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Vol. 287, Issue 3, 1007-1014, December 1998
Department of Psychology and Neuroscience Program, The University of Michigan, Ann Arbor, Michigan
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Abstract |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In previous studies the repeated administration of 0.5 to 1.0 mg/kg of amphetamine i.v. failed to induce psychomotor sensitization if the drug was administered to animals living in the test environment (at home). The same doses did induce sensitization if animals were transported to the test environment for each drug treatment. The purpose of the present experiment was to determine the extent to which this effect of environment is dose dependent. Rats either lived in test cages or were transported from the animal colony to test cages where they received an i.v. infusion of one of five doses of amphetamine (0.125, 0.5, 1.0, 4.0 or 8.0 mg/kg) or saline each day for 5 consecutive days. Rotational behavior was used as an index of psychomotor activation. After a 6-day drug-free period all animals were challenged with 0.5 mg/kg of amphetamine to determine the pretreatment dose necessary to induce sensitization. The effect of the drug-treatment environment was to shift the dose-effect curve for the induction of sensitization, such that significantly lower doses were necessary to induce sensitization when amphetamine was given in a novel environment. With high doses, however, sensitization occurred regardless of environmental condition. It is concluded that the circumstances surrounding drug administration can powerfully modulate the ability of psychostimulants to induce sensitization, but this effect is dose dependent.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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When
psychostimulant drugs are given repeatedly and intermittently there is
often a progressive and persistent increase in their ability to produce
psychomotor activation, a phenomenon known as behavioral sensitization
(Robinson and Becker, 1986
; Stewart and Badiani, 1993). Despite
considerable progress in recent years in elucidating the
neurobiological basis of sensitization, the exact conditions that
promote or retard the ability of psychostimulants to induce
sensitization are not yet well understood. There is, however,
accumulating evidence that the circumstances surrounding drug
administration can powerfully modulate both the induction and the
expression of sensitization (Robinson et al., 1998). For example, both the acute psychomotor response to amphetamine and the
rate of sensitization are greater if drug treatments are given in a
relatively novel test environment than if they are given in a
physically identical environment in which the animals live (Badiani
et al., 1995a, b, c).
This effect of environment is augmented further if most environmental
stimuli predictive of drug administration (e.g., presence of
the experimenter, handling) are eliminated, by use of remotely controlled i.v. infusions. Thus, in the absence of stimuli predictive of drug (at home) 0.5 to 1.0 mg/kg of amphetamine i.v. failed to induce
sensitization, whereas the same doses did induce sensitization if drug
administration was given after transport from the animal colony and
placement into a relatively novel test environment (Crombag et
al., 1996; Robinson et al., 1998). This raises the question: is it not possible to induce behavioral sensitization with
any dose of amphetamine if it is given at home in the absence of
environmental cues predictive of drug administration? If the answer to
this question is yes it would have important implications for how
sensitization is conceptualized. For example, sensitization is often
considered a nonassociative neuroadaptive process initiated by the
interaction of a ligand (amphetamine in this case) and its receptor
(i.e., it is a primarily pharmacological phenomenon). If a
simple environmental manipulation can completely prevent the induction
of sensitization, at any dose, this would establish that an as yet
unidentified nonpharmacological factor plays a necessary role in
promoting sensitization. However, it is possible that the contribution
of environment is not a necessary one, but a modulatory one. That is,
an environmental factor may modulate the sensitivity of the relevant
neural substrate to sensitization. In this case the effect of
environment should be to shift the dose-effect curve for the
induction of sensitization. Thus, the purpose of this experiment
was to determine the extent to which environmental modulation of
amphetamine sensitization is dose dependent.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjects
Male Sprague Dawley rats (Harlan Sprague Dawley Inc., Indianapolis, IN) weighing 200 to 225 g on arrival were housed individually in wire hanging cages in the main animal colony for 1 wk before any experimental manipulation. The animal room was maintained on a 14:10 hr light:dark cycle (lights on from 06:00 to 20:00 hr) with food and water available ad libitum.
Surgical Procedures
Rats were anesthetized with Nembutal (pentobarbital, 50 mg/ml)
supplemented with methoxyflurane, if necessary, and using standard stereotaxic surgical procedures a 21-gauge stainless steel guide cannula was placed on the dural surface above the nigrostriatal bundle
in one hemisphere (for half of the animals the guide cannula was placed
in the right hemisphere, and for the other half in the left
hemisphere). The coordinates for the guide cannula were: posterior to
bregma, 
3.0 mm; lateral, ±1.8 mm; ventral, 1.0 mm from the skull
surface (Paxinos and Watson, 1997). In addition, a length of 15-gauge
stainless steel tubing was fixed in front of the guide cannula (to be
used later as an anchor for a tether). An L-shaped piece of plastic
tubing was placed posterior to the guide cannulae, and was later used
to hold the end of the i.v. catheter. The entire assembly was fixed to
the skull using jeweler's screws and cranioplastic cement. A stylet
was inserted into the guide cannula following surgery to maintain patency.
Two to four days after guide cannula implantation all rats received a
unilateral lesion of the nigrostriatal bundle via the guide cannula
using the neurotoxin 6-hydroxydopamine (6-OHDA). This was done so that
drug-induced rotational behavior could be used as an index of
psychomotor activation. The rationale for assessing rotational behavior
has been discussed in detail elsewhere (Badiani et al.,
1995a; Robinson, 1984). Rats were pretreated with desipramine HCl (15 mg/ml) and between 30 and 60 min later a 29-gauge injection cannula was
lowered through the guide cannula into the nigrostriatal bundle. A
solution of 4 µl ascorbate-saline containing 8 µg of 6-OHDA.HCl was
infused over a 8-min period. After the infusion the injection cannula
was left in place for 2 min before it was raised and the stylet was
replaced. The animals were not anesthetized during this procedure. Two
weeks after the 6-OHDA lesion animals were administered 0.05 mg/kg of
apomorphine to assess the development of receptor supersensitivity.
This dose of apomorphine produces robust rotational behavior only if 90 to 95% of the striatal dopamine terminals are destroyed. Ten minutes after a s.c. injection of apomorphine rotational behavior was quantified for 2 min, and animals that made less than five rotations were excluded from the study.
Animals that passed the apomorphine screen received an intravenous
catheter 2 to 4 days later. The catheter and the surgical techniques
were similar to those described previously (Browman et al.,
1998; Crombag et al., 1996; Weeks, 1972). Briefly, under ether anesthesia (supplemented with methoxyflurane) one end of a
catheter consisting of 0.3-mm diameter silicone rubber tubing was
inserted into the right external jugular vein. The other end (PE 20 tubing) was passed s.c., exiting the skin on the nape of the neck, and
was secured to the head by the plastic tubing mounted to the skull. The
catheter was filled with 50 µl of a solution containing 50 mg/ml of
gentamicin. A stylet was then placed in the exterior end of the
catheter to maintain patency, and the animal was returned to its home
cage. The animals were left undisturbed the day after surgery, and
beginning 2 days after surgery catheters were flushed daily for the
duration of the experiment with 0.1 ml of a heparin solution (30 USP/ml
heparin in a 0.9% saline solution with a pH of 7.4).
Behavioral Testing Procedures
Group assignment and habituation.
After a 4-day recovery
period from the catheter implantation animals were assigned to one of
two groups; which will be called the home or novel group. Animals in
the home group were transported to a testing room where they were
housed for the duration of the experiment. The animals were housed in
circular plastic buckets that had a diameter of 25 cm at the base,
ground corn cob bedding on the floor and food and water available
ad libitum. In addition, white noise was present
continuously to mask extraneous sounds. During the entire experiment
these rats were tethered to a liquid swivel (modified from Brown
et al., 1976) via a lightweight flexible cable secured to
the post mounted on their skull. The swivel was fixed to a
counter-balanced arm suspended above the center of the bucket. Animals
in the novel group were housed in wire-hanging cages in the main animal
colony for the duration of the experiment.
Drug pretreatment. After the 5 days of habituation, animals in both the home and novel groups were assigned to one of six different subgroups, which received one of five doses of amphetamine (0.125, 0.5, 1.0, 4.0 or 8.0 mg/kg) or saline (0.0 mg/kg) for 5 consecutive daily infusions of the same dose. During this time animals in the home environment were treated in the same manner as during the habituation period, except the 40-µl portion of the infusion line closest to the catheter was filled with one of the 5 doses of amphetamine, or saline, and a tiny air bubble was placed between drug and saline to avoid diffusion of the drug into the saline. Again, after connecting the animals to the infusion line the experimenter left the room, and at either 1100, 1300 or 1500 hr the syringe pump was activated and delivered 80 µl at 20 µl/min over 4 min (20 µl catheter volume, 40 µl amphetamine/saline and 20 µl of heparin). The drug was infused at different times of the day so this could not serve as a cue predictive of drug administration. During the pretreatment phase animals in the novel group were transferred each day to a novel environment that was physically identical to the environment in which the animals in the home group were housed, their catheter was flushed with 0.1 ml of the heparin solution, and they were tethered and infused with amphetamine or saline in a manner identical to the home group.
Behavioral data were collected over a 2-hr period, after which animals in the novel group were returned to the main animal colony. Animals in the home group were left undisturbed until the end of the day, when the infusion line was removed. Rotational behavior was quantified by an automated program described previously (McFarlane et al., 1992), with one rotation defined as four consecutive 90° turns in the
same direction.
Challenge test. After the pretreatment phase drug administration was discontinued for 5 days, during which time animals were handled in a manner identical to that described above for the habituation period, with one exception. The first day after the pretreatment phase all animals received an infusion of saline (saline challenge), to test for a conditioned response. Data on the saline challenge day was only collected for 1 hr, as the duration of the conditioned response is relatively short compared to the response to amphetamine.
On the sixth day after the last pretreatment infusion all animals received a challenge infusion of a fixed dose (0.5 mg/kg) of amphetamine to test for the expression of sensitization, and again rotational behavior was quantified for 2 hr.Catheter Patency
To check for catheter patency at the end of the experiment, all animals received an i.v. infusion of 0.1 ml of sodium pentobarbital (50 mg/kg). The data from rats that did not become ataxic within 10 sec were excluded from analysis.
Data Analysis
Data are only presented for those animals that passed the apomorphine screening and catheter patency tests. The Ns for each group are as follows: 0.0 mg/kg (home N = 10; novel N = 10), 0.125 mg/kg (home N = 10; novel N = 8), 0.5 mg/kg (home N = 10; novel N = 10), 1.0 mg/kg (home N = 9; novel N = 9), 4.0 mg/kg (home N = 9; novel N = 9) and 8.0 mg/kg (home N = 11; novel N = 10). Group differences in the total number of rotations averaged across the entire test session in response to the first injection of amphetamine were assessed using planned Student's t tests, and the time course of the drug effect was analyzed using two-way ANOVAs with repeated measures (test environment, i.v. home and i.v. novel and time). Within subjects comparisons (day 1 vs. 5) were made using two-way ANOVAs for repeated measures (day and dose) followed by planned paired t test comparisons. Between subjects comparisons for the amphetamine challenge and the saline challenge were made using two-way ANOVAs, followed by planned t tests.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effects of acute amphetamine. Figure 1 shows the number of rotations averaged over the entire test session following the first infusion, as a function of dose and environmental condition. With increasing dose there was an increase in the number of rotations produced by amphetamine in both groups. Lower doses (0.125-1.0 mg/kg) produced significantly more rotations in the novel group than in the home group, but there were not group differences for the two highest doses tested (4.0 and 8.0 mg/kg) (see fig. 1 legend for statistics). Figure 2 illustrates the time course of the behavioral response to the first amphetamine treatment and shows that the enhanced response seen in the novel group was due primarily to an increase in the magnitude of the response. Indeed, the same dose-effect relations were obtained if only the initial drug response (first 5 min) was considered (data not shown).
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Effects of repeated amphetamine.
One index of sensitization is
provided by a within-subjects comparison of the psychomotor response on
the first day of drug treatment with that on the last day of drug
treatment (i.e., a comparison between day 1 vs.
5). The results of this analysis are shown in figure
3. The top two panels (fig. 3, A and B)
show data averaged across the entire 2-hr test session. When the data were analyzed over the entire test session the lowest dose to produce
sensitization (day 5 more than 1) was 0.5 mg/kg for both the home and
novel groups. The bottom two panels (fig. 3, C and D) provide an
analysis of the initial drug effect (i.e., the first 5-min
interval after drug administration). This was done because the two
major characteristics of sensitization are a more rapid onset of drug
effect and an increase in the magnitude (vs. just duration)
of drug effect (Leith and Kuczenski, 1982). Inspection of the time
course of the drug effect indicates that both of these characteristics
are captured by the initial drug response (i.e., the first 5 min after infusion). The dose necessary to produce sensitization as
indicated by an increased initial drug effect differed for the two
groups. For the novel group 0.5 mg/kg was required and for the home
group 1.0 mg/kg was required.
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Challenge test. A second index of sensitization is to compare the response of saline and drug-pretreated animals to a challenge infusion of a fixed dose. With a between-groups analysis, sensitization is indicated if drug-pretreated animals show a significantly greater psychomotor response to the drug challenge than saline-pretreated animals. In addition, in our experiment animals were pretreated with different doses of amphetamine, and therefore, it is possible to construct a dose-effect curve for the induction of sensitization. That is, it is possible to determine what pretreatment dose of amphetamine is required to induce sensitization.
Figure 4 shows the rotational behavior induced by a challenge infusion of 0.5 mg/kg of amphetamine, as a function of pretreatment dose and environmental condition. Figure 4, A and B show data averaged across the entire 2-hr test session and C and D show an analysis of the initial drug response (i.e., the first 5-min interval after drug administration). It is clear from inspection of Figure 4A that there was a large effect of environment on the induction of sensitization, such that the dose-effect curve for the induction of sensitization in the novel group was shifted to the left and upward, relative to the home group. A direct comparison of the effect of pretreatment dose and group on the induction of sensitization was complicated, however, by the large group difference in the acute response to amphetamine (i.e., between the groups pretreated with saline). Sensitization is indicated by the difference between the response of drug-pretreated and saline-pretreated animals, and this difference is better illustrated in Figure 4, B and D where the mean number of rotations for the respective saline-pretreated groups was subtracted from the scores for each animal in the appropriate amphetamine pretreated groups. Figure 4B shows that even after controlling for the group difference in the acute response to amphetamine there were still significant group differences in the dose-effect curves for the induction of sensitization. For the novel group the lowest pretreatment dose to produce sensitization (i.e., a significantly greater response than saline pretreated animals) was 0.5 mg/kg. For the home group a pretreatment dose of 1.0 mg/kg was required to induce sensitization.
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Saline challenge.
To determine whether the drug administration
procedure resulted in conditioned psychomotor activation, animals in
both groups received an infusion of saline following the drug treatment
phase. A two-way ANOVA was used to compare animals in the home
condition with animals in the novel condition. There was a significant
effect of environment (F = 12.413, P = .0006), but no effect
of dose (F = 1.519, P = .1903) and no environment by dose
interaction (F = 1.525, P = .1884). Only animals in the novel
group treated with 0.5 mg/kg or higher showed a significant increase in
rotations compared to saline pretreated animals (i.e., a
conditioned response) (for 0.5 mg/kg t = 5.690,
P < .0001).
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Our major purpose was to determine if it is possible to induce psychomotor sensitization if repeated i.v. infusions of amphetamine are given in the absence of any explicit environmental stimuli predictive of drug administration, such as transport, placement in a relatively novel test environment, the presence of an experimenter or handling. The results demonstrate that it was possible to induce sensitization under these conditions. Nevertheless, environmental condition (home vs. novel) did have a significant effect on the minimal dose of amphetamine required to induce sensitization. When amphetamine administration was paired with transport and placement into a relatively novel test cage (novel group), significantly lower doses of amphetamine were required to induce sensitization than when amphetamine was administered at home in the absence of any experimenter related stimuli (home group). With high doses, however, sensitization was induced regardless of environmental condition. Thus, the effect of environmental novelty was to reduce the dose necessary to induce psychomotor sensitization.
Effect of environment on the acute psychomotor response to
amphetamine.
We reported previously that the acute administration
of moderate doses of amphetamine, given either i.p. or i.v., produce greater psychomotor activation (locomotor activity or rotational behavior) when given in a relatively novel environment than when given
in a physically identical environment in which the animals live
(i.e., home) (Badiani et al., 1995a, b; Crombag
et al., 1996). Our study confirms these observations, and
further establishes that this effect of environment is limited to low
or moderate doses. The highest doses tested (4.0-8.0 mg/kg) produced a
comparable amount of rotational behavior in the home and novel groups.
These data suggest, therefore, that the effect of environmental novelty on the acute response to amphetamine is to enhance sensitivity to low
doses, but with no change in the maximal psychomotor response seen with
high doses (also see Badiani et al., 1997a). This effect of
environment on acute drug responsiveness seems to be relatively specific to amphetamine, because this same environmental manipulation has no effect on the acute rotational response to cocaine, when cocaine
is given either i.p. (Badiani et al., 1995b) or i.v.
(Browman et al., 1998).
). It also does not appear to involve modulation of
amphetamine's primary neuropharmacological effect, which is to enhance
the synaptic concentrations of dopamine. There is no effect of
environment (home vs. novel) on the ability of amphetamine to increase dopamine overflow in the caudate nucleus or the nucleus accumbens, as indicated by in vivo microdialysis (Browman
et al., 1995; Ostrander et al., 1997). There is,
however, a large effect of environment on the apparent postsynaptic
consequences of amphetamine administration. Badiani and colleagues
(1997b) have found that environmental novelty greatly enhances the
ability of amphetamine to induce the expression of mRNA for the
immediate early gene, c-fos, throughout the striatal
complex. Thus, the relationship between environmental modulation of
amphetamine-induced immediate early gene expression and its ability to
modulate the acute and long-term (see below) behavioral consequences of
amphetamine administration may yield new insights about the
neurobiological mechanisms by which environmental factors modulate drug action.
Effect of environment on the induction of amphetamine
sensitization.
We reported previously that the circumstances
surrounding drug administration also modulate the psychomotor
sensitization produced by repeated treatment with either amphetamine or
cocaine. When given i.p. to animals living in the test environment
(i.e., home) both amphetamine and cocaine induce
sensitization, but significantly less robust sensitization than if
animals receive the same treatments in a physically identical but novel
test environment (Badiani et al., 1995a, b, c). Furthermore,
when the experimenter-related stimuli that inevitably accompany i.p.
administrations were removed by the use of i.v. infusions at home, low
to moderate doses of amphetamine or cocaine failed to induce
sensitization (Browman et al., 1998; Crombag et
al., 1996; Robinson et al., 1998). Our study confirms
these observations, and further establishes that for amphetamine this
effect of environment is dose dependent. High doses of
amphetamine-induced sensitization regardless of environmental
condition. We recently reported that the same is true for the
psychomotor sensitization induced by cocaine (Browman et
al., 1998).
). In our study inspection of the time course of the
drug response indicates that analysis of the first 5-min interval best
captures these two features of the behavioral response. With i.v.
administration the largest behavioral response is seen during the first
5 min after drug administration, especially after sensitization (fig.
5). Thus, the analysis shown in figure 4, C and D indicates that the
environmental manipulation used did not set any absolute limit on the
ability of amphetamine to induce the neurobiological adaptations
responsible for behavioral sensitization. This conclusion is consistent
with our studies using cocaine rather than amphetamine (Browman
et al., 1998).
The apparent shift in maximal effect seen when the entire time course
of the drug response was considered appears to be due, therefore, to an
effect on the duration of the drug response. Some researchers have
reported that sensitization is sometimes characterized by an increase
in the duration of a drug response (Antelman, 1988), but others have
argued that this is not a necessary characteristic (Leith and
Kuczenski, 1982). It is certainly the case that different behavioral
components of the psychomotor response, occurring at different times
after drug administration, can be dissociated (Leith and Kuczenski,
1982). Thus, the significance of this finding for understanding how
environmental factors modulate the induction of sensitization will
probably have to wait until we better understand the phenomenon.
Another dissociation between different indices of behavioral
sensitization was seen in comparing the within- vs.
between-subjects analysis of the data averaged over the entire test
session. For the within-subjects analysis (day 1 vs. 5)
there was no difference in the dose required to induce sensitization in
the home and novel groups, but on the amphetamine challenge day
(between-subjects) there was a significant effect of environment on the
minimal dose required to induce sensitization (although note that for
the initial drug response, first 5-min interval, there was a
significant effect of environment for both indices). Similar
dissociations between within- and between-subjects estimates of
sensitization have been reported before. The reason for this difference
is not clear, but a couple of points are relevant. First, a
between-subjects analysis provides a more "conservative" index of
sensitization, as this approach controls for potential changes in
behavior due to repeated handling and other nonspecific variables
associated with the treatment protocol. These factors would be present
in both the drug and saline-pretreated animals, so would theoretically be accounted for by this comparison. Second, the challenge test involved a withdrawal period of 5 days. The expression of psychomotor sensitization is often time-dependent (Antelman, 1988) and the neuroadaptations seen early after the cessation of drug treatment may
differ from those seen later (Kalivas and Stewart, 1991; Paulson and
Robinson, 1995; White and Wolf, 1991). It is possible, therefore, that
environmental stimuli are especially effective in modulating the more
persistent neuroplastic adaptations involved in sensitization.
The mechanism(s) by which the environmental manipulations used
influence the induction of sensitization is not known. We have previously suggested that the mechanism may be related to differences in the availability of stimuli predictive of drug administration (Browman et al., 1998; Crombag et al., 1996). The
fact that a conditioned response was seen only in the novel group is
consistent with the notion that transport and associated stimuli might
increase the responsiveness of animals in the novel group, relative to animals in the home condition, and thus contribute to the expression of
sensitization. However, animals in the home group pretreated with doses
of 1.0 mg/kg or higher showed no evidence of a conditioned response,
but did express sensitization on the challenge day. Furthermore, it was
recently reported that presenting a discrete cue predictive of drug
administration has only a small effect on the induction of
sensitization in the home condition (Crombag et al., 1997).
These results suggest that drug predictability plays a minor role in
the effect of environmental novelty on sensitization, and that the
development of a conditioned response is not necessary for the
induction of sensitization.
Alternatively, it is possible that the differences observed between the
home and novel groups might be due to the action of the novel
environment as a stressor. It is known that exposure to a novel
environment produces neuroendocrine and neural changes indicative of
stress (Friedman and Ader, 1967), and it is possible that this may
facilitate the induction of sensitization in the novel group. However,
it has been reported that adrenalectomy does not block the effect of
environmental novelty on amphetamine sensitization, suggesting that
adrenal hormones are not involved (Badiani et al., 1995c).
Nevertheless, other stress-related hormones such as
corticotropin-releasing hormone could be involved (Cador et
al., 1993). Finally, the ability of environmental novelty to facilitate amphetamine induction of the immediate early gene, c-fos, as discussed above (Badiani et al.,
1997b), could also provide a mechanism by which the circumstances
surrounding drug administration modulates the long-term neurobiological
consequences of repeated amphetamine administrations.
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Footnotes |
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Accepted for publication July 17, 1998.
Received for publication February 11, 1998.
1 This work was supported by Grant DA 02494 from the National Institute on Drug Abuse to T.E.R. Preliminary data from this experiment was presented at the 23rd Meeting of the Society for Neuroscience, 1997.
Send reprint requests to: Dr. Terry E. Robinson, Biopsychology Program, Department of Psychology, The University of Michigan, 525 East University St., Ann Arbor, MI 48109-1109.
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Abbreviations |
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ANOVA, analysis of variation; 6-OHDA, six-hydroxydopamine.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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.05). C and D show the initial drug
response, i.e., the average of the first 5-min interval
after drug administration for animals in the home group (C) and novel
group (D). For the home group there was a significant effect of day
(F = 14.820, P = .0002), a significant effect of dose (F = 42.458, P < .0001) and a significant day by dose interaction
(F = 4.47, P = .0010). For the novel group there was also a
significant effect of day (F = 14.509, P = .0002), a
significant effect of dose (F = 43.962, P < .0001) and a
significant day by dose interaction (F = 2.635, P = .0281).
For the novel group a dose of 0.5 mg/kg was the lowest dose to produce
sensitization (P < .002), whereas for the home group a dose of
1.0 mg/kg was required (P = .0145).
