292 Bram Research, 515 (1990) 292-298

Elsevier

BRES 24054
Short Communications

Dopamine receptors mediate drug-induced but not Pavlovian conditioned

contralateral rotation in the unilateral 6-OHDA animal model

Robert J. Carey
Research and Development Servtce, VA Medtcal Center, and Department of Psychtatry, SUNY Health Sctences Center at Syracuse, Syracuse,
NY13210 (U.S A )

(Accepted 9 January 1990)

Key words Condmonlng, Apomorphine, D 1- and D2-receptor; Rotation, Dopamlne

Following Pavlovlan conditioning treatment sessions with apomorphlne, ammals receiving the paired treatment showed substantial
contralateral rotation when placed without drug into the test environment previously paired to the apomorphine (0 5 mg/kg) injection while
ammals in the unpaired control treatment showed only lpsilateral rotation. Subsequent tests with the O 1 antagonist (SCH 23390), or the D 2
antagonist (haloperidol) partially suppressed and the combined DI-D2 antagonists completely suppressed the apomorphme-induced response
of contralateral rotation. The identical contralateral rotation response occurring as a Pavlovlan conditioned response in the paired apomorphine
treatment group was not attenuated by dopamine receptor blockade In both paired and unpaired groups, the spontaneous ipsilateral rotation
response was completely blocked. Thus, non-dopammerglc mechanisms mediate conditioned rotation whereas the drug-reduced as well as the
spontaneous rotation responses require stimulation of stnatal dopamine receptors

Pharmacologically induced contralateral rotation in
rats with severe unilateral 6-hydroxydopamine (6-
O H D A ) lesions is a well-characterized antiparkinsonian
behavioral response to direct-acting dopaminergic agon-
ist d r u g s 15'16'19'25'26. This contralateral rotation re-
sponse can be activated by drugs which sttmulate either
DI or D 2 dopamine receptors. Interestingly, a number of
reports have demonstrated that this drug-reduced re-
sponse can be conditioned to the testing situation 7-11. In
agreement with Pavlovian conditioning principles, de-
tailed analyses of the rotation responses in terms of
rotation direction and patterns of partial to complete
rotations (i.e. frequency of 1/4, 1/2, 3/4 and 1/1 rotations)
has shown that the drug-induced and conditioned re-
sponse are qualitatively identical 1. This drug-induced
conditioned response is not only of interest in the context
of Pavlovian conditioning but it is also of mterest in terms
of the neuropharmacology of conditioned behavior as
well. This latter aspect becomes apparent when it is
realized that under non-drug conditions the unilateral
6 - O H D A animal has a strong response bias for the
opposite response of ipstlateral rotation. This response
bias is a reflection of the severe interhemispheric imbal-
ance between d o p a m m e neurons m the intact versus the
6 - O H D A hemtsphere. Typically, the conditioned contra-
lateral rotation response can be evoked when the
dopamlne level m the striatum of the 6 - O H D A hemi-
sphere Is reduced to 1 - 2 % of the intact hemisphere 9.
While direct acting dopaminergic agonists such as apo-
morphine induce rotation through direct stimulation of
the supersensitive receptors in the dopamine denervated
hemisphere 15'16'26, tt is not known how under non-drug
conditions the dopamine denervated striatum can be
activated to generate contralateral rotation as a condi-
tioned response.
One possible mechamsm by which dopamine could
mediate the conditioned contralateral rotation response
ts by means of the residual dopamine neurons in the
6 - O H D A hemisphere. That is, placement into the con-
ditioning test environment may trigger sufficient release
of dopamlne from surviving neurons to stimulate the
supersensitive dopamine receptors in the denervated
striatum and thereby activate contralateral rotation. Such
an effect may be considered to be analogous to the
paradoxical kinesia p h e n o m e n o n wherein akinetic Park-
insonian patients sometimes are able to briefly ambulate
under conditions of severe stress 1'3"21. Indeed, it is
usually the case that the conditioned rotation response in
the 6 - O H D A animals is also a brief one TM. Possibly,
then the drug conditioning procedure involves the con-
ditionmg of a dopaminergic stress response to the test
environment which results in the release of dopamine
from the residual dopamine neurons to stimulate the
supersensitive dopamine receptors 2. A n o t h e r possibility
is that the site for conditioned rotation induced by
activation of the supersensttwe dopamine receptors dur-

Correspondence R J, Carey, Research and Development Service, VA Medical Center, 800 Irving Avenue, Syracuse, NY 13210, U S,A

0006-8993/90/$03 50 (~) 1990 Elsevier Science Pubhshers B V (Biomedical Dwlslon)


ing the acquisition phase of conditioning may be at a
synaptic site(s) downstream from the striatal dopamine
receptors. In this case, non-dopaminergic systems could
be engaged by the conditioned stimulus and thereby
by-pass the dopamine receptors entirely 13.
Apomorphine acts on both the D 1 and D 2 dopamine
receptors so that D 1 and D 2 blockade is necessary to
eliminate the apomorphine-induced contralateral rota-
tional response 2'15. In the present study, dose levels of
the D 1 antagonist SCH 23390 and the D 2 antagonist
haloperidol were used, which, in combination, com-
pletely blocked the apomorphine-induced contralateral
rotation response. It was hypothesized that if conditioned
rotation is dependent upon dopamine release by neurons
due to a conditioned stress mechanism, then the effects
of D 1 and D 2 blockade on the conditioned rotation
response should parallel the effects of dopamine receptor
antagonism on the apomorphine-induced rotational re-
sponse. In contrast, if non-dopaminergic mechanisms
mediate the conditioned response, the dopaminergic
receptor blockade should have little effect on the elici-
tation of the conditioned contralateral rotation in the test
environment. In support of the latter possibility, the
present findings show that the D~, D 2 antagonists, which
in combination completely block apomorphine-induced
rotation, do not attenuate the same response when it
occurs as a Pavlovian conditioned response. These
observations point to a neuropharmacological disassoci-
ation between dopaminergic drug-induced versus condi-
tioned drug-induced behavior.
Eighteen adult male 400-500 g Sprague-Dawley rats
were used. They were assigned to paired (n = 6) and
unpaired (n = 12) groups of a Pavlovian conditioning
treatment paradigm. The animals were housed in indi-
vidual cages with a continuous access to food and water.
Cages were in a climate (22 + 1 C) and light controlled
room with 12 h light and dark cycles. Testing was
conducted during the light cycle only. The animals were
first prepared surgically by unilateral 6-OHDA lesions
prior to the administration of the conditioning protocol.
6-OHDA (Sigma) was injected stereotaxically at the A 9
and A10 areas of the substantia nigra using the following
coordinates: m9, 4.0 mm posterior to bregma, 7.5 mm
below dura and 2.0 mm lateral to the midline suture; A10,
4.0 mm posterior to bregma, 8.0 mm below dura and 1.0
mm lateral to the midline (the incisor bar was placed 3.2
mm above the interaural plane). At each site, 1.5/A of
3/~g//A (calculated as a free base) of 6-OHDA-HBr which
was dissolved in 0.15 M NaCI containing 0.2 mg/ml of
ascorbic acid was injected at a rate of 0.5/A/min. The
injections were started 1 min after the cannula was fixed
in position and removed 3 min after completion of
injection. Equithesin anesthesia (3 ml/kg) was used in all
293
surgery. Surgery was aseptic and antibiotics were admin-
istered to all animals immediately following surgery and
for one week postoperative.
Two weeks postsurgery and following a week of daily
5 min handling treatment, the animals were given 0.05
mg/kg of apomorphine in their home cage and the
number of contralateral rotations were recorded for a 10
min period. A minimal standard for inclusion was 10
contralateral (360) rotations. The selected animals were
then matched on contralateral rotation frequency, and
assigned to the paired and unpaired treatment groups.
These matched groups were then administered the paired
and unpaired drug-test environment treatment in a
Pavlovian conditioning protocol. In the paired group,
each animal was injected with apomorphine (0.05 mg/kg,
s.c.) 10 min prior to placement into the conditioning
chamber for a 10 minute duration. The animal was then
removed and placed back into its home cage. Animals in
the unpaired group received exactly the same treatment
except that the apomorphine injection was administered
30 min after removal from the conditioning chamber.
This treatment was repeated for four sessions spaced two
days apart. One unpaired group (n = 6) served as a
control for the paired group and the other unpaired
group (n = 6) was used to assess the effects of dopamine
antagonists on the apomorphine-induced rotational re-
sponse.
Two weeks after the last drug treatment, at which time
conditioned affects in this preparation exhibit optimal
responding levels23, all animals received a 10 min non-
drug test in the conditioning chamber on two successive
days. This non-drug testing was conducted in order to
establish the efficacy of the conditioning procedure for
inducing the conditioned response. Two non-drug tests
were given in order to extinguish the conditioned
response 8. Two days after the completion of the non-drug
testing, the animals were given a single apomorphine
reconditioning treatment which in this preparation is
sufficient to reinstate the conditioned response 8. At this
stage, the experimental procedure was initiated.
Once every two weeks the animals recewed a non-drug
conditioning test followed two days later by apomorphine
reconditioning treatment. This cycle of non-drug condi-
tioning tests followed by drug reconditioning was re-
peated four times. Prior to conditioning tests, however,
animals received a pretreatment of either 0.5 mg/kg
haloperidol, 0.1 mg/kg SCH 23390, 0.5 mg/kg haloperidol
plus 0.1 mg/kg SCH 23390 or vehicle. The pretreatments
were administered 1 h before the conditioning tests. The
unpaired groups used to assess the effects of the
dopamine antagonists on the apomorphine-induced ro-
tation received the same drug pretreatments 1 h before
the apomorphine tests. In all groups, the order of drug
294

APOMORPHINE TEST e--e PAIRFD ( . 0 5 APO P R [ )

CONTRALATERAL o - - o UNPAIRE0 ( 0 5 APO POST)

(,q
Z 300-
O
I.--
,<E
400-

1~
e* ( 20 CM
400-

300
:, 20 ( 30 CM
400

300
> 30 ( 55 CM

200- * 200- 200

rv
Z

100- "-e* 1 O0 - I O0,

0 9" . . . . . . ; ----e- . . . . . . . -e 0 t' - C v- - 0 "~ =: v- ----@- ....... "@

0.00 0.25 0.50 0.75 1.00 0.00 0.25 0 50 0 75 , O0 0 O0 0 25 0.50 0.75 1.00

IPSILATERAL
1 O0 - 100 100
20 C M ) 20<30CN >30 <55CM

75- 75 75
_o
<C
50 50

Z
I.LJ
~ 2 5 25 25

""" "'O~ ...... O*

0 T - ~- - 0
o . . . . . . . c2 . . . . . . . ~- . . . . . . . -~
: 0 - -o . . . . . . . o . . . . . . . ~ . . . . . . .
0.00 0.25 0.50 0.75 1.()0 0.00 0.25 0.00
0.50 0.75 1.00 0.25 0.50 0.75 1.00
FRACTIONAL ROTATION RESPONSES

Fig 1. Means and S.E.M.s of fracuonal rotation responses of <20 cm, to 20 to <30 cm and 30 to <55 cm m diameter. The paired group (n
= 6) received 0.05 mg/kg apomorphine 10 min pretest; the unpaired group (n = 6) received 0 05 mg/kg apomorphme 30 mln post test *P
< 0.01

testing was counterbalanced. One week later after com- contralateral rotation frequency. Three days later, the
pletion of the above listed tests, the paired animals were rats were injected with Equithesin 3 ml/kg and 3 min later
also tested with 0.05 mg/kg apomorphine plus the were sacrificed by decapitation. According to Schwarting
combined D 1 and D 2 pretreatments (0.1 mg/kg SCH and Huston 22 this procedure induces sedation without
23390 and 0.5 mg/kg haloperidol 1 h pretest) to insure altering brain catecholamine content. The brains were
that the paired treatment did not in some unexpected removed over ice and brain tissue was transected coron-
manner alter the drug-induced D 1 and D 2 blockade. ally at the level of the optic chiasma. The striata were
Spontaneous and drug-induced rotations in the condi- dissected from each hemisphere of the anterior section
tioning test chamber were measured automatically with a and used for biochemical analysis while the posterior
recently developed Video Image Analyzing System portion was used for histological evaluation of the
(VIAS) 6. This system incorporates an on-line digitizing of rejection site. The samples were then centrifuged and
analog images of a freely moving animal which are stored at -70 C. Within two days, the samples were
disc-stored. The stored records are subsequently evalu- assayed for catecholammes and indoleamines using high
ated by a computer software program. The computer performance liquid chromatography with electrochemical
evaluation of the stored data provided a detailed mea- detection (HPLC-EC) 17. The amines were separated with
surement of the linear distance traversed, direction of a reverse-phase column using a mobile phase prepared
rotation, number and diameter of 1/4, 1/2, 3/4 and full from acetonitrile and tetrahydrofuran solvents with so-
360 rotations. The rotation diameter scores include dium octyl sulfite added as an ion pair reagent. A glassy
circles of <20 cm, 20 to <30 cm and 30 to <55 cm. carbon working electrode was used in conjunction with a
One week after the completion of all testing, the Bioanalytical Systems 4B detector. The detector potential
animals were injected with 0.05 mg/kg of apomorphine was set at +0 8 V with respect to an Ag/AgCI reference
and 10 min later received a 10 min test. This final test was electrode. To evaluate #g/g wet tissue concentrations, the
performed to determine if the paired and unpaired amine peak heights to internal standard (dihydroxybenyla-
groups had equivalent 6-OHDA lesions as determined by mine) peak height ratios were determined.
 295

NON DRUG
CONTRALATERAL
100. [XT 1 100 IO0
< zo ca > 2 0 ( s o c,, '> 30 <S5 CN
e--ll
(/1 o--- o tlf,WKD
Z 75 75 7S
0
.<
0 50 i* SO 5O
r~.
Z
W 25. 25

o~ . . . . . . . . a.-..-- -
0 -.-~ 0
0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 I.O0 0.00 0.25 0.50 0.75 1.00

100- (XT 2 Ioo 100.

,~ 20 CM ~20 (30C~ ) 3 0 ( ~ CI
V)
Z 75- 75 75.
0
I'--
I--
0 50- 50" 50

Z
W 25- 25 25

0 0 P ~ ": : : o : " "'',-

0.00 025 OSO 075 1 oo 0.00 o 25 o,so o 7s i.oo o oo o.2s o.so o.'~s I.oo

IPSILATERAL
11111- EXT 1 1O0 100
( 20 cu ) 20 < 30 CM 30 ( 5 5 CM
O3 o -- o U I f ~ O
Z 75 75 75

p-
0 5o' riO 50

Z
~j 25 25 25

0
000 0.25 0.50 0.75 1.00 0.00 0 25 0 50 0 75 1 O0 0 O0 0.25 0.50 0.75 I O0

100, XT 2 100- 1oo

~20CN ) zo< ~o c , ) ,.'0( SS CM

z 75 75- 75

O 5o 50- 5o

z
w 25 25- 25

0
0.00 0 25 0.50 0.75 1.00 ).00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00
FRACTIONAL ROTATION RESPONSES

Fzg. 2. Means and S.E M s of fractional rotatzon responses for 3 rotation dmmeter levels <20 cm, 20 to <30 cm, and 30 to <55 cm. The two
tests, EXT 1 and EXT 2 refer to non-drug tests conducted two weeks after the apomorphme treatments. *P < 0.001.

Fig. 1 shows the effect of the a p o m o r p h i n e p a i r e d
versus u n p a i r e d t r e a t m e n t on rotational behavior. The
p a i r e d animals which received 0.05 mg/kg a p o m o r p h i n e
10 min prior to testing exhibited a high rate of small ( < 2 0
cm) d i a m e t e r contralateral rotation which is characteris-
tic of a p o m o r p h i n e t r e a t m e n t in animals with severe
unilateral 6 - O H D A lesions. In contrast, the unpaired
animals which were given the 0.05 mg/kg a p o m o r p h i n e
t r e a t m e n t 30 rain after the test session exhibited ipsila-
teral rotation exclusively. S p o n t a n e o u s ipsilateral rota-
tion is also characteristic for n o n - d r u g g e d rats with severe
unilateral 6 - O H D A lesions. Fig. 2 shows the non-drug
rotational b e h a v i o r of these same two groups of rats two
weeks after the a p o m o r p h i n e t r e a t m e n t . A s can be seen
296

C O N D I T I O N E D C O N T R A L A T E R A L ROTATION

--- Vehlll
100 o--o 5 Hal 100.
~,--~, .1 S C H
a--O 5 Hal, 1 SCH
u~ 8O PAIRED UNPAIRED
80-
gq
Z
0
n 60 60-
(/)
Ld
n,. 40 40-
z
i.i
~E 2O 20-

0 0 ,.:. =
0.00 0 25 0 50 0 75 1 O0 0 O0 0 25 0 50 0.75 1 ~)0

S P O N T A N E O U S I P S I L A T E R A L ROTATION

---O Vehicle
100- 0--0 $ Hal 100
,~--,:, I SCH
O--O $ H a l , I SCH
(/) 80- PAIRED 80 UNPAIRED
1,44
oq
Z
0 60- 60
1.
O'3
I.aJ
40- =," 40 =[,
Z
Ld
~E 20 " i" 20. - $,,

~a
""" o* - - " o
0 ~ " - 0 "= - u
0.00 0 25 0 50 0.75 1.00 0 O0 0.25 0.50 0.75 1.00
F R A C T I O N A L ROTATION R E S P O N S E S

Fig. 3. The upper half of Fig. 3 presents the means and S E.M s of contralateral rotaUon responses m paired and unpatred ammais following
vehicle, 0.1 mg/kg SCH 23390, 0.5 mg/kg haloperidol or combined 0 1 mg/kg SCH 23390 and 0.5 mg/kg haloperidol given 1 h pre-test The
lower half of Fig. 3 shows the spontaneous ipsilateral rotation rates in the paired and unpaired groups The fractional rotation responses are
<20 cm in diameter *P < 0 01

in the upper half of Fig. 2, the paired group selectively
exhibited contralateral rotation on the first non drug test.
While the absolute number of these rotations was
substantially less than the paired group exhibited when
given apomorphine, both the pattern of 1/4, 1/2, 3/4 and
1/1 rotations and rotation diameter (<20 cm) were
similar to what was exhibited by these animals when they
were treated with apomorphine. The absence of this
contralateral rotational behavior in the unpaired treat-
ment group indicates that the effect in the paired group
was related to the drug association with the test chamber
rather than to drug induced response sensitization. The
additional observation that the response extinguished by
the second non drug test further substantiates the
occurrence of contralateral rotation in the paired group
as a conditioned response. Except for the difference in
contralateral rotation on the first non drug test, the non
drug rotational behavior of the paired and unpaired
groups was virtually identical. Since the rotational re-
sponse in Figs. 1 and 2 as well as subsequent tests were
largely restricted to small diameter (<20 cm) responses,
the subsequent data presentations will be limited to
rotation responses of this diameter.
Fig. 3 shows the effect of the D1 and D2 antagomsts on
conditioned contralateral rotation and on the spontane-
ously occurring ipsilateral rotation compared with vehicle
treatment. In considering the vehicle data first, it can be
seen in the top half of Fig. 3 that only the paired group
of animals exhibited contralateral rotation. In agreement
with previous findings 1, the pattern of 1/4, 1/2, 3/4 and
1/1 rotations and the rotation diameter (<20 cm) of the
conditioned rotation response is virtually identical to
those of the apomorphine-induced contralateral rotation
response as shown in Fig. 1. The bottom half of Fig. 3
shows that the paired and unpaired groups exhibited
simdar ipsilateral rotation patterns under vehicle condi-
tions. Fig. 3 also shows the effects of D 1 and D2
antagonists on the conditioned contralateral rotation
response of the paired group of animals as compared to
the baseline provided by the control treatment animals of
the unpaired group. In the latter, no contralateral
rotational responses occurred indicating that the condi-
tioning effects observed in the paired group of animals
was due to the pairing of the apomorphine effects with
the test environment stimuli and not due to drug-induced
sensitization effects. Also, in th~s group, the effect of the
D 1 and D 2 antagonists was manifested by a complete
suppression of the spontaneously occurring ipsilateral

DRUG INDUCED CONTRALATERAL ROTATION
400 * APO
T o--o APO + HAL
o--o APO + SCH
(/3 ~--~ APO + HAL + SCH
'" 300
Z
0 reductions of <0.05 of the dopamine level of the intact
,.,(/) 200 ~ hemisphere in every animal. There were no statistical
L,J 100
:~ ~ *
000 0 25 0 50 0 75 1.00 1 25
FRACTIONAL ROTATION RESPONSES
Fig. 4. The means and S.E.M s of fraction contralateral rotauons
<20 cm in diameter in the unpaired treatment group of animals 10
min followmg 0.05 mg/kg apomorphme treatment given alone or
preceded (50 rain) by 0.1 mg/kg SCH 23390, 0.5 mg/kg halopendol
or combined 0.1 mg/kg SCH 23390 and 0 5 mg/kg haloperidol *P
< 0.01. Each drug treatment condition difference is staustically
s~gnificant from all other treatment condttlons.
rotation. The effect of the D t and D 2 antagonists on
conditioned behavior in the paired group of animals was
also confined to suppression of ipsilateral rotation. The
conditioned contralateral rotation response, however,
was either unaffected or enhanced. While D 1 and D 2
receptor blockers were ineffective with regard to the
conditioned contralateral rotation response, these drugs
were highly effective in suppressing apomorphine in-
duced contralateral rotation. Fig. 4 shows that the D 1 and
D 2 antagonists separately attenuated drug-induced rota-
tion and when given in combination, produced an almost
complete suppression of the apomorphine-induced con-
tralateral rotation. These latter results demonstrate the
efficacy of the D 1 and D E antagonist doses employed to
block both the supersensitive and normosensitive dopa-
mine receptors. Thus, the preservation of the conditioned
contralateral rotation response under conditions of D 1
and O 2 blockade could not be attributed to a lack of
efficacy of the D 1 and D E dose levels employed.
To insure that animals in the paired group were not m
some way different from the unpaired group showing a
D1-D 2 blockade of the apomorphine-induced contrala-
teral rotation response, the paired animals were also
tested for their response to 0.05 mg/kg apomorphine in
the presence of the D 1 - D 2 blockade. As was the case for
the unpaired animals, the same drug-induced D 1 - D 2
blockade completely blocked apomorphine induced ro-
tation in the paired group. Additionally, one week after
the conclusion of the D1-D 2 tests, all groups, paired and
unpaired, were tested and compared for their rotational
response to 0.05 mg/kg apomorphine. The animals
regardless of group assignment exhibited rotation rates
comparable to those in Fig. 1 for the apomorphine paired
297
treatment and there were no statistical differences among
groups. Three days after this test, all animals were
sacrificed and striatal dopamine measurements were
performed. All 3 lesion groups had severe losses of
striatal dopamine in the 6 - O H D A hemisphere with
differences among groups in terms of striatal dopamine
concentration in the striatal samples from the 6 - O H D A
and intact hemispheres.
The present results are consistent with a number of
observations of the conditioning of drug-induced behav-
ioral responses in a variety of paradigms and
preparations 5'7-11'14'2'24. Such results have shown that
conditioning of drug effects is a reliable phenomenon
with important clinical implications for stimulant drugs.
Generally, however, these important empirical observa-
tions have not lent themselves to further analysis of
central mechanisms because the drugs used have multiple
neurochemical actions (e.g. amphetamine) and the be-
havioral indices have been indirect (e.g. photocell
activity) 5A4'24 so that the connection of a drug mechanism
to conditioned behavior becomes a formidable experi-
mental obstacle. In contrast, the present study features a
selective dopaminergic drug treatment, apomorphine,
which involves highly specific striatal dopaminergic
mechanisms that are uniquely coupled to directly observ-
able behavioral indices 26. These features make the
present animal model a suitable one for analyzing
Pavlovian and pharmacological processes. In agreement
with Pavlovian principles is, the conditioned response in
this animal model is qualitatively identical to the uncon-
ditioned drug-induced response (e.g. in terms of 1/4, 1/2,
3/4 and 1/1 turns and rotation diameter, <20 c m ) 9. Given
this identity of conditioned and unconditioned responses,
it was appropriate to attempt a pharmacological evalua-
tion of the mechanisms underlying conditioned behavior.
With the unconditioned response of apomorphine con-
tralateral rotation blocked by the dopamine receptor
antagonists haloperidol and SCH 23390, it was possible to
answer the question of whether the conditioned response
is also mediated by the same neuropharmacological
mechanisms.
The findings obtained in the present study argue
decisively for a disassociation between the pharmacology
of the conditioned versus the unconditioned response 4'5.
In fact, the D1-D 2 blockade which systematically atten-
uated the dopaminergic response of apomorphine-in-
duced contralateral rotation as well as completely block-
ing the spontaneously occurring ipsilateral rotation had
no effect upon the conditioned contralateral rotational
response. Indeed, the finding that blockade of both the
D 1 and D 2 dopamine receptors did not even attenuate the
298
conditioned contralateral rotation response while, at the
same time, the c o m b i n e d r e c e p t o r b l o c k a d e completely
suppressed the a p o m o r p h i n e - i n d u c e d rotation appears to
rule out a paradoxical kinesis interpretation of the
o b s e r v e d conditioned rotation effects.
D o p a m i n e has a well-established role m mediating
motoric functions and is an important transmitter in
learning processes 4. In light of the present findings,
however, the d o p a m i n e receptors do not a p p e a r to be the
locus where conditioning occurs. R a t h e r , d o p a m i n e by
initiating behavior m a y simply m a k e it possible for
conditioning to occur between stimuli and responses with
d o p a m i n e itself not being a part of this connection. In
1 Antelman, S.M. and Caggiula, A.R., Tails of stress-related
behavior: a neuropharmacological model. In I Hanln and E.
Usdin (Eds.), An,real Models m Psychiatry and Neurology,
Pergamon, New York, 1977, pp. 427-446.
2 Arnt, J. and Hyttel, J., Differential mvolvement of dopamine
D-1 and D-2 receptors in the circling behaviour induced by
apomorphine, SK & F 38393, pergohde and LY 17155 m
6-hydroxydopamine-lesioned rats, Psychopharmacology, 85
(1985) 346-352.
3 Babinski, J., Jarkowski, B. and Plechet, V, Kinesm paradoxale,
Rev. Neurol., 37 (1921) 1266-1270.
4 Beninger, R.J., The role of dopamlne m locomotor actiwty and
learnmg, Bram Res. Rev., 6 (1983) 173-176.
5 Beninger, R J and Hahn, B.L., Pimozide blocks estabhshment
but not expression of amphetamine-induced decreases in re-
sponding for brain stimulation, Science, 220 (1983) 1304-1306.
6 Bonatz, A., Steiner, H. and Huston, J.P., Video image analysis
of behavior by microcomputer: categorization of turning and
locomotion after 6-OI-IDA injection into the substantia mgra, J
Neurosct. Methods, 22 (1987) 13-26.
7 Carey, R.J., A conditioned anti-parkinsonmn drug effect m the
heml-parkinsonian rat, Psychopharmacology, 89 (1986) 269-
272.
8 Carey, R.J., Application of the unilateral 6-hydroxydopamme
rat model of rotational behavior to the study of conditioned drug
effects, J. Neurosci. Methods, 22 (1988) 253-261
9 Carey, R.J., Conditioned rotational behawor in rats with
unilateral 6-hydroxydopamine lesions of the substantia mgra,
Brain Research, 365 (1986) 379-382.
10 Carey, R.J., Stimulant drugs as condmoned and unconditioned
stimuh m a classical conditioning paradigm, Drug Dev Res., 16
(1989) 305-315.
11 Casas, M., Guix, G., Prat, S., Frere, S., Cadafalch, J. and Jane,
F., Conditioning of rotational behavior after the administration
of a single dose of apomorphine in rats with unilateral dener-
vation of the dopaminerglc nigrostriatal pathway, relevance to
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Parkinsons disease. T h e observation of a vigorous anti-
parkinsonian response g e n e r a t e d by the d o p a m i n e de-
nervated hemisphere under conditions of d o p a m i n e
receptor b l o c k a d e c o m b i n e d with d o p a m i n e denervation
points to the potential i m p o r t a n c e of n o n - d o p a m i n e r g i c
mechanisms as candidates for new initiatives in the
pharmacological amelioration of Parkinsonism.
This research was supported by a Veterans Adminlstrat~on Merit
Review Grant and by a NaUonal Institute of Drug Abuse Grant
5RO1DA0536602.
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