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Vol. 282, Issue 2, 787-794, 1997
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
Materials & Methods
Results
Discussion
References
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We report on the effect of environment on amphetamine sensitization in rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system. The rats were either housed in the test environment (HOME) or exposed to it only during the treatments (NOVEL). In experiment 1, the rats received seven consecutive i.p. injections of either saline or 2 mg/kg amphetamine. After 1 wk withdrawal the rotational response to 2 mg/kg amphetamine i.p. (i.e., amphetamine challenge) was compared in saline- vs. amphetamine-pretreated animals. Although both HOME and NOVEL groups sensitized, the magnitude of sensitization was greater in the NOVEL group. In the NOVEL group there was also a greater conditioned response to drug-related cues. In experiment 2 a dose-effect curve (0.75, 1.5, 3.0 and 6.0 mg/kg amphetamine i.p.) was determined before and after six i.p. injections of 4.0 mg/kg amphetamine. Sensitization was indicated by a parallel shift to the left of the dose-effect curve in both groups, but this shift was 2.6 times greater in the NOVEL group than in the HOME group. Finally, in experiment 3, we found that environment- and sensitization-dependent differences in the psychomotor response to amphetamine were not accompanied by differences in the concentration of amphetamine in the plasma or in the striatum.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
that are given repeated administrations of psychostimulant drugs, such
as amphetamine and cocaine, develop a progressive and persistent
hypersensitivity (sensitization) to their psychomotor activating
effects (Robinson and Becker, 1986
; Stewart and Badiani, 1993).
Although the mechanism(s) responsible for this phenomenon is not known,
there is evidence that behavioral sensitization is accompanied by
long-lasting neuroadaptations, including adaptations in the mesolimbic
dopamine system (for reviews, see Kalivas and Stewart, 1991; Robinson
and Becker, 1986). It has been hypothesized that these
sensitization-related neuroadaptations may contribute to the
development of compulsive patterns of drug-seeking and drug-taking
behavior in addicts (Robinson and Berridge, 1993). Therefore, the
identification of the factors that influence sensitization in animals
may provide some insight into the sources of variability in the
susceptibility to addiction.
The neuropharmacological actions of amphetamine and cocaine have been
relatively well characterized. These drugs increase the synaptic
concentration of monoamines in a dose-dependent manner because of their
actions on monoamine transporters (for reviews, see Dunwiddie and
Brodie, 1993; Seiden et al., 1993; White and Bunney, 1993).
It is tempting, therefore, to view the psychomotor response to such
drugs as simply a consequence of their direct neuropharmacological
actions on specific neural substrates, and, similarly, behavioral
sensitization as the result of adaptations in these neural substrates
due to their repeated activation. There is evidence, however, that
drug-induced behavior is a function of the interaction between the drug
and the environmental stimuli associated with drug administration. For
example, in a recent series of papers we have reported that both the
acute psychomotor response to amphetamine and the rate of amphetamine
and cocaine sensitization are greater for rats treated in a "novel"
(NOVEL) test environment than for rats treated in a physically
identical environment in which the animals live (HOME) (Badiani
et al., 1995a, b, c). Indeed, if the cues associated with
i.p. injections are eliminated by giving unsignaled i.v. infusions of
amphetamine, the acute response to amphetamine becomes negligible and
sensitization may not occur (Crombag et al., 1996); for a
review, see Robinson et al., 1997).
In our earlier studies the effect of environment on sensitization was quantified using a within-subject design, that is, by the rate of increase in amphetamine-induced psychomotor activation over consecutive test sessions (rate of sensitization). Amphetamine sensitization can be quantified, however, in two different ways as well: 1) as the difference in drug effect between drug- and vehicle-pretreated animals (between-subject design) when both groups are given a "challenge" injection of the same dose of the drug (this design is most appropriate to study the expression of sensitization following a period of withdrawal); and 2) as a shift to the left in a dose-effect curve. It is not known whether these different measures simply capture different aspects of the same phenomenon, or whether they correspond to different sensitization-related phenomena that may or may not share the same neurobiological substrates.
The goal of this study was 3-fold. The first aim was to assess whether exposure to a NOVEL environment would enhance the induction of sensitization when animals were tested following withdrawal from amphetamine (experiment 1). The second aim was to determine whether an intermittent amphetamine treatment given under the NOVEL condition would produce a greater shift to the left in the dose-effect curve for the psychomotor activating effects of amphetamine, relative to the HOME condition (experiment 2). A third aim was to determine if environment- and/or sensitization-dependent differences in amphetamine response were accompanied by differences in the concentration of amphetamine in the plasma or in the brain (experiment 3).
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
A total of 120 male Sprague-Dawley rats (Harlan Sprague Dawley Inc., Indianapolis, IN), weighing 175 to 250 g at the beginning of the experiments, were used. The rats were housed individually in a room with a 14/10 hr light/dark cycle (lights on from 06:00 to 20:00 hr), and had ad libitum access to food and water. The rats were habituated to the colony room for 1 wk before any experimental manipulation.
6-OHDA Lesion and Rotational Behavior
Rotational behavior in rats with a unilateral 6-OHDA lesion of
the mesostriatal dopamine system was used as an index of the psychomotor activating effects of amphetamine. The rationale for using
this preparation has been discussed in detail elsewhere (Badiani
et al., 1995c). Briefly, there are three main
reasons for studying rotational behavior in rats with a unilateral
6-OHDA lesion rather than the more common measurement of locomotor
activity in rats without a lesion. First, the dose-effect curve for
amphetamine-induced rotational behavior is linear over a wide range of
doses (Ungerstedt and Arbuthnott, 1970), whereas the dose-effect curve
for amphetamine-induced locomotor activity in rats without a 6-OHDA
lesion is not. Second, the progressive increase in drug effect during
sensitization results in a progressive increase in rotational behavior,
whereas this is not necessarily the case with locomotor activity (Segal
and Schuckit, 1983). Third, exposure to the NOVEL environment in
saline-injected rats produces negligible rotational behavior, whereas
this induces a marked increase in locomotor activity (Badiani et
al., 1995a, b).
The rats were pretreated with desipramine to protect noradrenergic
terminals (Breese and Traylor, 1971), anaesthetized with sodium
pentobarbital, and then given a unilateral 6-OHDA lesion of the medial
forebrain bundle, using procedures similar to those described
previously (Robinson, 1984). Briefly, 8 µg of 6-OHDA were infused in
4 µl of a saline-ascorbate solution over an 8 min-period, via a
29-gauge stainless steel cannula. The animals were then allowed to
recover from surgery for at least 10 days before they were given 0.05 mg/kg of apomorphine s.c., to assess the development of dopamine
receptor supersensitivity. This test is a good indicator of the size of
the lesion because a robust rotational response to such a low dose of
apomorphine occurs only after at least 90 to 95% of striatal dopamine
terminals are destroyed (Hefti et al., 1980a, b). Rotational
behavior was quantified 10 min after apomorphine and animals that made
less than five rotations/min were excluded from the study.
Procedures
Experiment 1 (effect of environment on the expression of amphetamine sensitization following withdrawal). Fifty rats were used. Half of them (HOME groups) were housed in a testing room in cylindrical (25 cm diameter, 36 cm high), plastic buckets equipped with drinking tubes. The floors of these buckets were covered with ground corn cob bedding. The other rats (NOVEL groups) were housed in stainless steel hanging cages located in the main animal colony room. The waste trays below these cages were covered with pine wood shavings. After 1 wk of habituation to these housing conditions NOVEL rats were transferred every day (12:00-13:00 hr) from their home cages in the animal colony to the testing room and placed in plastic buckets identical to those in which HOME rats lived, including the presence of ground corn cob bedding, food and water. They then received an i.p. injection of either saline (SAL-NOVEL; n = 12) or 2.0 mg/kg of amphetamine (AMPH-NOVEL; n = 13). This procedure was repeated on seven consecutive days. At the same time HOME rats received an i.p. injection of either saline (SAL-HOME; n = 12) or 2.0 mg/kg of amphetamine (AMPH-HOME; n = 13) in their home cages. Thus, it must be emphasized that the cages in which HOME and NOVEL rats received amphetamine were physically identical, but this was a "novel" environment for one group and the home environment for the other group. The day after the last injection of amphetamine, all groups were given an i.p. injection of saline (Saline Challenge), under the same conditions in which they received the repeated treatments, to assess for the presence of conditioned hyperactivity. One week after the saline challenge, all groups received an i.p. injection of 2.0 mg/kg of amphetamine (Amphetamine Challenge), to test for the expression of amphetamine sensitization.
All test sessions lasted 90 min, after which time NOVEL rats were returned to their hanging cages in the animal colony. The behavior of the animals was videotaped during the first, third, fifth, seventh test sessions, the Saline Challenge and the Amphetamine Challenge. Rotational behavior was quantified by viewing the videotapes. One rotation was defined as a complete 360° turn.Experiment 2 (effect of environment on sensitization-induced shift in the dose-effect curve). Thirty-eight rats were were housed and tested under either HOME (n = 17) or NOVEL (n = 21) conditions, as described for experiment 1. The treatment schedule consisted of three phases, separated by 72 hr during which the animals were left undisturbed. In the first phase (day 1) both HOME and NOVEL groups were divided into four subgroups that received (12:00-13:00 hr) one of four doses (0.75, 1.5, 3.0 or 6.0 mg/kg, i.p.) of amphetamine, producing an ACUTE dose-effect curve. During the second phase (days 4-16) all rats received six i.p. injections of 4.0 mg/kg amphetamine, one every other day. The dose of 4.0 mg/kg was chosen because it was roughly intermediate between the three doses (1.5, 3.0 and 6.0 mg/kg) producing a reliable psychomotor response in the HOME group (see "Results"). During the last phase (day 19) each rat received the same dose it received on day 1 of testing, producing a SENSITIZED dose-effect curve. Rotational behavior was quantified as in experiment 1.
Experiment 3 (plasma and striatal amphetamine concentrations). Experiment 3 was conducted to determine if the results obtained in experiment 1 (see "Results") could be attributed to differences in amphetamine pharmacokinetics. This was done by quantifying the amphetamine concentrations in the plasma and in the striatum of HOME and NOVEL rats after either a single injection (HOME-ACUTE and NOVEL-ACUTE) or the last of seven consecutive injections (HOME-SENSITIZED and NOVEL-SENSITIZED) of 2.0 mg/kg amphetamine. The rats were killed 50 min after drug administration, because in experiment 1 this was the point at which there was maximal rotational behavior. The rats were removed from the cages, transported to an adjacent room and quickly (<1 min after removal from the cage) decapitated with a guillotine. Trunk blood was collected in heparinized tubes and after centrifugation the plasma was stored at -20°C. The brains were quickly dissected and the entire striatum was dissected, weighed, homogenized and then stored at -20°C until assayed. Standards were prepared by adding amphetamine to plasma and brain samples of nontreated animals. Plasma and the tissue samples were assayed at the Center for Human Toxicology, University of Utah, using gas chromatography coupled with mass spectrometry.
Drugs. 6-OHDA hydrobromide was freshly dissolved (2 mg/ml) in a cold solution of 0.9 mg/ml NaCl (saline) and 0.1 mg/ml L-ascorbic acid. Desipramine hydrochloride was dissolved (15 mg/ml, weight of the salt) in distilled water and given i.p. (15 mg/kg). Apomorphine hydrochloride was freshly dissolved (0.1 mg/ml, weight of the salt) in saline and 0.01 mg/ml of L-ascorbic acid and injected s.c. in the nape of the neck (0.05 mg/kg). D-Amphetamine sulfate was dissolved (1 mg/ml, weight of the salt) in saline and administered i.p.. Sodium pentobarbital, dissolved (64.8 mg/ml) in a 10% ethanol solution (The Butler Company, Columbus, OH), was given i.p. (52 mg/kg).
Data Analysis and Statistics
HOME vs. NOVEL differences in the acute response to amphetamine (experiment 1) were assessed with a planned one-tail Student's t test on the data from the first test session. The data for the AMPH-HOME and AMPH-NOVEL groups on the first, third, fifth and seventh test session were analyzed with a two-way ANOVA with repeated measures (test environment, two levels, HOME and NOVEL; test session, four levels). The data from the first 5 min after the first and seventh amphetamine injections were analyzed with a two-way ANOVA with repeated measures (test environment, two levels, HOME and NOVEL; test session, two levels, first and seventh). Linear regression analyses were performed for each individual rat and for each treatment group to quantify the rate of sensitization (a positive slope indicates sensitization and a high slope coefficient indicates rapid sensitization). A Student's t test was used to determine if there was a significant difference between the two groups in the slope coefficients calculated for individual rats (i.e., if there was a difference in the rate of sensitization).
The data from the Saline Challenge and the Amphetamine Challenge tests (experiment 1) were analyzed with two-way ANOVAs (pretreatment, two levels, SAL and AMPH; test environment, two levels), followed by Fisher's PLSD post-hoc comparisons.
The data from experiment 2 were analyzed with a repeated measure analysis of covariance (grouping factor: test environment, two levels, HOME and NOVEL; covariate: dose, four levels; repeated measures on sensitization, two levels, ACUTE and SENSITIZED), after testing the homogeneity of slopes assumption. The magnitude of the shift in the dose-effect curve induced by the amphetamine pretreatment was quantified as the difference between the dose of amphetamine required to produce the same effect in the ACUTE and in the SENSITIZED condition. Usually this is done for the dose that produce 50% of the maximal drug effect (ED50). The observed dose-effect curves, however, did not allow us to identify a maximal effect. Therefore, we compared the doses that produced 50% of the response to 6.0 mg/kg amphetamine in the SENSITIZED condition.
The data from experiment 3 were analyzed with two-way ANOVAs (sensitization, two levels, ACUTE and SENSITIZED; test environment, two levels, HOME and NOVEL).
The results of the statistical analyses are reported in the figure
legends to make the following section more readable. However, all
statements made in "Results" are supported by significant statistical tests (P 
.05).
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Experiment 1.
Figure 1A shows
the effects of seven consecutive daily i.p. injections of saline or 2.0 mg/kg amphetamine on rotational behavior for rats in the HOME and NOVEL
groups. Rotational behavior was negligible in both the SAL-HOME and the
SAL-NOVEL group in all test sessions. In both AMPH-HOME and AMPH-NOVEL
groups the first injection of amphetamine induced a robust rotational
response that sensitized over repeated test sessions (as indicated by
positive slope coefficients). There were, however, significant HOME
vs. NOVEL differences in the magnitude of these effects. In
the AMPH-NOVEL group there was a greater acute response to amphetamine
and a greater rate of sensitization, as indicated by significant group differences in the mean slope coefficients.
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Experiment 2.
Figure 4 shows the effect of 0.75, 1.5, 3.0 and
6.0 mg/kg of amphetamine i.p., before (ACUTE) and after (SENSITIZED)
intermittent amphetamine treatment with 4.0 mg/kg of amphetamine i.p..
In both the HOME (fig. 4, left panel) and
in the NOVEL (fig. 4, middle panel) groups intermittent amphetamine
resulted in a shift to the left in the dose-effect curve
(i.e., produced sensitization). The magnitude of this shift,
however, was significantly greater in the NOVEL group than in the HOME
group, as indicated by an environment by sensitization interaction
(analysis of covariance). In the HOME group sensitization was
characterized by a shift to the left by about 1.1 mg/kg (see "Data
Analysis"), and by about 2.9 mg/kg in the NOVEL group. Therefore, the
shift for the NOVEL group was 2.6 times that for the HOME group.
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Experiment 3.
Figure 5 shows the
concentrations of amphetamine in blood plasma and in the striatum of
HOME and NOVEL groups, 50 min after either a single injection
(HOME-AMPH 1 and NOVEL-AMPH 1 groups) or the last of seven consecutive
daily injections of 2.0 mg/kg amphetamine (HOME-AMPH 7 and NOVEL-AMPH 7 groups). There were no significant differences between the
concentrations of amphetamine produced by the first vs. the
seventh injection of amphetamine, nor between the HOME vs.
NOVEL conditions (all P > .114).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The following major findings are reported in the present study. 1) Repeated amphetamine treatments paired with exposure to a NOVEL environment result in greater rate of sensitization (experiment 1), a greater sensitization after drug withdrawal (experiment 1), and a greater sensitization-induced shift in the dose-effect curve (experiment 2), relative to the same treatments given to rats tested in a HOME environment. 2) The conditioned rotational response to drug-associated stimuli in animals that had previously received amphetamine in the NOVEL environment was greater than in those that received the drug in the HOME environment (experiment 1). 3) HOME vs. NOVEL differences in peak amphetamine effects do not depend on differences in plasma or striatal amphetamine concentrations (experiment 3).
Environmental modulation of the acute psychomotor response to
amphetamine.
We have previously reported that the acute
psychomotor response to amphetamine is greater when the drug is
administered in a NOVEL vs. a HOME environment (Badiani
et al., 1995a, b, c). Although the results of experiment 1 confirm these previous findings, the results of experiment 2 suggest
that this effect of environment on the acute response to amphetamine is
seen only with low doses (<3.0 mg/kg). It is quite possible that the
exposure to a NOVEL environment could not increase further the already
robust behavioral response induced by higher doses of amphetamine. This
hypothesis requires, however, further investigation (see also Results
section). Nevertheless, the fact that the NOVEL environment failed to
increase the acute effects of 3.0 and 6.0 mg/kg of amphetamine, whereas it enhanced the sensitized response to the same doses (see below) should not be considered surprising. We have reported previously that
the effect of a NOVEL environment on sensitization to psychostimulants appears to be independent of its effect on the acute drug response (Badiani et al., 1995a, b). Indeed, there is some evidence
that different mechanisms may be involved in amphetamine-induced
increases of NAcc dopamine in sensitized vs. nonsensitized
animals. For example, the increase in NAcc dopamine response to acute
amphetamine is a calcium-independent process, whereas the
sensitization-related enhancement of this response appears to be
calcium-dependent (Warburton et al., 1996).
c; Friedman
and Ader, 1967; Hennessy et al., 1977). Indeed, it is has
been reported that exposure to stressors can potentiate the acute
effects of amphetamine on stereotyped behavior (Anisman et
al., 1985; Williams and Barber, 1989). In an initial test of this
hypothesis we found that although exposure to a NOVEL environment can
activate the HPA axis and increase plasma corticosterone, HOME
vs. NOVEL differences in the acute effects of amphetamine on
rotational behavior are not dependent on a stress- (novelty) induced
release of adrenal hormones, because they are not eliminated by
adrenalectomy (Badiani et al., 1995c). Thus, if
the enhancing effects of a NOVEL environment are due to its
stress-inducing properties, other effects of stress, independent of the
adrenal response, must be involved. For example, there is evidence that
CRH mechanisms participate in the stress response independently of
their activating effects on the HPA axis (Berridge and Dunn, 1989;
Britton et al., 1986; Cador et al., 1993). The hypothesis that CRH contributes to the enhancement in the acute effect
of amphetamine seen in the NOVEL environment remains to be tested.
In a preliminary study we also investigated whether the enhancement in
the acute response to amphetamine seen in the NOVEL environment was
coupled with a correspondent enhancement of dopamine transmission in
the dorso-lateral striatum or accumbens, but no differences in
amphetamine-induced dopamine release were found (Robinson and Badiani,
1994). This suggests that the modulatory action of environment could be
mediated by changes taking place downstream from the dopaminergic
terminals in the striatum (e.g., by changes in the activity
of glutamatergic afferents from the prefrontal cortex, amygdala,
thalamus or hippocampus).
Environmental modulation of amphetamine sensitization.
Our
results confirm and extend our previous reports that repeated
amphetamine administrations result in greater sensitization when the
treatments are given in a NOVEL vs. a HOME environment (Badiani et al., 1995a, b, c). In these earlier studies a
single dose of amphetamine was used and the expression of sensitization after a long period of drug withdrawal was not assessed. We report now
that the enhancement in amphetamine sensitization observed in a NOVEL
vs. a HOME environment is an enduring phenomenon, being evident when an amphetamine challenge was administered after 1 wk of
withdrawal from the drug. This is important because there is some
evidence that the neuroadaptations responsible for the development of
sensitization after brief periods of withdrawal from the drug may be
different from those involved in its expression after longer periods
withdrawal (Ackerman and White, 1992; Kalivas and Duffy, 1993; Kalivas
et al., 1993; Robinson et al., 1988; Segal and
Kuczenski, 1992a, b). Furthermore, we found that sensitization resulted
in a parallel shift to the left in the dose-response curve to
amphetamine for a range of doses from 0.75 to 6.0 m/kg (consistent with
the idea that sensitization is accompanied by an increase in drug
potency), and that the shift was greater when the treatments were given
in the NOVEL environment.
) we found no
differences in the concentration of amphetamine in either plasma or
striatum after the seventh vs. the first amphetamine injection (experiment 3) in either the HOME or the NOVEL group. This
indicates that dispositional changes did not contribute significantly to the development of amphetamine sensitization or to its modulation by
environmental factors.
As for the acute effects of amphetamine, the enhancing effects of a
NOVEL environment on amphetamine sensitization could be due the actions
of a novel environment as a stressor. Indeed, there is evidence that
animals exposed to intermittent stress develop sensitization to the
psychomotor activating effects of amphetamine (Antelman et
al., 1980; Badiani et al., 1992; Robinson et
al., 1985). However, we have found that adrenalectomy does not
diminish HOME vs. NOVEL differences in amphetamine
sensitization (Badiani et al., 1995c), suggesting
that if stress-related changes are involved at all, they must be
independent of the adrenal response to stress. Alternatively, the
stress associated with exposure to a NOVEL environment may act by
impinging more directly on the neural substrates of amphetamine
sensitization. One such substrate might involve the mesolimbic dopamine
system, which has been shown to undergo sensitization after repeated
amphetamine.
It may also be possible to think about HOME vs. NOVEL
differences in amphetamine sensitization within the framework of
associative learning theory, because the expression of behavioral
sensitization can be gated by stimuli associated with drug treatments
(Anagnostaras and Robinson, 1996; Post et al., 1981; Tilson
and Rech, 1973; Vezina and Stewart, 1984). It has been argued, for
example, that sensitization may be due in part to an enhancement in
drug response produced by the ability of amphetamine-associated stimuli
to acquire CS properties, thereby producing a CR (Hinson and Poulos,
1981; Pert et al., 1990; Tilson and Rech, 1973) and/or
modifying the drug response (Anagnostaras and Robinson, 1996; Badiani
and Robinson, 1994; Stewart, 1992; Stewart and Badiani, 1993). Indeed,
the response to a Saline Challenge in experiment 1 (figs. 1B and 4)
indicates that there was a CR to treatment-associated cues under both
environmental conditions, and that this conditioned hyperactivity was
greater in the AMPH-NOVEL group than in the AMPH-HOME group. It is not clear what kind of cue(s) elicited this CR and produced group differences in its magnitude. Amphetamine-associated cues can be
divided in three types. The first type of cue is represented by the
injection procedures, such as handling and needle prick, and is common
to both environmental conditions. The second type of cue is represented
by amphetamine-induced interoceptive cues, and, presumably, is also
common to both environmental conditions. (It is possible, however, that
both interoceptive cues and injection-related cues had different
salience under the HOME vs. the NOVEL conditions because of
the different level of arousal or stress experienced by the animals.)
The third type of cue is unique to the NOVEL group and includes
transportation to the testing room and exposure to a novel test cage.
Whatever cue(s) is involved, an analysis of the magnitude and
time-course of the conditioned hyperactivity seen in
amphetamine-pretreated animals during the Saline Challenge, indicates
this CR is not sufficient to account for the phenomenon of amphetamine
sensitization. First, the magnitude of the CR during the Saline
Challenge (AMPH-pretreated minus SAL-pretreated saline-induced activity) was negligible in comparison with the magnitude of
sensitization during the Amphetamine Challenge (AMPH-pretreated minus
SAL-pretreated amphetamine-induced activity). There were CRs of 10 and
37 rotations in the AMPH-HOME and AMPH-NOVEL groups, respectively,
vs. sensitization-induced increases of 168 and 295 rotations, in the same groups. Second, the CR was maximal in the five
minute interval immediately after the Saline Challenge, whereas the
sensitization- and environment-related differences in drug effect were
maximal between 30 and 50 min after the Amphetamine Challenge. Thus, if
the CR elicited by amphetamine-associated cues cannot entirely account
for the expression of amphetamine sensitization and for the
environmental modulation of sensitization, it appears that
amphetamine-associated cues must have acted by modifying the magnitude
of the drug response.
Conclusions. The present data indicate that environmental stimuli associated with amphetamine treatment have an enduring and powerful influence on the magnitude of amphetamine sensitization. This environmental control cannot be accounted for by changes in amphetamine pharmacokinetics. We have discussed how these effects of environment on amphetamine sensitization are possibly related to its actions as a stressor and/or to its ability to facilitate associative learning.
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Acknowledgments |
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The authors thank Drs. David E. Moody and Rodger L. Foltz, and their coworkers at the Center for Human Toxicology of University of Utah for conducting the plasma and striatum assays. We thank also Amy Braunsteiner, Steve Simmerville, and Donna De Jonghe for the assistance in conducting the experiments.
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Footnotes |
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Accepted for publication April 21, 1997.
Received for publication January 7, 1997.
1 This research was supported by Grant 02494 from the NIDA.
Send reprint requests to: Dr. Aldo Badiani, Department of Psychology, The University of Michigan, 525 E. University St., Ann Arbor, MI 48109-1109.
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Abbreviations |
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6-OHDA, six-hydroxydopamine; SAL, 0.9% NaCl solution; AMPH, d-amphetamine; CS, conditioned stimulus; CR, conditioned response; NAcc, nucleus accumbens; HPA axis, hypothalamo-pituitary-adrenal axis; CRH, corticotropin-releasing-hormone. .
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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