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Vol. 281, Issue 2, 699-706, 1997
Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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It is well established that behavioral sensitization to psychomotor
stimulants is associated with adaptations in the mesoaccumbens dopamine
(DA) system. We showed previously that the responsiveness of ventral
tegmental area (VTA) DA neurons to glutamate was significantly enhanced
in amphetamine- and cocaine-pretreated rats tested after 3 days of
withdrawal, which suggests that adaptations in excitatory amino acid
transmission also contribute to sensitization. The purpose of the
present study was to determine the subtype of excitatory amino acid
receptor responsible for this effect and to examine its persistence
during withdrawal. Extracellular single cell recording and
microiontophoresis were used to investigate possible alterations in the
ability of glutamate agonists
[(S)-
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), and
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-t-ACPD)] to stimulate the
firing of VTA DA neurons after 3 days of withdrawal from repeated
administration of saline, cocaine or amphetamine. Current-response
curves showed that responses to iontophoretic AMPA, but not NMDA or
1S,3R-t-ACPD were
significantly enhanced in cocaine- or amphetamine-pretreated rats in
that neurons entered into a state of apparent depolarization block at
significantly lower iontophoretic currents. When rats were tested for
responsiveness to iontophoretic glutamate after 14 days of withdrawal,
there was no significant difference between cocaine- or amphetamine- and saline-pretreated rats with respect to glutamate current-response curves. These results suggest that increased responsiveness of AMPA
receptors on VTA DA neurons may contribute to sensitization at early
withdrawal times, but that this alteration, like others described
within the VTA, is transient.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Repeated administration of
psychomotor stimulants leads to sensitization (augmentation) of their
locomotor stimulatory effects (Robinson and Becker, 1986
; Kalivas and
Stewart, 1991). Although the ventral striatal region known as the
nucleus accumbens is clearly the major site involved in
stimulant-induced locomotion (Jackson et al., 1975;
Pijnenburg et al., 1976) and in the expression of
sensitization (Paulson and Robinson, 1991; Cador et al.,
1995), the processes responsible for the initiation of the
sensitization process appear to occur within the midbrain VTA (Kalivas
and Weber, 1988; Vezina and Stewart, 1990; Cador et al.,
1995; Perugini and Vezina, 1994), the site of DA perikarya which give
rise to the mesoaccumbens DA system. The precise neuroadaptations that
induce behavioral sensitization remain to be elucidated. Most evidence implicates alterations in the functioning of DA neurons, including subsensitivity of DA D2-like receptor autoregulation of impulse activity (Kamata and Rebec, 1984; White and Wang, 1984; Henry et
al., 1989; Ackerman and White, 1990), enhancement of the basal firing activity of the DA neurons (White and Wang, 1984; Henry et
al., 1989) and increased release of dendritic DA in VTA (Kalivas and Duffy, 1993b), effects that are probably inextricably related to
one another (Wolf et al., 1993, 1994).
However, recent discoveries have placed a new emphasis on the potential
role of EAAs in the initiation of behavioral sensitization. Many
studies have shown that NMDA receptor antagonists prevent the
development of sensitization when coadministered repeatedly with
amphetamine or cocaine (Karler et al., 1989, 1990, 1991, 1994; Wolf and Khansa, 1991; Kalivas and Alesdatter, 1993; Stewart and
Druhan, 1993; Wolf and Jeziorski, 1993; Haracz et al., 1995; Ida et al., 1995; Shoaib et al., 1995; Wolf
et al., 1995; Kim et al., 1996), as well as with
methamphetamine (Ohmori et al., 1994) or morphine (Wolf and
Jeziorski, 1993; Jeziorski et al., 1994). MK-801 also blocks
cellular changes in the mesoaccumbens DA system that normally accompany
the development of behavioral sensitization (Wolf et al.,
1994). AMPA receptors may also be involved in the initiation of
behavioral sensitization, although there may be differences between
stimulants and between mice and rats (Karler et al., 1991,
1994; Pierce et al., 1996; Li et al., 1996).
Because sensitization is initiated in the VTA and can be prevented by
intra-VTA administration of NMDA antagonists (Kalivas and Alesdatter,
1993), it is plausible that alterations in glutamate receptor function
in the VTA play an important role in the sensitization process. In a
previous study, we demonstrated that repeated administration of cocaine
or amphetamine resulted in enhanced responsiveness of VTA DA neurons to
iontophoretic application of glutamate, whereas nucleus accumbens
neurons exhibited subsensitivity to glutamate's excitatory effects
(White et al., 1995b). Repeated cocaine administration has
been found to increase levels of the AMPA receptor subunit GluR1 and
the NMDA receptor subunit NR1 in the VTA (Fitzgerald et al.,
1996), effects which may be related to the increased
electrophysiological responsiveness to glutamate in the VTA. The
present study sought to identify the EAA receptor subtype(s)
responsible for increased responsiveness to glutamate, using
iontophoretic application of NMDA, AMPA and the metabotropic glutamate
receptor agonist 1S,3R-t-ACPD. In addition,
because sensitization is known to involve different cellular
alterations at short and long withdrawals (e.g., Wolf et al., 1993), we determined whether enhanced responsiveness
to glutamate persisted 14 days after the termination of repeated cocaine or amphetamine administration.
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Methods |
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Abstract
Introduction
Methods
Results
Discussion
References
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Animals and drug treatment.
All procedures were performed in
strict accordance with the Guide for the Care and Use of Laboratory
Animals as adopted and promulgated by the National Institutes of Health
and were approved by the Institutional Animal Care and Use Committee of
the Chicago Medical School. Male Sprague-Dawley rats (Harlan,
Indianapolis, IN), weighing 225 to 249 g at the start of
experiments, were used in all studies. Rats were housed two per cage
with free access to food and water in a colony room maintained under
constant temperature (21-23°C) and humidity (40-50%) on a 12-hr
light/dark schedule (7:00 A.M., on; 7:00 P.M.,
off). There were at least 3 days of habituation to the colony before
any treatment began. Each rat received i.p. injections of either
cocaine HCl (15.0 mg/kg), d-amphetamine sulfate (5.0 mg/kg)
or saline (1.0 ml/kg) once daily for 5 consecutive days, with all
injections administered in home cages. These treatment regimens have
been demonstrated previously to produce robust behavioral sensitization
(Kalivas and Duffy, 1993a; Wolf and Jeziorski, 1993).
Surgery.
Each rat, on either the third or fourteenth day
after the last injection of the treatment regimen, was anesthetized
with chloral hydrate (400 mg/kg i.p.) and mounted in a stereotaxic
frame. Body temperature was maintained at 36-37°C with a
thermostatically controlled heating pad. A tail vein was catheterized
for administration of additional anesthetic as needed. A burr hole was
drilled in the skull and the dura was retracted from the area overlying
the VTA (A 3.0-3.5, L 0.5-1.0, V 6.5-8) (Paxinos and Watson, 1986).
Single-unit recording and microiontophoresis.
Procedures for
extracellular recording from VTA DA neurons have been detailed
previously (Henry et al., 1989). Five barrel glass
micropipettes were pulled and broken back under a microscope to achieve
a tip diameter of approximately 4 to 7 µm. The center recording
barrel of each micropipette was filled with 2 M NaCl saturated with 1%
Fast Green dye (2-5 megohm impedance). One side barrel of the
micropipette was filled with 2 M NaCl for automatic current balancing,
whereas the remaining side barrel contained combinations of the
following drugs: AMPA (0.01 M, pH 8), NMDA (0.1 M, pH 8),
1S,3R-t-ACPD (0.01 M, pH 8) or
l-glutamate acid monosodium salt (GLU; 0.1 M, pH 8).
Retaining currents of +8 to +10 nA were applied to drug barrels (20-70
megohm impedance) between ejection periods. Electrical signals were
passed through a high-impedance amplifier and displayed on an
oscilloscope. Individual action potentials were discriminated,
monitored with an audio amplifier and digitized for off-line analysis.
; Wang, 1981). Each neuron was recorded for 3 to 5 min to establish a stable base-line firing rate. Glutamate agonists were then administered iontophoretically for a 40-sec period.
At the end of that 40-sec period, the current applied to the drug
barrel was doubled until the cell entered a state of apparent
depolarization block. This state was defined as a loss of detectable
activity after increases in firing rate accompanied by burst firing,
diminished spike amplitude and increased spike duration (Grace and
Bunney, 1986). For purposes of quantifying the number of neurons in a
state of apparent depolarization block at each iontophoretic current of
glutamate agonist, we operationally defined this state as follows:
drug-induced firing rate below 50% of the maximal firing rate during
the 40-sec iontophoretic application of a particular drug current, with
continued decline to the point of inactivity at higher currents (White
et al., 1995b). Once this state of inactivity was achieved,
no additional currents were tested and the cell was then assigned a
firing rate of "0" for all higher currents. All cells used in this
study recovered fully from apparent depolarization block when glutamate
agonist iontophoresis was discontinued.
Histology. At the end of the experiment, the final recording site was marked by passing a 25 nA cathodal current through the recording barrel for 20 min to deposit a spot of Fast Green dye. The rat was then perfused with saline followed by 10% buffered formalin for 15 min. Serial coronal sections were cut at 50-µm intervals and stained with cresyl violet and neutral red. The Fast Green dye spot served as a reference point to extrapolate the location of other recorded cells. All cells included in the present analysis were confirmed to lie within the VTA.
Drugs. (+)-Amphetamine sulfate was provided by the Research Technology Branch of the National Institute on Drug Abuse. (±)-Cocaine hydrochloride was obtained from Sigma (St Louis, MO). AMPA, NMDA and 1S,3R-t-ACPD were obtained from Research Biochemicals International (Natick, MA). Doses refer to salt weights.
Statistical analysis.
Data were analyzed either with
Student's t test or two-way ANOVA with repeated measures on
one variable (iontophoretic current). Subsequent planned comparisons
between treatment and control means were conducted with Dunnett's test
with = 0.05. Tests for significance between two proportions were
conducted with the Fisher's exact probability test.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Responses of VTA DA neurons to AMPA.
In saline-pretreated
(control) rats, iontophoretically applied AMPA, at currents of 1 to 4 nA, caused a current-dependent increase in the firing rate of VTA DA
neurons (figs. 1A1 and 2A). As the
iontophoretic current increased further, DA neurons began to fire in
bursts, with decreasing spike amplitude and increasing waveform
duration. Finally, they entered a state of apparent depolarization block (Grace and Bunney, 1986), as defined operationally under "Methods."
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Responses of VTA DA neurons to NMDA. Iontophoretic administration of NMDA, at currents of 1 to 4 nA, caused a current-dependent increase in the firing rates of VTA DA neurons in all three groups. At currents of 8 nA or more, NMDA drove the neurons into a state of apparent depolarization block (figs.1A2, 1B2, 1C2 and 2B). The number of neurons entering depolarization block at each current was similar in all groups (fig. 2B). ANOVA revealed no significant differences in the current-response curves between the control group and either the cocaine (F1,25 = 0.26, P = .62) or amphetamine (F1,22 = 0.98, P = .33) groups.
Responses of VTA DA neurons to 1S,3R-t-ACPD. Iontophoretic administration of the metabotropic glutamate receptor agonist 1S,3R-t-ACPD, at currents of 1 to 128 nA, caused a current-dependent increase in the firing rate of VTA DA neurons in all three groups (figs. 1A3, 1B3, 1C3 and 2C). This effect was considerably less robust than that observed in response to NMDA or AMPA, and depolarization block was never observed. Neurons returned immediately to their base-line firing rates after ejection of 1S,3R-t-ACPD was discontinued. ANOVA revealed no significant differences in current-response curves between the control group and cocaine (F1,27 = 0.024, P = .85) or amphetamine (F1,26 = 0.13, P = .72) groups.
Responses of VTA DA neurons to glutamate after 14 days of
withdrawal from repeated cocaine or amphetamine.
In all
experiments described above, as well as our previous report that
responsiveness to iontophoretic glutamate was enhanced in VTA DA
neurons recorded from amphetamine- or cocaine-pretreated rats (White
et al., 1995b), electrophysiological recordings were performed 3 days after the last injection of psychomotor stimulant. To
examine the persistence of altered responsiveness, responses of VTA DA
neurons to glutamate were examined after 14 days of withdrawal from
treatment with saline, cocaine or amphetamine. In all three groups,
currents of 1 to 4 nA caused a current-dependent increase in firing
rate, whereas higher currents (8 nA or more) drove neurons into a state
of apparent depolarization block (figs. 3 and
4). ANOVA revealed no significant differences in
current-response curves between the control and cocaine
(F1,27 = 0.068, P = .89) or amphetamine
(F1,26 = 0.41, P = .54) groups. These
findings suggest that psychomotor stimulant-induced alterations in the responsiveness of VTA DA neurons to glutamate are relatively transient in nature. Additional studies demonstrated that VTA DA neurons recorded
after 14 days of withdrawal from cocaine or amphetamine also failed to
exhibit alterations in responsiveness to iontophoretic application of
AMPA or NMDA (data not shown).
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We showed previously that repeated administration of psychomotor
stimulants increased the responsiveness of VTA DA neurons to glutamate
in that neurons entered a state of apparent depolarization inactivation
(or block) at lower iontophoretic ejection currents of glutamate (White
et al., 1995b). In the present study, we determined the
subtype(s) of glutamate receptors involved in the alteration. After a
3-day withdrawal from repeated administration of cocaine or
amphetamine, VTA DA neurons were significantly more likely to enter a
state of apparent depolarization block during administration of AMPA.
No differences in responsiveness to NMDA or the metabotropic glutamate
agonist 1S,3R-t-ACPD were found between saline-
and stimulant-pretreated rats. These findings suggest that the lower threshold for induction of depolarization block in stimulant-pretreated rats is caused by alterations in AMPA receptor responsiveness. In
additional experiments, we found that responsiveness of VTA DA neurons
to iontophoretic glutamate had returned to normal after 14 days of
withdrawal from amphetamine or cocaine.
Repeated cocaine or amphetamine selectively alters responsiveness
to AMPA.
In saline-pretreated rats, VTA DA neurons exhibited
excitation after iontophoretic administration of AMPA, NMDA and the
metabotropic glutamate receptor agonist
1S,3R-t-ACPD, consistent with previous reports that all three glutamate receptor subtypes are present on
midbrain DA neurons (Seutin et al., 1990; Mereu et
al., 1991; Mercuri et al., 1992, 1993; Overton and
Clark, 1992; Wang and French, 1993a, b; Wu et al., 1994;
Zhang et al., 1994). Our results demonstrate a selective
alteration in the responsiveness to AMPA in VTA DA neurons recorded 3 days after withdrawal from repeated cocaine or amphetamine. The major
effect was decreased threshold for induction of apparent depolarization
inactivation in response to iontophoretic application of AMPA, as was
reported previously for iontophoretic application of glutamate (White
et al., 1995b). Why was increased responsiveness to AMPA
manifest as a change in threshold for depolarization inactivation? As
illustrated by figure 2, DA neurons are firing at almost maximal rates
in the absence of iontophoretic drug application, presumably in
response to endogenous glutamatergic drive. Because responses to
iontophoretic AMPA are superimposed on this endogenous drive, AMPA
produces only small increases in firing rate before driving cells into depolarization inactivation. Under such conditions, it is not surprising that a change in responsiveness to iontophoretic AMPA was
most evident at the high end of the current-response relationship, that
is, at currents capable of eliciting depolarization inactivation.
, b)
showed that low concentrations of glutamate excite VTA DA neurons via a preferential effect on the NMDA receptor, with AMPA
receptors coming into play only at higher glutamate concentrations.
These investigators also demonstrated concentration-dependent biphasic effects of AMPA and NMDA, with low concentrations depolarizing and
activating VTA DA neurons and high concentrations inducing depolarization block (Wang and French, 1993a, b; Wang et
al., 1994). Such findings are consistent with our results
regarding alterations in the effects of EAAs after chronic treatment
with psychomotor stimulants. Thus, if only AMPA receptors are altered by repeated administration of amphetamine or cocaine, one would expect
no alteration in the rate-enhancing effects of low glutamate currents
(mediated by NMDA receptors), but significant alteration in the
response to higher iontophoretic glutamate currents (mediated by AMPA
receptors), as was observed with iontophoretic glutamate administration
in our previous study (White et al., 1995b). Interestingly, when AMPA was used as the iontophoretically applied agonist, VTA DA
neurons in stimulant-pretreated rats showed a trend toward increased
responsiveness to the rate-enhancing effects of low iontophoretic
currents, as well as lower threshold for induction of depolarization
block (fig. 2). This is presumably because AMPA receptors are mediating
both components of the response in stimulant-pretreated rats because of
increased AMPA receptor sensitivity.
Increased responsiveness of VTA DA neurons to AMPA is
transient.
Previous work has established that the induction and
maintenance of behavioral sensitization is a complex process, with
different cellular alterations contributing at different times. At
short withdrawal times, cellular alterations in the VTA predominate, consistent with studies establishing VTA as the site of initiation of
sensitization (Kalivas and Weber, 1988; Vezina and Stewart, 1990; Cador
et al., 1995; Perugini and Vezina, 1994). Such alterations are generally transient. For example, psychomotor stimulant-induced subsensitivity of impulse-modulating somatodendritic DA autoreceptors is obvious at short withdrawal times (1-3 days), is less evident at
intermediate withdrawal times (5-8 days) and is absent at longer withdrawal times (10-14 days) (White and Wang, 1984; Ackerman and
White, 1990; Wolf et al., 1993). Decreased VTA levels of the inhibitory G-protein subunits Gi
and
Go have been observed in chronic
cocaine-treated rats 1 or 6 hr, but not 24 hr, after discontinuing
daily injections (Nestler et al., 1990; Striplin and
Kalivas, 1992). Basal extracellular DA levels in the VTA are elevated
in cocaine- compared with saline-pretreated rats when measured 1 day
after discontinuing daily treatments, but not after 14 days (Kalivas
and Duffy, 1993b). These various measures are probably related to each
other, and to the increase in basal DA cell firing rate observed after
short withdrawals from repeated administration of amphetamine or
cocaine (White and Wang, 1984; Henry et al., 1989). Our
failure to observe increased basal firing rates in the present study
likely relates to the larger sample size and shorter withdrawal periods
used in these previous studies (White and Wang, 1984; Henry et
al., 1989).
; Henry et
al., 1989). On the other hand, decreased inhibitory tone caused by
DA autoreceptor subsensitivity might lead to an apparent increase in
responsiveness to the excitatory transmitter glutamate. This is
unlikely to account completely for the change in glutamate
responsiveness, because Fitzgerald et al. (1996) have found
increased levels of the NMDA subunit NR1 and the AMPA receptor subunit
GluR1 in the VTA after 1 day of withdrawal from repeated cocaine
administration. The elevation in GluR1 levels could contribute to the
observed increase in electrophysiological responsiveness to AMPA
reported herein. Our failure to observe a change in responsiveness to
NMDA after a 3-day withdrawal may suggest that the increase in NR1
levels is less persistent than that of GluR1, that the increase in NR1 levels occurs in non-DA neurons within the VTA or that the increase in
NR1 levels is not sufficient to increase responsiveness of the
population of oligomeric NMDA receptors on VTA DA neurons. Taken
together, the available evidence suggests that both DA and EAA receptor
mechanisms in VTA are altered by repeated stimulant administration.
Such alterations are likely to be interrelated, given that EAA receptor
blockers prevent the development of DA autoreceptor subsensitivity
(Wolf et al., 1994) and that the level of EAA receptor
stimulation can regulate DA D2 receptor expression (Healy and
Meador-Woodruff, 1996; Nair et al., 1996).
The mechanism by which repeated psychomotor stimulant administration
might alter AMPA receptor expression or receptor sensitivity is
unknown. However, cocaine and amphetamine have been reported to
increase extracellular glutamate levels in the VTA (Kalivas and Duffy,
1995; Xue et al., 1996). It is possible that repeated elevation of glutamate levels in the VTA, upon repeated stimulant injection, results in compensatory alterations in EAA receptor function.
Role of AMPA receptors in behavioral sensitization.
Much
evidence is consistent with the idea that excitatory tone to VTA DA
neurons is increased shortly after discontinuation of repeated
psychomotor stimulant administration. As discussed above, increased
excitatory tone could account for increased basal activity of DA cells
and increased somatodendritic DA release. Does increased excitatory
tone play a role in the development of sensitization? Perhaps it does,
given that: 1) disinhibition of VTA DA cells by uncoupling inhibitory
DA and GABAB receptors from associated G-proteins with
pertussis toxin results in an augmented locomotor response to cocaine
(Steketee and Kalivas, 1991); and 2) repeated electrical stimulation of
the VTA elicits locomotor sensitization to amphetamine (Ben-Shahar and
Ettenberg, 1994).
, argue that up-regulation of EAA receptors in VTA may be a mechanism underlying increased tonic excitation of VTA DA neurons.
Indeed, midbrain DA neurons in amphetamine-pretreated rats show
enhanced reactivity to electrical stimulation of the prefrontal cortex,
which sends EAA-containing projections to the VTA (Tong et
al., 1995). Interestingly, the latter study reported different
changes at 2 and 10 days of withdrawal, although both were consistent
with increased excitability of DA neurons. It is also possible that
alterations in the activity of prefrontal cortical neurons that project
to VTA contribute to the postulated increase in excitatory tone (White
et al., 1995a). However, even if this is not the case and
alterations occur exclusively at the level of EAA receptor expression
by VTA DA neurons, excitatory inputs originating in the prefrontal
cortex are likely to provide the stimulation needed for the expression
of such alterations. Thus, locomotor sensitization is prevented by
interruption of the prefrontal cortex-VTA pathway, whether by intra-VTA
administration of NMDA antagonists (Kalivas and Alesdatter, 1993) or by
ibotenic acid lesions of the prefrontal cortex (Wolf et al.,
1995; Li and Wolf, 1997). Conversely, electrical kindling of the
prefrontal cortex results in behavioral sensitization to cocaine
(Schenk and Snow, 1994). These reports are consistent with the
important role of prefrontal cortical afferents in regulating the
firing pattern and activity of VTA DA neurons (Gariano and Groves,
1988; Murase et al., 1993; Svensson and Tung, 1989; Tong
et al., 1996).
Psychomotor stimulants are known to inhibit the firing of VTA DA
neurons by increasing somatodendritic DA levels and thereby activating
impulse-modulating DA autoreceptors (see Wolf and Roth, 1987; White,
1996 for reviews). Is this inconsistent with the hypothesis that
sensitization requires increased excitatory tone to VTA DA neurons? Not
necessarily. Although the acute effect of elevation of VTA DA levels by
psychomotor stimulants may be inhibition of DA cell firing, their acute
administration also leads to rapid desensitization of DA autoreceptors
(Seutin et al., 1991). With chronic administration of
psychomotor stimulants, the duration of DA autoreceptor desensitization
is prolonged (see above). This, along with other compensatory changes,
including increased responsiveness to AMPA, leads to increases in
excitatory drive during the time between repeated injections of
psychomotor stimulants, as evidenced by increased basal firing rates of
VTA DA neurons after short withdrawals from repeated stimulant
administration (White and Wang, 1984; Henry et al., 1989).
Many lines of evidence argue that transient changes in VTA observed at
short withdrawals, all of which are consistent with increased
excitatory drive to VTA DA cells (see above), are necessary
prerequisites for the induction of longer lasting changes in the
nucleus accumbens that may underlie the persistence of behavioral
sensitization. For example, several previous studies have suggested
that autoreceptor subsensitivity must occur, albeit transiently, for D1
receptor supersensitivity in nucleus accumbens to show persistence
(e.g., see Ackerman and White, 1990; Wolf et al.,
1994). Those who argue against a role for DA autoreceptor
subsensitivity in the initiation of sensitization, based on the
inability of D2 receptor antagonists to prevent its development (Vezina
and Stewart, 1989; Bjijou et al., 1996), have overlooked the
fact that D2 receptor antagonists also disinhibit the activity of VTA
DA neurons (see White,1996, for review).
The major difference observed in VTA DA neurons recorded from cocaine-
or amphetamine-pretreated rats in the present study was increased
sensitivity to depolarization block. How might this be related to the
function of VTA DA neurons and to psychomotor stimulant withdrawal?
Midbrain DA neurons respond to salient (motivationally arousing)
environmental stimuli with transient bursts of impulses that are
thought to contribute to the setting of a motivational state by
alerting other neuronal systems, in particular the nucleus accumbens,
that subserve reward-seeking and goal-directed activity (Schultz and
Romo, 1990). Increased sensitivity to depolarization block, perhaps in
response to alterations in cortical drive, would render DA neurons less
capable of communicating information about salient stimuli to their
targets. This, in turn, might render rats less responsive to their
environment. This could be related to the reduced motivation, anergia
and anhedonia observed in humans during withdrawal from psychomotor
stimulant addiction (Gawin and Ellinwood, 1988; Gawin, 1991).
Because increased sensitivity to glutamate-mediated depolarization
inactivation is a transient effect, it is likely involved only in
behavioral alterations accompanying short withdrawals (see above), or
perhaps also in the "transfer" of sensitization to the nucleus
accumbens, where it is expressed (Paulson and Robinson, 1991; Cador
et al., 1995). However, it is possible that alterations in
EAA transmission elsewhere in brain contribute, albeit via different mechanisms and circuits, to behavioral effects at longer withdrawals. Thus, recent reports suggest that repeated administration of psychomotor stimulants can lead to long-lasting changes in EAA
systems. For example, repeated administration of low-dose methamphetamine results in enhancement of K+-stimulated
glutamate efflux in prefrontal cortex measured after 7 days of
withdrawal (Stephans and Yamamoto, 1995). Alterations in the effect of
cocaine on glutamate efflux in nucleus accumbens core, and in
behavioral effects of intra-nucleus accumbens injections of AMPA and
the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), have been demonstrated after 21 days of withdrawal from repeated cocaine (Pierce et al., 1996). We have found
decreased levels of mRNA for the AMPA receptor subunits GluR1 and GluR2 in the nucleus accumbens after 14 days, but not 3 days, of withdrawal from repeated amphetamine (Lu et al., in press). Thus,
stimulant-induced alterations in EAA transmission may contribute to
both the development and the persistence of behavioral sensitization.
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Acknowledgments |
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The authors gratefully acknowledge Nha Lien and Pamela Alvarcz for technical assistance.
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Footnotes |
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Accepted for publication January 30, 1997.
Received for publication September 13, 1996.
1 This work was supported by U.S. Public Health Service Grants DA07735 and DA09621 (to M.E.W.) and by DA04093 and Research Scientist Development Award DA00207 (to F.J.W.).
Send reprint requests to: Marina E. Wolf, Ph.D., Department of Neuroscience, FUHS/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064.
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Abbreviations |
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1S, 3R-t-ACPD,
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
acid;
AMPA, (S)--amino-3-hydroxy-5-methyl-4-isoxazole
propionate;
DA, dopamine;
NMDA, N-methyl-D-aspartate;
VTA, ventral tegmental area;
ANOVA, analysis of variance;
EAA, excitatory
amino acid.
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References |
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Abstract
Introduction
Methods
Results
Discussion
References
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and Go in discrete regions of rat brain.
J. Neurochem.
55: 1079-1082, 1990[Medline].This article has been cited by other articles:
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 C.-C. Huang, H.-J. Lin, and K.-S. Hsu Repeated Cocaine Administration Promotes Long-Term Potentiation Induction in Rat Medial Prefrontal Cortex Cereb Cortex, August 1, 2007; 17(8): 1877 - 1888. [Abstract] [Full Text] [PDF]
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 S. N. Blythe, J. F. Atherton, and M. D. Bevan Synaptic Activation of Dendritic AMPA and NMDA Receptors Generates Transient High-Frequency Firing in Substantia Nigra Dopamine Neurons In Vitro J Neurophysiol, April 1, 2007; 97(4): 2837 - 2850. [Abstract] [Full Text] [PDF]
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 J. McDaid, M. P. Graham, and T. C. Napier Methamphetamine-Induced Sensitization Differentially Alters pCREB and {Delta}FosB throughout the Limbic Circuit of the Mammalian Brain Mol. Pharmacol., December 1, 2006; 70(6): 2064 - 2074. [Abstract] [Full Text] [PDF]
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C. C. Canavier and R. S. Landry An Increase in AMPA and a Decrease in SK Conductance Increase Burst Firing by Different Mechanisms in a Model of a Dopamine Neuron In Vivo J Neurophysiol, November 1, 2006; 96(5): 2549 - 2563. [Abstract] [Full Text] [PDF]
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 J. McDaid, J. E. Dal |
