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Vol. 281, Issue 1, 54-61, 1997
Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington
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Abstract |
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Abstract
Introduction
Methods
Results
Discussion
References
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Male Sprague-Dawley rats that were naive or that had been treated with five daily saline or cocaine injections (15 mg/kg i.p.) were subsequently challenged with an injection of cocaine, and extracellular dopamine content in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis. Cocaine challenge increased extracellular dopamine levels from base line in all three groups of rats, but the augmentation was significantly reduced in the cocaine-pretreated group, compared with the saline-pretreated group. In contrast, mPFC dopamine levels were not different among groups after challenge with systemic d-amphetamine. To test whether repeated cocaine treatment led to altered releasability of dopamine from mPFC terminals, challenge with KCl (10, 30 or 100 mM) or d-amphetamine (3, 30 or 300 µM) was made via infusion through the dialysis probe into the mPFC. No differences in dopamine levels were found between treatment groups for either drug at any dose. To determine whether the effects of cocaine were mediated by local actions within mPFC dopamine terminals, a cocaine challenge was administered through the microdialysis probe (1, 10 or 100 µM). In contrast to the systemic cocaine challenge, local infusion of cocaine elicited a significant increase in daily cocaine-pretreated rats, compared with saline-pretreated controls, at the lowest dose tested, with no differences at the higher two doses. In summary, daily cocaine-pretreated rats demonstrated a suppressed mPFC dopamine response to subsequent systemic, but not local, cocaine challenge. The results suggest that this apparent tolerance is not due to altered releasability of dopamine from mPFC terminals and may rely on altered afferent regulation of mesocortical dopamine neurons.
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Introduction |
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Abstract
Introduction
Methods
Results
Discussion
References
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Repeated psychostimulant
administration produces a progressive increase in the locomotor
response in rodents, a process referred to as behavioral sensitization.
The neuronal circuitry consistently implicated in mediating
psychostimulant-induced locomotion and behavioral sensitization
involves dopaminergic neurons projecting from the VTA to the nucleus
accumbens (Kelley and Iversen, 1975
; Robinson et al., 1988;
Kalivas and Duffy, 1990; Pettit et al., 1990). In
vivo microdialysis studies have revealed that cocaine-induced elevations of extracellular dopamine concentrations in the nucleus accumbens are augmented in rats behaviorally sensitized to cocaine (Kalivas and Duffy, 1990; Pettit et al., 1990).
Although the role of the mesoaccumbens dopamine pathway in
cocaine-induced sensitization has been well studied, the role of the
mPFC in sensitization is only beginning to be explored. Descending regulation by the mPFC on subcortical structures important for the
development and expression of behavioral sensitization has been more
extensively examined. Both spontaneous locomotor activity (Tassin
et al., 1978) and acute amphetamine-induced locomotion are
modulated by mPFC dopamine transmission (Thierry et al.,
1979; Vezina et al., 1991). A negative correlation between
locomotor activity and mPFC dopamine levels has been reported (Tassin
et al., 1978). Dopamine plays an inhibitory role in mPFC
neurons, because application of dopamine to PFC neurons inhibits the
firing of these cells (Bunney and Aghajanian, 1976; Williams and
Goldman-Rakic, 1995). The relationship between mPFC dopamine and
locomotion is believed to occur directly via the inhibitory
action of dopamine on EAA neurons in the mPFC and indirectly
via dopamine-mediated increases in 
-aminobutyric acid
release (Sesack and Bunney, 1989; Retaux et al., 1991).
Therefore, dopamine release in the mPFC is postulated to influence
locomotion via inhibition of EAA neurons projecting to
subcortical sites (Carter and Pycock, 1980; Sesack et al.,
1989; Berendse et al., 1992). Direct EAA projections have been identified from the mPFC to the nucleus accumbens, as well as to
dopaminergic and nondopaminergic neurons in the VTA (Carter, 1980;
Sesack and Pickel, 1992).
Dopamine levels in the nucleus accumbens and striatum are regulated by
mPFC EAA efferents (Louilot et al., 1989; Taber et al., 1995; Karreman and Moghaddam, 1996). EAA efferents from the mPFC modulate mesolimbic dopamine release by inducing burst firing in
these neurons (Gariano and Groves, 1988; Murase et al.,
1993). The primary pathway for mPFC regulation of dopamine levels in the nucleus accumbens/striatum appears to be indirectly via
EAA projections from the mPFC to the VTA. Taber et al.
(1995) showed that direct electrical stimulation of the mPFC produces
an increase in nucleus accumbens dopamine levels, which is blocked by
glutamate antagonist infusion into the VTA. Karreman and Moghaddam
(1996) have also provided strong evidence for indirect modulation of striatal dopamine levels by mPFC EAA output to the substantia nigra,
rather than through a direct corticostriatal pathway.
Evidence is emerging that the mPFC may play an important role in
behavioral sensitization and the reinforcing effects of
psychostimulants. Rats have been shown to self-administer cocaine
directly into the mPFC (Goeders and Smith, 1983), and destruction of
mPFC dopamine terminals by 6-hydroxydopamine treatment results in the
acquisition and maintenance of subthreshold doses of cocaine
self-administration (Schenk et al., 1991). Behavioral
sensitization to repeated amphetamine or repeated sex-related olfactory
cues is augmented in rats with 6-hydroxydopamine lesions in the mPFC
(Mitchell and Gratton, 1992; Banks and Gratton, 1995). Also, lesion of
EAA neurons in the mPFC by ibotenic acid prevents amphetamine-induced
sensitization (Wolf et al., 1995). These reports are
consistent with an inhibitory role for mPFC dopamine on EAA efferents
to subcortical sites modulating behavioral sensitization and reward
processes.
A previous study in this laboratory examined the effects of
cross-sensitization on mPFC dopamine levels (Sorg and Kalivas, 1993).
Repeated exposure to footshock stress produced a decreased responsiveness of mPFC dopamine to a subsequent acute cocaine injection
1 week later. The converse of this cross-sensitization experiment
showed that repeated cocaine administration produced complete blockade
of the footshock-induced increase in mPFC dopamine levels. Thus, in
contrast to dopamine transmission in the nucleus accumbens, tolerance
rather than sensitization was observed in the mPFC. The goal of the
present study was to examine whether repeated cocaine administration
would produce the same effect on mPFC extracellular dopamine levels
after a subsequent cocaine or amphetamine challenge and to further
explore potential mechanisms mediating the tolerance phenomenon. The
effect of systemic cocaine and amphetamine on extracellular dopamine
content in the mPFC was assessed in daily cocaine- and
saline-pretreated rats. A second series of experiments used intra-mPFC
challenge of KCl, amphetamine or cocaine infusion through the
microdialysis probe to determine whether the systemic effects of
cocaine or amphetamine were mediated locally.
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Methods |
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Methods
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Discussion
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Drugs. Cocaine hydrochloride and d-amphetamine sulfate (gifts from the National Institute on Drug Abuse) were dissolved in isotonic saline for systemic injection and artificial CSF (see below) for intracranial infusion.
Animal housing and surgery.
All procedures were conducted
according to the National Institutes of Health Guide for the Care and
Use of Laboratory Animals. Male Sprague-Dawley rats (Simonsen
Laboratories, Gilroy, CA), weighing 250 to 320 g at the time of
surgery, were given free access to food and water in a temperature- and
humidity-controlled room with a 12-hr light cycle, with lights on at
7:00 A.M. For surgery, rats were anesthetized with
Equithesin (3.0 ml/kg i.p.) and placed into a stereotaxic apparatus.
Unilateral chronic guide cannulae (20 gauge) were placed into the right
hemisphere at +3.2 mm from bregma, ±0.6 mm from midline and 
1.5 mm
from the skull (Paxinos and Watson, 1986). All rats were housed
individually, in stainless steel hanging cages, for at least 5 days
after surgery before the beginning of daily injections (at least 16 days before the dialysis day). All naive rats were left unhandled after
surgery and housed for the same times as their daily saline- or
cocaine-treated counterparts between surgery and the microdialysis day.
Behavioral measures. Behavioral activity was monitored in photocell chambers (Omnitech Electronics, Columbus, OH). Each monitor was housed in individual wooden boxes with individual lighting (10 W) and a fan to attenuate outside noise. Measures of horizontal photocell beam breaks were obtained at 20-min intervals, simultaneously with dialysis sample collection.
Experimental paradigm. A total of six experiments was performed. Three experiments were performed in which systemic injections were administered during microdialysis. Three additional experiments were carried out using local infusion of drugs through the microdialysis probe.
For all experiments involving systemic drug challenge, rats were administered either no pretreatment (naive), saline (1 ml/kg i.p.) or cocaine hydrochloride (15 mg/ml i.p.) once daily for 5 days. Six days later, the rats were placed into the photocell chambers, and dialysis probes were inserted through the chronic guide cannulae the evening before the experiment. Probe placement was performed the night before the experiment, to minimize damage-induced dopamine release during the experiment (Westerink and DeVries, 1988). The infusion pumps remained
off during the night; the next morning, artificial CSF (5.0 mM glucose,
5 mM KCl, 120 mM NaCl, 1.4 mM CaCl2, 1.2 mM
MgCl2, 0.15% phosphate-buffered saline, pH 7.4) was
infused through the probe at a rate of 2.0 µl/min. After at least 2 hr of infusion, five 20-min base-line samples were collected, after
which an acute challenge of saline (1 ml/kg i.p.), cocaine
hydrochloride (15 mg/kg i.p.) or d-amphetamine sulfate (1.75 mg/kg i.p.) was administered. Sample collection continued at 20-min
intervals for a minimum of 140 min. Average basal levels were
calculated by averaging three of the five base-line values.
For experiments involving local drug infusion into the mPFC, rats were
treated as described above, with the exception of the cocaine infusion
study, in which naive rats were not used. Local infusion of KCl,
d-amphetamine sulfate or cocaine dissolved in artificial CSF
replaced systemic drug challenge. Three doses of each drug were given,
as follows: KCl, 10, 30 and 100 mM (NaCl in artificial CSF adjusted to
115, 95 and 25 mM, respectively); d-amphetamine sulfate, 3, 30 and 300 µM; cocaine hydrochloride, 1, 10 and 100 µM. Five 20-min
samples were collected after each switch of drug concentration was
made.
In vivo dialysis and dopamine measurement.
Dialysis probes (Robinson and Whishaw, 1988) with a membrane region 250 µm in diameter and 3 mm in length were inserted 3 mm below the guide
cannulae. Dialysis samples were collected into 20 µl of mobile phase
containing 2.0 pmol of dihydroxybenzylamine as an internal standard.
The concentration of dopamine was measured using high performance
liquid chromatography with coulometric electrochemical detection, as
previously described (Sorg and Kalivas, 1991).
Histology and data analysis.
At the completion of the
experiments, the animals were given an overdose of sodium pentobarbital
and perfused through the heart with phosphate-buffered saline followed
by 10% formalin/isotonic saline. Coronal slices (100 µm) were
stained with cresyl violet, and probe placement was determined by light
microscopy. Behavioral and neurochemical data were analyzed with a
two-way ANOVA with one repeated measure over time (all time course
data) or dose (figs. 3C, 4C and 5C). All P values reported from the
two-way ANOVAs represent adjusted P values according to the
Greenhouse-Geisser approach. In the case of a significant interaction,
a least-squares difference analysis was performed. Basal levels of
dopamine were analyzed with a one-way ANOVA. When data were transformed
to percentage of base-line values, each animal's response to drug
infusion or injection was divided by its own average basal value.
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Results |
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Abstract
Introduction
Methods
Results
Discussion
References
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Systemic challenge.
Figure 1, A to C, shows the
response to an acute saline injection in naive, daily saline-pretreated
and daily cocaine-pretreated rats. Although dopamine was increased
after saline injection in all groups, no significant differences among
treatment groups were found. Basal levels of dopamine were not
significantly different among treatment groups (P = .68). Acute
saline injection induced a slight increase in horizontal locomotor
activity that was not different among the treatment groups (fig. 1C).
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Intra-mPFC challenge. To test whether repeated cocaine treatment led to alterations in the releasability of dopamine in the mPFC, KCl was infused through the microdialysis probe placed in the mPFC. The results are shown in figure 3. Basal levels of dopamine were not different among groups (P = .35). No differences were detected among any of the three treatment groups at the three doses tested when data were examined as absolute values or as percentage of base-line levels.
The likelihood that cytoplasmic dopamine levels may have been altered was tested by infusing various doses of d-amphetamine through the microdialysis probe in the mPFC. Basal levels of dopamine were not different among treatment groups (P = .58). Figure 4 demonstrates that infusion of d-amphetamine through the probe did not produce differences among the treatment groups at any of the doses tested, although a tendency toward lower levels of dopamine was found in naive rats.
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Discussion |
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Abstract
Introduction
Methods
Results
Discussion
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The main findings from the present study can be summarized as follows. 1) Compared with saline-treated controls, mesoprefrontal dopamine neurons in cocaine-sensitized rats demonstrated apparent tolerance to the effects of subsequent systemic cocaine but not systemic amphetamine. 2) The tolerance was not due to decreased releasability of dopamine from vesicular or cytoplasmic pools in mPFC terminals, as determined by local mPFC infusion of KCl or amphetamine through the dialysis probe. 3) Local infusion of cocaine through the dialysis probe into the mPFC did not mimic the effects of systemic cocaine but tended toward the opposite response, suggesting that tolerance of mPFC dopamine detected after systemic cocaine injection may be mediated by afferents to mesocortical dopamine neurons.
Systemic cocaine and amphetamine.
The decline of
cocaine-induced increases in mPFC dopamine levels in cocaine-sensitized
rats is in contrast to consistent findings of an augmentation in
extracellular dopamine levels occurring in mesoaccumbens projections
after daily cocaine pretreatment (Robinson et al., 1988;
Kalivas and Duffy, 1990; Pettit et al., 1990). However,
previous findings from this laboratory have shown a similar phenomenon
in the mPFC in a cocaine/stress cross-sensitization paradigm (Sorg and
Kalivas, 1993). In those experiments, daily cocaine produced a complete
blockade of the acute footshock-induced increase in mPFC dopamine; in
the converse experiment, daily footshock stress induced a tolerance to
systemic cocaine-induced increases in dopamine levels, compared with
daily sham-treated (handled) controls. Both cocaine-induced release and
stress-induced release of dopamine are impulse-dependent, whereas the
effects of amphetamine are only partially dependent on impulse flow
(Kuczenski, 1983; Mantz et al., 1989). Therefore, the
differences in dopamine levels produced by daily saline and cocaine
pretreatment after cocaine challenge may depend primarily on
impulse-mediated dopamine release.
),
local KCl infusion or systemic amphetamine administration (Stephans and
Yamamoto, 1995) elicits an augmentation in dopamine levels. Thus,
mesoprefrontal neurons are capable of sensitized responding if repeated
amphetamine is used as the sensitizing stimulus. Differences between
repeated amphetamine and cocaine may lie in their different mechanisms
of action (Carboni et al., 1989; Cadoni et al.,
1995). Relevant to the induction of sensitization is the demonstration
that cocaine does not decrease firing of mesoprefrontal neurons,
whereas amphetamine inhibits these neurons (Chiodo et al.,
1984; White et al., 1987), and both drugs inhibit firing of
mesoaccumbens neurons (White et al., 1987; Einhorn et al., 1988). The lack of impulse-regulating autoreceptors on
prefrontocortical neurons (Chiodo et al., 1984) or weak
feedback via the reciprocal projection from the mPFC to the
VTA may explain the absence of inhibition by cocaine, whereas the
mechanism of the depressive effect of amphetamine on mesocortical
neurons remains unknown. Thus, initiation of sensitization of
dopaminergic pathways after repeated systemic psychostimulant
administration may depend on the ability of a repeated intermittent
stimulus to attenuate or arrest impulses in the vicinity of the VTA.
Although behavioral sensitization was present in cocaine-challenged
animals, daily cocaine-pretreated rats given an amphetamine challenge
failed to demonstrate sensitized behavioral responding. Previously, we
demonstrated a nonsignificant trend toward cross-sensitization of
locomotor activity in response to acute cocaine after daily footshock
stress (Sorg and Kalivas, 1993). In that study, as well as the present
work, it was noted that, when rats are implanted with a microdialysis
probe in the mPFC, locomotor activity is diminished, compared with
those implanted in the nucleus accumbens (Kalivas and Duffy, 1990,
1993). Thus, placement of a dialysis probe into the mPFC may impose a
reduced upper limit on locomotor output. The increased response in
locomotor activity after amphetamine, compared with that after cocaine
challenge, in the present study may indicate an approach to this upper
limit; that is, when animals are implanted in the mPFC, the dose of
amphetamine used (1.75 mg/kg i.p.) may be high enough to cause maximal
increases in all pretreatment groups. Alternatively, this dose of
amphetamine may produce some stereotypic behavior in daily
cocaine-pretreated rats to a greater extent than in saline-pretreated
controls. Some stereotypic movements would not necessarily have been
detected by the automated photocell system and would compete with
locomotor activity, potentially diminishing any differences between
treatment groups.
Local mPFC infusion of KCl, amphetamine and cocaine.
The
absence of differences among treatment groups receiving intra-mPFC
infusion of KCl suggests that no difference in the ability of mPFC
dopamine terminals to release dopamine from vesicular stores was
present. Similarly, local infusion of d-amphetamine into the
mPFC did not produce differences in extracellular dopamine concentrations among treatment groups. Amphetamine is believed to
promote dopamine release from nonvesicular stores at lower concentrations via reversal of the dopamine transporter
(Fischer and Cho, 1979; Liang and Rutledge, 1982). At higher
concentrations, amphetamine also depletes vesicular dopamine storage by
destroying the proton gradient and thus releasing dopamine into the
cytoplasm, whereby it can be released via the dopamine
transporter (Sulzer and Rayport, 1990; Cadoni et al., 1995).
Unlike KCl-induced release, amphetamine-induced increases in
extracellular dopamine are independent of Ca++ influx
(Carboni et al., 1989; Westerink et al., 1989).
The finding that no differences existed among groups at any of the
doses of amphetamine tested suggests that the ability to release
dopamine from the cytoplasmic pool is unaltered in daily
cocaine-pretreated rats, compared with controls. Of significance is
that KCl and amphetamine can release dopamine independent of cell
firing (Kuczenski, 1983). Thus, tolerance of the dopamine response to
acute cocaine treatment (present study) or footshock stress (Sorg and
Kalivas, 1993) may be discernible only when dopamine release is
primarily impulse-dependent.
) and 2) at levels approximating brain cocaine levels after a 15 mg/kg injection (Nicolaysen et al., 1988) does not mimic the dopamine
response after a systemic cocaine challenge suggests that afferent
regulation of mesocortical dopamine neurons is altered. It is likely
that the site of modification is afferent projections to dopamine
neurons, because tolerance is observed only after challenge with
stimuli that are primarily dependent on impulse flow (cocaine or
stress) and not with amphetamine or local KCl infusion, whose effects on dopamine release are at least partially independent of impulses. Several neurotransmitters that regulate dopamine neurons in the VTA
(Kalivas, 1993) may be involved.
Although daily saline injections were given to rats to control for the
handling and injection procedures associated with cocaine injections,
the response of mPFC dopamine levels in unhandled (naive) animals was
also examined. Previously, naive animals demonstrated a dopamine
response to acute footshock stress that was between that of saline- and
cocaine-pretreated rats, with saline-pretreated animals showing the
most robust increase in mPFC dopamine levels (Sorg and Kalivas, 1993).
Also, in the converse experiment, a cocaine challenge elicited a
similar increase in mPFC dopamine in both naive rats and rats given
repeated daily footshock, whereas daily sham shock-pretreated animals
demonstrated the most robust increase. Previous work has demonstrated
that handling of rats alters several responses related to the
mesocorticolimbic dopamine system (Robinson et al., 1987;
Peris et al., 1990; Meiergerd et al., 1996). A
possible explanation for enhanced responsiveness of the mesocortical
dopamine system in daily saline-pretreated animals is that this
manipulation may produce a sensitization of mPFC dopamine to subsequent
cocaine. Evidence points to a role for mPFC dopamine in the acquisition
of a coping response (D'Angio et al., 1988; Deutch and
Young, 1995). Therefore, rats given repeated daily handling and
injections of saline may represent fully adapted animals that exhibit
the greatest response to a subsequent novel stimulus such as cocaine or
footshock. The lack of adaptation to the handling and injection
procedures in naive rats or maladaptation in daily cocaine-pretreated
rats may suppress this coping response. Although the mPFC dopamine
responses to a cocaine challenge were similar in naive and daily
cocaine-treated rats, this finding does not imply that naive and daily
cocaine-treated animals are identical with regard to the mPFC. For
example, recent in vitro data indicate that the rate of
dopamine uptake in the mPFC is increased in daily cocaine-pretreated
rats, compared with saline-pretreated or naive animals (Meiergerd
et al., 1996).
Repeated cocaine treatment in rodents has served as an animal model for
cocaine-induced psychosis and schizophrenia. The present data may have
implications for the observed hypodopaminergic function in the
prefrontal cortex of individuals presenting with negative symptoms of
schizophrenia (Kahn and Davis, 1995). Another animal model of psychosis
has been developed in which the ventral hippocampus is lesioned in rats
(Lipska and Weinberger, 1993). One of the manifestations of such
lesions is decreased mPFC dopamine turnover (Lipska et al.,
1992). Thus, it has been posited that idiopathic and drug-induced
psychoses alter the function of subcortical sites via
altered cortical regulation. The site of initiation may be different
with idiopathic psychosis occurring as a result of hippocampal damage,
whereas cocaine- or stress-induced psychosis may be initiated via altered prefrontocortical function (P. W. Kalivas and B. A. Sorg, submitted).
Summary and conclusions.
The results from the present study
suggest that 1) mesoprefrontal dopamine neurons in cocaine-sensitized
rats demonstrate tolerance to the effects of subsequent systemic
cocaine, but not systemic amphetamine, compared with saline controls,
2) the tolerance is not due to decreased releasability of dopamine from
mPFC terminals, as determined by local mPFC infusion of KCl or
amphetamine through the dialysis probe, and 3) local infusion of
cocaine through the dialysis probe into the mPFC does not mimic the
effects of systemic cocaine but tends toward the opposite response. The
present results, together with previous observations (Sorg and Kalivas,
1993), suggest that tolerance of mPFC dopamine is detected only when the expression depends primarily on impulse-mediated increases in
extracellular dopamine concentrations. The inability to mimic systemic
cocaine effects with local mPFC cocaine infusion further supports the
idea that tolerance of mPFC dopamine in response to systemic cocaine
injection is mediated by afferents to mesocortical dopamine neurons.
The suppression of the mPFC dopamine response in the present study
vs. the sensitization of this pathway previously reported in
amphetamine-sensitized animals indicates that the mPFC dopamine
response to subsequent stimuli may depend on the sensitizing stimulus.
Differential responsiveness of mesocortical neurons to amphetamine and
cocaine may lead to clues regarding mechanisms triggering the
development of dopamine neuron sensitization.
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Acknowledgments |
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The authors thank Dr. Bryan K. Slinker (Washington State University) for helpful discussions regarding statistical analysis of the data.
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Footnotes |
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Accepted for publication December 9, 1996.
Received for publication January 17, 1996.
1 This work was supported by United States Public Health Service Grants DA08212 (B.A.S.), DA03906 and MH40817 and Research Career Development Award DA00153 (P.W.K.).
Send reprint requests to: Barbara A. Sorg, Program in Neuroscience, Department of VCAPP, Washington State University, Pullman, WA 99164-6520.
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Abbreviations |
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ANOVA, analysis of variance; CSF, cerebrospinal fluid; EAA, excitatory amino acid; mPFC, medial prefrontal cortex; VTA, ventral tegmental area.
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References |
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Abstract
Introduction
Methods
Results
Discussion
References
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-endorphin release in rats previously sensitized to amphetamine.
Neuropharmacol.
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