Brain Research Bulletin,Vol. 29, pp. 675- 680, 1992
Printed in the USA. All rights reserved.
Copyright
RAPID
0361- 9230/92 $5.00 + .OO
0 1992 Pergamon Press Ltd.
COM M UNICATION
Evidence for Opiate-Dopamine CrossSensitization in Nucleus Accumbens:
Studies of Conditioned Reward
S. TIFFANY
CUNNINGHAM*
AND
ANN
E. KELLEY’
*Department of Psychology, Harvard University, Cambridge, MA 02138
fDepartment of Psychology, Northeastern University, Boston, MA 02115
Received
20 March
1992; Accepted
12 April
1992
CUNNINGHAM, S. T. AND A. E. KELLEY. Evidence for opiate-dopamine cross- sensitization in nucleus accumbens: Studies
ofcondifioned reward. BRAIN RES BULL. 29(5), 675-680, 1992.-We investigated opiate-amphetamine interactions within the
nucleus accumbens in responding for conditioned reward. Separate groups of animals received 4-day intra-accumbens treatment
with either saline, morphine (0.5 &0.5 r.d), [D-Ala2 NMe-Phe4 Gly-olS]-Enkephalin (DAMGO; I.0 &0.5 PI), or [D-Pen2,5]Enkephalin (DPEN; 2.0 pg/O.5 ~1). On two subsequent test days, these rats were given a challenge of d-amphetamine (2.0 and
10.0 pg/O.5 ~1) and responding for conditioned reward was measured. In the conditioned reinforcement (CR) procedure, fooddeprived animals were trained in an initial phase to associate a food reward (primary reinforcement) with a compound stimulus
(light/click). In the next phase, a lever was introduced and responding on the lever produced the compound stimulus alone
(secondary reinforcement). Previous evidence shows that psychostimulants but not opiates markedly potentiate responding for
conditioned reward. In the present design, animals previously treated with either morphine or DAMGO (preferential mu agonists)
showed potentiated lever responding following amphetamine challenges, relative to either DPEN- or saline-treated animals. These
findings show that prior exposure of nucleus accumbens neurons to /l-selective opiates induces sensitization to the effects of
amphetamine. The results are discussed in terms of opioid effects on dopamine transmission and second messenger systems.
Opioids
Receptor subtypes
Dopamine
Cross-sensitization
OPIATE and psychostimulant
drugs share several characteristics regarding their behavioral
and rewarding effects in animals. Peripheral or central administration
of these substances
can result in hypermotility
(7,9,14,2 1,24,25,32). In addition,
these drugs are self-administered
by animals (IO, 13,15,43)
and are capable of inducing behavioral sensitization
( 18,19).
Behavioral sensitization
is defined as a potentiated
behavioral
response to a drug following prior chronic treatment
with the
drug. For example, multiple exposure to opiates produces a
progressively
enhanced
locomotor
response
to the drug
(16,19,41). One region which has been implicated
in both
stimulant- and opiate-induced
sensitization
is the ventral tegmental area (VTA), the cell body region for A10 dopamine
neurons (4 1). For example, repeated microinjection
of morphine or the opioid peptide,
[D-Ala2-NMe-Phe4-Gly-o15]Enkephalin
(DAMGO)
(41) or enkephalin
(16,19) into the
VTA results in a progressively augmented locomotor response.
Conditioned reinforcement
Similar behavioral
effects have been reported with multiple
injections
of amphetamine,
such that chronic injection
of
amphetamine
into the VTA but not the nucleus accumbens
sensitizes rats to systemic amphetamine
and cocaine (20).
More recent data suggest the nucleus accumbens,
a major
terminal field for A 10 dopamine neurons, may also contribute
to stimulant-induced
sensitization
(29). Paulson and Robinson (29) found that repeated systemic administration
of
amphetamine
results in an enhanced locomotor
response to
amphetamine
injected into the nucleus accumbens.
Interestingly, opiates and psychostimulants
also cross-sensitize to one other. For example, multiple intra-VTA treatments
of d-amphetamine
will result in an augmented response to a
subthreshold
dose of systemic morphine, as measured by locomotor activity (36,42). The reverse situation has also been demonstrated, such that multiple systemic morphine injections sensitizes animals to systemic amphetamine
(40). In addition, intra-
’ Requests for reprints should be addressed to Ann E. Kelley, Department of Psychology, Northeastern University, 125 Nightingale Hall, Boston,
MA 02115.
675
zyxwvu
676
CUNNINGHAM
VTA enkephalin infusions sensitize animals to systemic amphetamine or cocaine ( 12,I6).
Most of the investigations that have examined the effects of
cross-sensitization
between opiates and psychostimulants
have
focused on motor activity (12,16,36,40). However, little is known
about the effects of opiate-psychostimulant
cross-sensitization
on reinforcement
processes. In the following experiments,
the
effects of prior treatment with opiates on sensitivity to amphetamine were examined using a conditioned
reinforcement
procedure.
In the conditioned reinforcement (CR) paradigm, an animal’s
reactivity to reward-related
stimuli is determined (34). Hungry
rats are trained using classical conditioning to associate a compound stimulus with a food reward. The animals are then tested
for operant responding for presentation of the conditioned stimulus. Acquisition of this new behavior, lever pressing, is a measure of the potency of the compound stimulus as the conditioned
reinforcer (26). The nucleus accumbens is an important neural
site for psychostimulant-potentiated
responding for CR (5,23,38).
Intra-accumbens
morphine and opioid peptides, however, fail
to elevate responding for conditioned reward (6), suggesting that
psychostimulants
and opiates affect reward-related
responding
differentially. However, in a previous dose-response
study with
intra-accumbens
morphine. we noted that following several days
treatment with intra-accumbens
morphine, animals showed elevated responding to intra-accumbens
amphetamine
(6). Therefore, in the present study. sensitivity to amphetamine
was compared in animals previously treated with morphine, selective
opioid peptides, or saline injections in the nucleus accumbens.
ME-I'HOD
Thirty-eight male Sprague-Dawley
rats (Charles River Laboratories, Wilmington,
MA) were used for these experiments.
Animals were handled by the experimenter on arrival and housed
in pairs in Plexiglas cages with wire grid floors. Eight to 15 g of
food were given to the rats daily to maintain them at 85% of
their free-feeding body weight and water was freely available.
The ambient photoperiod
was 12 h, with lights on from 07:OO
to 19:OO h.
On the day of surgery (which took place after the classical
conditioning
phase) animals were anesthetized with nembutal
(50 mg/kg, IP) and given atropine (0.1 ml. s.c.). A Kopf stereotaxis was used to implant stainless steel cannula guides (23-gauge)
2.5 mm above nucleus accumbens.
Based on the atlas of Pellegrino and Cushman (30) with incisor bar 5 mm above interaural zero, the coordinates were, in millimeters: antero-posterior
$3.5 from bregma; lateral-medio
21.7 from midline; dorsoventral -5.7 from skull surface. Liquid acrylic and a light-curable
dental resin were used to affix the cannulae to skull screws. Following surgery, wire stylets were placed in cannulae to prevent
occlusion and animals were allowed a minimum of 2 days recovery.
The following drugs were used for these experiments:
Morphine sulfate (Penick Corp.. Lyndhurst. NJ), d-amphetamine
(Sigma Chemical Co., St. Louis, MO), [D-Ala2 NMe-Phe4 Glyol5]-Enkephalin
(DAMGO) (Bachem Inc.. Torrance, CA), [DPen2.5]-Enkephalin
(DPEN) (Bachem), and bovine serum albumin (BSA. 10% solution) (Sigma). BSA was used to coat the
microinjection
tubing (PE-10, Clay Adams) to prevent the pep-
AND
KELLEY
tides from adhering to the walls of the tubing. On each test day,
wire stylets were removed and a precut dental square broach
was used to clear the cannulae. Stainless steel injector needles
(30-gauge), 12.5 mm in length, were used to deliver the drugs.
A microdrive pump (Harvard Apparatus) connected to the injectors via tubing delivered the drugs over 1 min 33 s with I
min diffusion. Prior to the onset of testing, animals were given
a preliminary saline infusion to familiarize them with the procedure.
A detailed description of the conditioned reinforcement
paradigm has been published elsewhere (22). To summarize, fooddeprived rats were initially trained in a classical conditioning
phase to associate a compound stimulus (light/click) with a food
reward. In the next phase. a lever was placed in the apparatus
and operant responding delivered the conditioned stimulus alone
(no food). All drugs were administered during this second phase
and total lever presses for the conditioned stimulus was recorded
over a 45-min test session. On four separate test days, separate
groups of animals received either intra-accumbens
saline, morphine (0.5 pg/O.5 ccl), [D-Ala2 NMe-Phe4 Gly-olS]-Enkephalin
(DAMGO, a p agonist: I .O pg/O.5 PI), or [D-Pen2,5]-Enkephalin
(DPEN. a 6 agonist: 2.0 Kg/O.5 ~1). On two subsequent test days,
challenges with intra-accumbens
d-amphetamine
(2.0 and 10.0
pg/O.5 hl) were administered.
Animals in the morphine and
DAMGO pretreatment groups were given a 30-min delay (based
on previous observations of maximum enhancement
of motor
activity) (6) before introduction
to the testing apparatus. All
other groups were placed in chambers immediately
following
drug infusion.
Data were analyzed using an IBM-compatible
CRunch Interactive Statistical Package (CRISP). A between-subjects analysis
of variance (ANOVA) was performed to test for overall differences between pretreatment
groups. When appropriate,
a twofactor ANOVA (group X treatment day) was used to determine
treatment X day interactions.
At the termination of the experiment, subjects were given an
overdose of nembutal and perfused transcardially first with saline
followed by 10% formalin. Following in situ fixation, the brains
were removed and stored in formalin. Coronal sections (60 pm)
were made and stained with cresyl violet to verify cannula track
and injector tip location. Fig. 2 (discussed in detail later) is a
photomicrograph
of the histology of a representative
subject.
RESULTS
Animals given the 4-day treatments of morphine showed a
sensitized response to amphetamine
challenges. This pretreatment group had potentiated amphetamine-induced
responding
relative to the other treatment groups. The first analysis was a
pretreatment
group X dose ANOVA on the scores following
amphetamine
challenge. This analysis indicated a significant difference between the saline and morphine groups, F( 1, 18) =
13.96, p < 0.002 (Fig. 1A and B). There was no group X dose
interaction indicating that both groups responded similarly to
the two doses of amphetamine.
In addition, a between-groups
ANOVA on the scores of the 4-day pretreatments
was carried
out for the morphine and saline groups. No significant difference
OPIATE-DOPAMINE
617
CROSS-SENSITIZATION
A
B
250
(N=ll)
250
1
(N=S)
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
1
200
fn
1
3
g
150-
E
E
loo-
?
0
0
DOSE
2
0
SALINE
AMPH
(pg10.5
250
*
l
T
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
0.5
10
0.5
0.5
~1)
DOSE
2
10
AMP”
AMPH
0.5
MORPHINE
AMPH
C
*
l
(pg10.5
pl)
D
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
(N=lO)
(Nd)
250
1
I
200 -
200
zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML
z
3
150-
:
1
2
AMPH
DAM GO
DOSE
(pg10.5
AMPH
2
2
OPEN
DOSE
~1)
(pg10.5
2
10
AMPH
AMP”
pl)
FIG. 1. (A-D) Effects of 4day intra-accumbens (A) saline, (B) morphine, (C) DAMGO (p agonist), or (D) DPEN (6 agonist) pre-exposure on
amphetamine-induced responding for conditioned reward. Bars represent mean lever presses y SEM. zyxwvutsrqponmlkjihgfedcbaZYXWVUTS
* p < 0.05,
**p
< 0.01, relative to salinepretreated amphetamine response.
was found suggesting that morphine itself does not potentiate
CR responding.
Figure 1 (C and D) shows the response to amphetamine
in
animals pretreated with either DAMGO (p agonist) or DPEN
(6 agonist). Amphetamine
responding for conditioned
reward
was potentiated in the DAMGO pretreatment
animals. A twofactor ANOVA on the amphetamine
scores of the DAMGO and
saline pretreatment
groups showed a significant group effect,
F( I, 19) = 5.48, p < 0.03 and no group X dose interaction.
Analysis of the DAMGO and saline 4-day pretreatment
scores
revealed no significant differences between groups. An ANOVA
performed on amphetamine
scores in the DPEN pretreatment
group did not reveal any significant effect relative to amphetamine scores in the saline pretreatment group. A between-groups
ANOVA on the 4-day treatment for DPEN and saline, however,
revealed a significant difference, F( 1, 17) = 4.93, p < 0.04.
DISCUSSION
In the present experiments,
either morphine or DAMGO
repeated prior administration
into the nucleus accumbens
of
po-
tentiated amphetamine-induced
responding for conditioned reward. There are several points to address in consideration
of
this finding. First, the effects of the opioids themselves; second,
the enhanced
response to amphetamine;
third, the possible
mechanisms
underlying cross-sensitization.
In the current paradigm, neither morphine nor DAMGO (both ~1agonists) elevated
responding for conditioned
reward; response levels on all test
days were similar to those following saline infusion. This profile
is in agreement with a recent dose-response
study of opiate infusion into nucleus accumbens (6). That study demonstrated
that nucleus accumbens infusion ofopiates increased locomotor
activity but did not affect CR responding.
DPEN (a 15agonist) did induce a significant elevation in responding (compared with the saline group). This increase is
somewhat surprising because in the previous dose-response study
(6) no increase in CR responding was found following DPEN
infusion. This finding may be related to evidence that &agonists
are more potent in eliciting dopamine release than ~1agonists
(3 1). Also, a-agonists induce more robust motor activation relative to pm-agonists (67). Note, however, that the level of DPEN-
678
CUNNINGHAM
AND
KELLEY
FIG. 2. Photomicrograph of coronal section depicting cannula tracks and injection tips within nucleus
accumbens.
group.
The cresyl violet-stained
section
is from a representative
induced responding is well below that observed for amphetamine.
Thus, based on knowledge of previous work, we do not consider
this increase to be a true potentiation
effect (6).
We did not observe progressive sensitization
to opioid infusion into the accumbens; responding was similar on all 4 test
days. This finding is in agreement with previous studies using
locomotor activity as a measure for sensitization
to intra-accumbens opiates and DAMGO following repeated exposure to
these drugs (4 1). For example, Vezina and colleagues (41) reported that multiple exposure to opiates in the ventral tegmental
area but not in the nucleus accumbens resulted in a progressively
greater locomotor response with repeated injections.
The most significant finding in the present experiments was
that preexposure of the nucleus accumbens to opiates enhances
the animal’s response to amphetamine
injections in that site.
As noted earlier, there have been reports of opiate-amphetamine
cross-sensitization
in measurements
of motor activity and employing systemic injections. Here we have demonstrated
crosssensitization utilizing a reward-related paradigm and have shown
that this effect may be induced at the level of the nucleus accumbens.
In support of this general idea, Paulson and Robinson (29)
found potentiated
behavioral
response to intra-accumbens
amphetamine
21 days following the termination
of multiple
systemic injections of amphetamine.
These authors concluded
that the nucleus accumbens is important for the expression of
sensitization
to amphetamine
while the A10 cell body region
may mediate its induction (29). In consideration
of the present
data, we suggest that the nucleus accumbens may also mediate
long-term changes associated with the induction of sensitization.
The observed cross-sensitization
was manifested differentially
via the opiate receptor subtypes because previous exposure to
subject
in the DPEN
pretreatment
the delta agonist, DPEN, did not enhance amphetamine-induced
responding. Morphine binds both mu and delta receptor subtypes
whereas DAMGO binds selectively at the mu receptor; pretreatment with either drug potentiated
lever pressing elicited by
amphetamine.
Thus, it is likely that the mu receptor subtype
mediates opiate-amphetamine
cross-sensitization
in nucleus accumbens. Another distinction between the different receptorspecific peptides and their role in behavior has been cited in
locomotor activity studies. Preferential mu agonists induce hypomotility followed by hypermotility
wheras delta agonists induce an immediate onset of hyperactivity (6,7,14). Moreover,
b-agonist-induced
activity may involve dopamine
release,
whereas p-agonist-induced
activity is independent
of dopamine
release in nucleus accumbens (2 I ,32,37).
Psychostimulants,
particularly those which potently release
dopamine, have been shown to potentiate responding for conditioned reward (4,23,33,35). The nucleus accumbens has been
shown to be a site sensitive to amphetamine-induced
responding
for conditioned
reward (22,38). In the aforementioned
experiments, CR responding following intra-accumbens
amphetamine
challenges in the saline pretreatment
group was lower than that
previously observed in this laboratory (23). Partial extinction
may underlie this diminished responding because animals did
not receive amphetamine
challenges until test days 5 and 6. The
responding did not completely extinguish but repeated testing
without amphetamine may have resulted in decreased magnitude
of the impact of the CR.
In the present experimental
design, animals received morphine pretreatment
and subsequent amphetamine
challenges in
the same test environment.
There is evidence in the literature
that environmental
conditioning contributes to opiate-amphetamine cross-sensitization
in locomotor activity (36,40). Further
research is currently being done to determine whether condi-
OPIATE-DOPAMINE
679
CROSS-SENSITIZATION
tioning factors contribute to the observed cross-sensitization in
the CR paradigm.
Although the precise neural mechanisms underlying crosssensitization are not yet known, one may speculate about several
possibilities. The first possibility to consider is whether multiple
injections of opiates into the nucleus accumbens induce an alteration in dopamine transmission. There is abundant evidence
that the dopamine system regulates activity of the opioid peptides
in the striatum (1,2,17,27,37,44). It may follow that repeated
stimulation of the opiate system elicits changes in dopaminergic
activity. Chronic morphine administration has inhibitory effects
on the phosphorylation of tyrosine hydroxylase in the nucleus
accumbens, implicating a decrease in dopamine production at
the terminal region (3). A decrease in dopamine production may
result in increased sensitivity of dopamine receptors.
Opiate-induced changes in second messenger systems may
also contribute to cross-sensitization.
Recent biochemical data
suggest that chronic morphine treatment results in a variety of
changes in signal transduction
mechanisms.
For example,
chronic prenatal exposure to morphine elevated striatal in vitro
D 1 receptor-mediated adenylate cyclase activity in offspring (8).
Terwilliger and colleagues (39) demonstrated that daily subcutaneous implantations of morphine pellets increased both ade-
nylate cyclase activity as well as cyclic AMP-dependent protein
kinase activity in the nucleus accumbens and other brain regions.
In another study, long-term exposure to morphine elevated pertussis toxin-induced adenosine diphosphate (ADP)-ribosylation
of G-proteins (28) which exert inhibitory actions on secondmessenger systems. A down-regulation in the inhibitory G-proteins on the cyclic-AMP system was reported in both the nucleus
accumbens and locus coereleus following chronic morphine exposure ( 11,28,39). If chronic or subchronic exposure to opiates
induces up-regulation in cyclic AMP and dopamine also utilizes
this second-messenger for signal transduction, one could expect
that this effector system mediates the phenomenon of crosssensitization.
Taken together, these data suggest that the nucleus accumbens
is a neural site involved in opiate-amphetamine
cross-sensitization in a reward paradigm, and that opiates and psychostimulants act on common postsynaptic systems. These findings may
have implications
for human polydrug use and addiction. Repeated use of opiates may induce long-term neuronal changes
that result in increased sensitivity to stimulants.
ACKNOWLEDGEMENT
This research was supported by Grant DA04788 from the National
lnstitue on Drug Abuse.
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