mechanisms to ketamine catalepsy and respiratory apneusis could be mediated by nicotinic cholinoceptors. Other putative neurotransmitters cannot be excluded from a possible role in mediation of ketamine catalepsy and respiratory apneusis. antiserotoninergic neuroleptlc methiothepln,
The predominantly
in a subsedative dose, reduced
muscle tonus and respiratory apneusis in some dogs in the present study, but these effects had a slow onset and were not as striking (%.e. muscle flaccidity was not as marked) as in dogs pretreated with atropine.
Dogs pretreated with a
subsedative dose of pimozide manifested marked catalepsy and respiratory apneusis, but these dogs were also conscious or only briefly and lightly anesthetized, and it was difficult to determine how much muscle tonus and respiratory apneusis was due to ketamine and how much was due to volitional or excitatory activity of the animals. Ketamine-lnduced muscle jerking and emergent delirium were both enhanced by a subsedatlve dose of plmozide, by atropine, and by the small dose of chlorpromazine.
The latter drug is known to possess both antidopamlnerglc and anti-
cholinergic properties.
The results suggest dopamlnerglc and muscarinic
cholinoceptive receptors could both play an adaptive role in modulating the myoclonic and deliriant effects of ketamine in dogs.
Atropine itself is a
Pharmacological Research Communications, VoL 6, No. 3, T974
298
deliriant drug, and this property could have contributed to the prolonged emergent delirium seen in atropine-pretreated dogs even though none of these dogs manifested delirium before administration of ketamine. Sedative doses of me~hlothepin or chlorpromazine enhanced ketamine anesthesia and reduced or prevented the various "side effects" of ketamine in the present study.
These are probably nonspec~fic effects of sedation and may be
useful in clinical anesthesia.
A number of sedative drugs or neuroleptics in
sedative dose are already being used to improve ketamlne anesthesia in man and animals. In the cat, it was suggested that serotonin may function both in adaptation to central depressant effects of ketamine and in mediation of catalepsy and respiratory apneusis, and that dopamine may mediate ketanLine-lnduced cle Jerking (Hatch, 1973).
mus-
The present study indicates that brain mechanisms
involved with the various effects of ketamine in dogs could be quite different and much more complex than the mechanisms suggested for cats. Weingarten's
(1972) proposal that ketamine catalepsy may be related to
stimulation of the mouoaminergic portion of a balanced monoaminergic-cholinerglc system was supported by the cat study (Hatch, 1973).
However, the pre-
sent study with dogs suggests that, in some species, ketaminecatalepsy may be mere closely related to a muscarinic-nlcotinic
cholinergic imbalance, with
monoam/nes playing a less important role.
ACKNOWLEDGEMENTS This work supported by the Ontario Ministry of Agriculture and Food. Drugs used in this study were supplied by the courtesy of several manufacturers: ketamine HCI from Parke, Davis & Co., Ann Arbor, Michigan, U.S.A.; methiothepin maleate from F. Hoffman-La Roche & Co., Basel, Switzerland; mecamylamlne HCI from Merck, Sharp and Dohme, Into, West Point, Pennsylvania, U.S.A.; and pimozide from Janssen Pharmaceuticals, Beerse, Belgium.
Pharmacological Research Communications, Vol. 6, No. 3, 1974
REFERENCES Albanus, L.: (1970), Acta Pharm, col. et Toxicol. 28, 305-326. Albanus, L., Aquilonluss S.-M., Sundwall, A., and Winbladh, B.: (1969)p Acta Pharmacol. et Toxlcol. 27, 81-96. And~n, N.-E., Butcher, S.G., Corrodl, H., Fuxe, K., and Ungerstedt, U.: (1970), Europ. J. Pharmaeol. Ii, 303-314. Authler, L., Sindon, A., Chapados, R., and Barry, P.P.: (1972), Canad. Anaesth. Soc. J. 19, 445-452. Hatch, R.C.: (1973), Pharmacol. Res. Commun. ~, 311-319. Monachon, M.-A., Burkard, W.P., 3alfre, M., and Haefely, W.: (1972), Naunyn-Schmiedeberg's Arch. Pharmacol. 27__4, 192-197. Steel, R.G.D., and Torrle, J.H.: (1960), Principles and Frocedures of Statistics, McGraw-Hill Book Company, Inc., New York, 73-75. Welngarten, S.M.: (1972), J. Neurosurgo 37, 429-433. White, R.P., Nash, C.B., Westerbeke, E.J., and Possanza, J.: (1961), Arch. Int. Pharmacodyn. 132, 349-363.
299
289
KETAMINE CATALEPSY AND ANESTHESIA IN DOGS PRETREATED WITH ANTISEROTONERGIC OR ANTIDOPAMINERGIC NEUROLEPTICS OR WITH ANTICHOLINERGIC AGENTS
Roger C. Hatch 1 Department of Biomedical Sciences University of Guelph, Guelph, Ontario, Canada NIG 2WI /eceiv~d 6 iJcvenber I c~'~,~
SUMMARY
Pretreatment with methlothepin or chlorpromazi~e prevents catalepsy,
prolongs duration of anesthesia and recovery, ~revents apneustic respiration, and favors disappearance of llmb-withdrawal and jaw reflexes in dogs injected intramuscularly with a minimum anesthetic dose of ketamlne.
These effects re-
late to degree of sedation produced by the neuroleptics, and therefore may be nonspeclfic.
A subsedative dose of plmozlde antagonizes ketamlne anesthesia
and potentiates catalepsy, respiratory apneusis, and emergent delirium. tive doses of plmozide are less effective in these regards.
Seda-
Mecamylamine en-
hances ketamlne catalepsy and respiratory apneusls, and lightens (but does not shorten) anesthesia.
Atropine prevents ketamlne catalepsy and antagonizes re-
spiratory apneusls, but potentiates muscle jerking, prolongs recovery time, and greatly prolongs emergent delirium.
The results seem to implicate dopaminer-
glc, nicotinic cholinoceptive, and muscarinlc chollnoceptive mechanisms in a complex system of mediation and modulation of canine responses to ketamlne. This system is different from one previously proposed for the cat.
Ipresent address: Diagnostic Assistance Laboratory, College of Veterinary Medicine, The University of Georgia, Athens, Georgla, 30602, U.S.A.
Pharmaco/ogica/ Research Communications, Vol. 6, No. 3, 1974
290
Weingarten (1972) postulated that ketamine catalepsy might be due to stimulation.of the monoaminergic component of a balanced cholinergic-monoaminergic system in the brain.
In rabbits, the anticholinergic agent procyclidine en-
hanced ketamine catalepsy (Authier & others, 1972).
In cats, the antiserotonergic
neuroleptic agent methiothepin (Monach0n &rothers, 1972) prevented ketamine catalepsy, but plmozide (an antidopaminergic neuroleptic, And~n & others, 1970) and chlorpromazine (a neurolepticof mixed antlmonoamine activity) did not affect ketamine catalepsy (Hatch, 1973).
Thus, it appeared that ketamine catalepsy may
indeed relate to a cholinergic-monoaminergic imbalanc~,land that the monoamine of interest in this regard might be serotonin. The purpose of the present study was to examine the validity of the proposed cholinergic-serotonergic mechanism of ketamine catalepsy in dogs.
This species
is particularly susceptible uo the cataleptic and deliriant effects of ketamine.
METHODS
Eighteen 8.5 - 12.0 kg Beagle dogs of both sexes were allotted to 3
groups of 6 dogs each.
Group I dogs were given an intramuscular (i.m,) injec-
tion of methlothepin vehicle (30% v/v propyleneglycol in water).
Group 2 and
3 dogs were given an i.m. injection of 0.03 and 0.I mg/kg methlothepin maleate respectively.
Thirty minutes later, overt signs and behavior were noted and
then the dogs were given a minimum anesthetic dose (20 mg/kg i.m.) of ketamlne HC1.
With this dose of ketamlne, muscle tonus is pronounced in neck, limbs,
and abdomen.
There is usually foreleg extensor rigidity and jerking of the
limbs or faclal or neck muscles during onset of anesthesia.
Respiration is
irregular and apneustlc, reflexes are well preserved, and anesthesia is brief. About half of a given group of dogs will manifest emergent delirium (whining or loud crying, constant limb and head movements, wide open but apparently unseeing eyes, and semi-conscious attempts to remain upright).
The delirium
Pharmacological Research Communications, VoL 6, No. 3, 1974
291
is reminiscent of the delirium induced by atropine in dogs (see White & others, 1961; Albanus & others, 1969; Albanus, 1970). Measured data included onset of anesthesia (to loss of righting reflex), duration of anesthesia (to ability to hold up the head and follow gross movements with the eyes), ambulation time (from awakening to ability to walk when assisted), and recovery time (anesthesia plus ambulation time). Observations made at onset of anesthesia and at i0 minute intervals thereafter included presence of foreleg extensor rigidity and muscle Jerking, presence of tonus in neck, limb, and abdominal muscles, character of respiration, and presence of limb-withdrawal and Jaw reflexes.
Signs of emergent delirium
were noted when they occurred. The following week, the experiment was repeated using saline instead of methlothepln vehicle in group i. i.m.) of methlothepln.
Group 2 dogs were given a large dose (i mg/kg
A small dose (i mg/kg i.m.) of ch!orpromazine was given
to group 3 dogs. In subsequent biweekly experiments, the principals received a large dose (5 mg/kg i.m.) of chlorpromazlne HC!, small and large doses of plmozide (0.2, 0.5, 5.0 mg/kg i.m.), or a single dose of either mecamylamlne HCI (I.0 mg/kg i.m.) or atropine sulfate (0.5 mg/kg i.m.).
In plmozlde-treated dogs, 45 - 60
minutes elapsed before administration of ketamine. Measured data were analyzed using Student's t_-test for unpaired observations (Steel & Torrie, 1960).
RESULTS
A subsedatlve dose (0.I mg/kg) of methiothepin had little effect on
measured indices of ketamlne anesthesia (Table i).
Muscle tonus and respira-
tory apneusis were gradually abolished by this dose in some of the dogs. Extensor rigidity, reflex activity, muscle jerking, and emergent delirlumwere
Pharmacological Research Communications, VoL 6, No. 3, 1974
292
Effect of Methiothepin, Chlorpromazine, Pimozide, Mecamylamine, or Atropine Pretreatment on Mean (~ SEM) Onset and Duration of Anesthesia, Ambulation Time, and Recovery Time in Dogs Given Ketamine HCI
Table I.
Effects of Ketamine HCl, 20 mg/kg i.m.
Group a
Onset of
Duration
Ambulation
Recovery
Anesthesia c
Anesthesia d
Time e
Time f
(mln)
(min)
(rain)
(rain)
(N = 6)
Pretreatment b
1
Vehicle, i ml
4.4 ~0.5
22.1 ±1.4
21.2 ±2.8
43.3 2 3.1
Methlothepin, 0.i
4.3 ±0.3
26.2 ±2.3
25.8 ±7.0
51.9 ± 6.5
Methlothepln, 0.3
3.5 ~Q.5
33.7±5.0
30.2 ±3.1
63.8 ± 3.8*
3 -
i
3
f
.
.
.
.
.
.
.
.
.
.
,i
•
.
.
.
.
.
.
.
-
.
.
.
.
.
.
Saline, i ml
3.6 ±0.5
21.8 ±2.3
19.0 ±2.4
40.8 ± 3.2
Methiothepln, l.O
2;6 ±0.4
34.3 ±2.4*
56.1±5.4"
90.4 ±10.4'
Chlorpromazine, 1.0
2.4 _+0.4
22.4 _+I.I
16.5 ±1.8
38.9 ± 2.5 24.0 2 3.8
,
,
,
i
Saline, I ml
5.1 ~0.8
16.1 23.1
7.9 ±I.I
2
Chlorpromazlne, 5.0
2.8 ~0.3,*
32.8 ,2.2"
62.5 ~8.1"*
3
Pimozfde, 0.2
glO.0 ~0.0"*
g2.1 21.5"
1
Sallne, 1 ml
5.6 ~1.2
14.5 ~2.1
11.9 ~1.7
26.4 ~ 3.2
2
Pimozlde, D.5
h5.3 ±1.3
h7.9 ±2.9
hlg.0 ±3.9
h26.9 ± 4.2
3
Pimozide, 5.0
2.1 ~0.2"
19.3 ±1.5
16.5 ±2.7
35.8 ± 3.0
I
Saline, 1 ml
3.1 _+0.4
13.5 +1.6
18.6 +3.4
32.1 + 4.0 !
2
Mecam~!amine, I.O
i2.3 _+O.2
i16.1 _+0.6
21.6 ±2.8
37~7 ± 3.0
3
Atropine, 0.5
J49.6 ±5.3**
17.7 ±3.1
J67.4 ~ 6.7*
2.4 _~0.4
95.2 ± 8.1**
g25.2 ~3.1"* g27.2 2 2.9 i
aGroups reused at weekly or biweekly intervals (see text), bDoses in mg/kg as the salt, given ~i.m; 3Ominutes before ketamine (45 - 60 minutes allowed for
Pharmacologicat Research Communications, Vol. 6; No. 3, 1974
293
.
imozide) ' ~ e a s u r e d from i n j e c t i o n of ketamine t o l o s s of r i g h t i n g r e f l e x . 'Measured from l o s s of r i g h t i n g r e f l e x t o a b i l i t y t o hold up t h e head and follow gross 'movem n t a with t h e eyes. e ~ e a s u r e dfrom awakening t o a b i l i t y t o walk when a s s i s t e d . 'Anesthesia p l u s ambulstion t i m e . g ~ n l y2 dogs l o s t t h e r i g h t i n g r e f l e x . The o t h e r 4 dogs were not included i n c a l c u l a t i o n of mean onset and d u r a t i o n of ane s t h e s i a . A l l 6 dogs 1 ~ s fthe a b i l i t y t o stand and walk, however. dog d i d not l o s e t h e r i g h t i n g r e f l e x and was not included i n c a l c u l a t i o n of mean onset and duration of anesthesia. iAnesthesia very l i g h t in a l l 6 dogs (heads were r a i s e d and r e f l e x e s were sharp). j ~ r o l o n ~ eadn e s t h e s i a and recovery due mainly t o a prolonged emergent delirium i n a l l 6 dogs. *Difference from c o n t r o l group s i g n i f i c a n t (P(0.05). **Difference frbm c o n t r o l group highly s i g n i f i c a n t (Pe0.001) , Expected week t o week v a r i a t i o n i n ,"normal" response t o ketamine (due t o t o l e r a n c e lnecbanisms and i n d i v i d u a l ' v a r i a t i o n ) n e c e s s i t a t e d the group of p a r a l l e l c o n t r o l dogs.
not ,diminished (Table 2). Sedative doses (0.3,
1.0 mg/kg) of methiothepin prolonged d u r a t i o n of
anesthesia, amburation time, and recovery time i n s dose dependent manner (Table 1 ) .
These doses, a l s o reduced o r abolished extensor r i g i d i t y , muscle
tonus, r e s p i r a t o r y apneusis, limb-withdrawal and jaw r e f l e x e s , sporadic muscle jerking, and emergent delirium (Table. 2). A mildly s e d a t i v e dos,e (1.0 mg/kg) of chlorprornazine had no e f f e c t on
measured i n d i c e s of ketamine a n e s t h e s i a (Tab1.e I).
Muscle tonus, r e s p i r a t o r y
apneusis, and reflex a c t i v S t y gradually disappeared i n some of t h e dogs, but muscle j e r k i n g and emergent*d e i i r i m weye Lncreased in.incidence (Table 2). '
The l a r g e r dose (5.0 mg/kg) of chlorpromazfne was markedly sedative.
Onset
of a n e s t h e s i a was shortened and o t h e r measured i n d i c e s of a n e ~ t h e s i awere prolonged (Table
I).
Extensor r i g i d i t y was prevented i n 5 dogs, while muscle
tonus and r e s p i r a t o r y apneusis w e r e abolished i n a l l 6 dogs.
Reflex a c t i v i t y
and muscle j e r k i n g disappeared i n some dogs, b u t emergent delirium was s t i l l a prominent f e a t u r e of recovery (Table 2). After pretreatment with a subsedative dose (0.2 mg/kg) of pimozide, 4 dogs did n o t l o s e t h e r i g h t i n g r e f l e x .
Onset of a n e s t h e s i a w a s prolonged to 10 minutes
i n each of t h e 2 dogs t h a t did l o s e the r i g h t i n g r e f l e x , and d u r a t i o n of a n e s t h e s i a i n
2 0
6
0 3
5 1
4
0 6
5
Methiothepin, 0.i
Methiothepin, 0.3
Saline, i ml
Methiothepln, 1.0
Chlorpromazine, 1.0
Saline, i ml
Chlorpromazlne, 5.0
2
3
i
2
3
i
Pimozide, 0.2
3
6
6
Vehicle, i ml
1
3
0
tonus c
rigidityb
Pretreatment a
(N = 6)
0
0
6f
1 6f
6
6
6
5
0
3
6
Muscle
Extensor
Apneustic, irregular respiration
6g
z
6
~
0
6
2
6
6
Limbwithdrawal reflex
6g
4
6
4
I
6
3
6
6
reflex
Jaw
5h
2
4
5i
4
3
5
0
2 6
3
3
3
4
4
4
3
delirium e
jerking d
4
Emergent
Muscle
After Ketamlne HCI (20 mg/kg i.m.), Number of Dogs Mmnifesting:
Effect of Methiothepin, Chlorpromazine, Pimozide, Mecamylamine, or Atropine Pretreatment on Extensor Rigidity, Tonus in Neck, Limb, and Abdominal Muscles, Character of Respiration, Limb-Withdrawal and Jaw Reflexes, Muscle Jerking, and Emergent Delirium in Dogs Given Ketamine HCI
Group a
Table 2.
5"
O
~O CO
Saline, i ml
Pimozlde, 0.5
Pimozide, 5.0
Saline, i ml
Mecamylamlne, 1.0
Atropine, 0.5
i
2
3
1
2
3
01
6k
6
6J
6
5
tonus c
21
6k
6
6 6
6
6
6
6
6
5 6
6
6
5
i
6
6
5
reflex
Jaw
Limbwithdrawal reflex
Apneustic, irregular respiration
6TM
3
4
61
3
5
3
3
delirium e
Emergent
4
2
1
3
Jerking
Muscle
~pp
asee Table;l. bStlffenlng of forelegs at onset of anesthesia. CResistance in neck, llmb, and abdominal muscles. ~Sporadlc jerking of limbs, neck, or facial muscles at onset of anesthesia, eVocallzation, arently unseeing eyes, and semiconscious struggling to rise or maintain equilibrium during recovery. ~e" dog manifested 2 stlmulus-induced tonic seizures during onset of anesthesia. The seizures lasted less than 1 minute and were confined to the forelimbs, neck, and facial musculature, and app@rently to the intercostal muscles and diaphragm, gReflexes were very brisk compared to control an£mals, nMuscle Jerking was more frequent and more pronounced than in control animals. ~Delirium was ~ r e severe. ~ocaiization was very loud and Body movements were more vigorous than in control animals. One dog manifested_l seizure as described above, kcatalepsy and respiratory apneusls more intense than in control animals, iSkeletal muscles completely flaccid I - 5 minutes after onset of anesthesia, but sporadic Jerking of limbs and head was much more intense than in control animals. The Jerking was seen in all 6 dogs and occurred continuously throughout anesthesia. Respiratory apneusls was prevented in 4 dogs, but respiration was irregular in all 6 dogs due to the intensity of muscle jerking, mEmergent delirium was no more severe than that seen in control animals, but it occurred in all 6 dogs and it was markedly prolonged (Table 1).
01
5k
5
6J
6
6
rlgldity b
Pretreatment a
(N = 6)
Muscle
After Ketamine RCI (20 mg/kg i.m.), Number of Dogs Manifesting:
Extensor
(Continued)
Groupa
Table 2.
~O CP On
9
-'~"
O
296
Pharmacological Research Communications, VoL 6, No. 3, 1974
these 2 dogs was drastically shortened.
All 6 dogs lost the ability to stand,
Ambulation time was prolonged but total recovery time was not affected (Table i). This apparent antagonism of ketamlne anesthesia was further characterized by maintenance of extensor riEidity and muscle tonus, occurrence of 2 touch-induced seizures in i dog (see legend, Table 2), apneustic, irregular respiration, brisk llmb-wlthdrawal reflexes and tight closure of the Jaw, muscle jerking in l~mbs and headwhich was less sporadic and more intense than in control dogs, and dellriumwhich was of higher incidence and greater severity than in control dogs (Table 2). Sedative doses (0.5, 5.0 mg/kg) of plmozlde were less effective than the subseda=Ive dose in antagonizing ketam/ne anesthesia and enhancing vaYious
"slde effects" of ketamlne. M~camylamine pretreatment caused a much lighter ketamine anesthesia than in control dogs, but none Of the measured indices of anesthesia was shortened or prolonged (Table I).
This drug also intensified extensor rigidity, muscle
tonus, and respiratory apneusis (Table 2). Atropine prolonged ke~amine anesthesia and recovery time (Table I).
These
effects were largely due to prolonged emergent dellrlumwhlch occurred in all 6 dogs (Table 2).
Atropine also prevented ketamine catalepsy and reduced the
incidence of respiratory apneusis.
Muscle jerking occurred throughout anes-
thesla in all 6 dogs and was less sporadic and more intense than In control dogs.
DZSCUSSION
I/hen drugs that probably have numerous biochemical effects are used
as tools to Investlgate how another drug acts, ewper~mental results can only give suggestive evidence of mechanism of drug action.
In the present study,
ketamlne anesthesia was antagonized by a subsedative dose of the antidopaminerglc neuroleptlc pimozlde, and partly antagonized by the nicotinic chollnoceptor
297
Pharmacological Research Communications, VoL 6, No. 3, 1974 blocking agent mecamylamine.
These results suggest dopaminergic and nicotinic
cholinoceptive receptors could be involved in mediation of ketamine anesthesia in the dog. Ketam~ne catalepsy (extensor rigidity and increased muscle tonus) and respiratory apneusis were enhanced by mecamylamine and prevented by the muscarinic cholinoceptor
antagonist atropine.
These observations suggest that ketamine
catalepsy and respiratory apneusls in dogs could be mediated by muscarinic cholinoceptive mechanisms, and that adaptation mechanisms to ketamine catalepsy and respiratory apneusis could be mediated by nicotinic cholinoceptors. Other putative neurotransmitters cannot be excluded from a possible role in mediation of ketamine catalepsy and respiratory apneusis. antiserotoninergic neuroleptlc methiothepln,
The predominantly
in a subsedative dose, reduced
muscle tonus and respiratory apneusis in some dogs in the present study, but these effects had a slow onset and were not as striking (%.e. muscle flaccidity was not as marked) as in dogs pretreated with atropine.
Dogs pretreated with a
subsedative dose of pimozide manifested marked catalepsy and respiratory apneusis, but these dogs were also conscious or only briefly and lightly anesthetized, and it was difficult to determine how much muscle tonus and respiratory apneusis was due to ketamine and how much was due to volitional or excitatory activity of the animals. Ketamine-lnduced muscle jerking and emergent delirium were both enhanced by a subsedatlve dose of plmozide, by atropine, and by the small dose of chlorpromazine.
The latter drug is known to possess both antidopamlnerglc and anti-
cholinergic properties.
The results suggest dopamlnerglc and muscarinic
cholinoceptive receptors could both play an adaptive role in modulating the myoclonic and deliriant effects of ketamine in dogs.
Atropine itself is a
Pharmacological Research Communications, VoL 6, No. 3, T974
298
deliriant drug, and this property could have contributed to the prolonged emergent delirium seen in atropine-pretreated dogs even though none of these dogs manifested delirium before administration of ketamine. Sedative doses of me~hlothepin or chlorpromazine enhanced ketamine anesthesia and reduced or prevented the various "side effects" of ketamine in the present study.
These are probably nonspec~fic effects of sedation and may be
useful in clinical anesthesia.
A number of sedative drugs or neuroleptics in
sedative dose are already being used to improve ketamlne anesthesia in man and animals. In the cat, it was suggested that serotonin may function both in adaptation to central depressant effects of ketamine and in mediation of catalepsy and respiratory apneusis, and that dopamine may mediate ketanLine-lnduced cle Jerking (Hatch, 1973).
mus-
The present study indicates that brain mechanisms
involved with the various effects of ketamine in dogs could be quite different and much more complex than the mechanisms suggested for cats. Weingarten's
(1972) proposal that ketamine catalepsy may be related to
stimulation of the mouoaminergic portion of a balanced monoaminergic-cholinerglc system was supported by the cat study (Hatch, 1973).
However, the pre-
sent study with dogs suggests that, in some species, ketaminecatalepsy may be mere closely related to a muscarinic-nlcotinic
cholinergic imbalance, with
monoam/nes playing a less important role.
ACKNOWLEDGEMENTS This work supported by the Ontario Ministry of Agriculture and Food. Drugs used in this study were supplied by the courtesy of several manufacturers: ketamine HCI from Parke, Davis & Co., Ann Arbor, Michigan, U.S.A.; methiothepin maleate from F. Hoffman-La Roche & Co., Basel, Switzerland; mecamylamlne HCI from Merck, Sharp and Dohme, Into, West Point, Pennsylvania, U.S.A.; and pimozide from Janssen Pharmaceuticals, Beerse, Belgium.
Pharmacological Research Communications, Vol. 6, No. 3, 1974
REFERENCES Albanus, L.: (1970), Acta Pharm, col. et Toxicol. 28, 305-326. Albanus, L., Aquilonluss S.-M., Sundwall, A., and Winbladh, B.: (1969)p Acta Pharmacol. et Toxlcol. 27, 81-96. And~n, N.-E., Butcher, S.G., Corrodl, H., Fuxe, K., and Ungerstedt, U.: (1970), Europ. J. Pharmaeol. Ii, 303-314. Authler, L., Sindon, A., Chapados, R., and Barry, P.P.: (1972), Canad. Anaesth. Soc. J. 19, 445-452. Hatch, R.C.: (1973), Pharmacol. Res. Commun. ~, 311-319. Monachon, M.-A., Burkard, W.P., 3alfre, M., and Haefely, W.: (1972), Naunyn-Schmiedeberg's Arch. Pharmacol. 27__4, 192-197. Steel, R.G.D., and Torrle, J.H.: (1960), Principles and Frocedures of Statistics, McGraw-Hill Book Company, Inc., New York, 73-75. Welngarten, S.M.: (1972), J. Neurosurgo 37, 429-433. White, R.P., Nash, C.B., Westerbeke, E.J., and Possanza, J.: (1961), Arch. Int. Pharmacodyn. 132, 349-363.
299