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Volume 17, Number 21,
Issue of November 1, 1997
pp. 8491-8497
Copyright ©1997 Society for Neuroscience
Persistent Structural Modifications in Nucleus Accumbens and
Prefrontal Cortex Neurons Produced by Previous Experience with
Amphetamine
Terry E. Robinson1 and
Bryan Kolb2
1 Department of Psychology and Neuroscience Program,
The University of Michigan, Ann Arbor, Michigan 48109, and
2 Department of Psychology, University of Lethbridge,
Lethbridge, Alberta T1K 3M4, Canada
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Experience-dependent changes in behavior are thought to involve
structural modifications in the nervous system, especially alterations
in patterns of synaptic connectivity. Repeated experience with drugs of
abuse can result in very long-lasting changes in behavior, including a
persistent hypersensitivity (sensitization) to their psychomotor
activating and rewarding effects. It was hypothesized, therefore, that
repeated treatment with the psychomotor stimulant drug amphetamine,
which produces robust sensitization, would produce structural
adaptations in brain regions that mediate its psychomotor activating
and rewarding effects. Consistent with this hypothesis, it was found
that amphetamine treatment altered the morphology of neurons in the
nucleus accumbens and prefrontal cortex. Exposure to amphetamine
produced a long-lasting (>1 month) increase in the length of
dendrites, in the density of dendritic spines, and in the number of
branched spines on the major output cells of the nucleus accumbens, the
medium spiny neurons, as indicated by analysis of Golgi-stained
material. Amphetamine treatment produced similar effects on the apical
(but not basilar) dendrites of layer III pyramidal neurons in the
prefrontal cortex. The ability of amphetamine to alter patterns of
synaptic connectivity in these structures may contribute to some of the
long-term behavioral consequences of repeated amphetamine use,
including amphetamine psychosis and addiction.
Key words:
amphetamine;
sensitization;
Golgi staining;
nucleus
accumbens;
prefrontal cortex;
plasticity;
psychostimulant drugs
INTRODUCTION
The repeated intermittent
administration of many drugs of abuse results in a progressive increase
in their psychomotor activating and rewarding effects, a phenomenon
known as behavioral sensitization (Segal and Schuckit, 1983
; Robinson
and Becker, 1986; Robinson and Berridge, 1993). Behavioral
sensitization is interesting for at least two reasons. First, it is a
compelling example of experience-dependent plasticity. Sensitized
animals remain hypersensitive to the psychomotor activating and
rewarding effects of drugs for months to years (Paulson et al., 1991;
Valadez and Schenk, 1994). Second, the neuroadaptations that underlie
behavioral sensitization may contribute to drug-induced
psychopathology in humans (Segal and Schuckit, 1983; Robinson and
Becker, 1986; Robinson and Berridge, 1993; Berridge and Robinson,
1995).
The psychomotor activating and rewarding effects of psychostimulant
drugs are mediated by their actions on the nucleus accumbens or related
circuitry, especially afferents arising from dopamine-containing cells
in the ventral tegmental area and glutamate-containing cells in the
prefrontal cortex (Wise and Bozarth, 1987; Koob and Bloom, 1988;
Carlezon and Wise, 1996). For this reason, studies on the neurobiological basis of behavioral sensitization have focused on the
accumbens system. A number of neurochemical and neurophysiological correlates have been found, including an increase in the ability of
amphetamine, cocaine, or morphine to enhance the overflow of dopamine
in the nucleus accumbens (Robinson and Becker, 1986; Kalivas and
Stewart, 1991) and dopamine D1 receptor hypersensitivity (Henry and White, 1991; White and Wolf, 1991). However,
experience-dependent changes in behavior that can persist for months,
years, or a lifetime may not be mediated simply by changes in
neurotransmitter dynamics or receptor characteristics, because of the
rapid turnover of proteins involved in these processes (Greenough,
1984). Researchers who study other forms of experience-dependent
plasticity, such as that involved in learning, environmental
enrichment, or recovery of function, have emphasized that truly
persistent alterations in behavior are probably mediated by structural
modifications in neural circuitry, especially alterations in patterns
of synaptic connectivity (Greenough, 1984; Greenough and Bailey, 1988;
Kolb et al., 1997b).
Thus, the purpose of the experiment reported here was to determine
whether an amphetamine treatment regimen known to produce robust and
persistent behavioral sensitization would produce structural modifications in the nervous system similar to those seen in
association with other forms of experience-dependent plasticity.
Because the behaviors that are sensitized by amphetamine are mediated
in part by drug actions in the nucleus accumbens and prefrontal cortex, we hypothesized that neurons in these brain regions would be affected. A common approach to examine the impact of experience on synaptic organization is to use Golgi-stained material to quantify the structure
of dendrites (Greenough, 1984; Greenough et al., 1990; Kolb et al.,
1997b). In adult animals there is a good relationship between the
dendritic surface available for synapses and the number of synapses on
a neuron (Greenough and Chang, 1988; Harris and Kater, 1994; Purves,
1994). Therefore, we used this method to quantify the effect of
repeated amphetamine treatment on the dendritic structure of medium
spiny neurons in the nucleus accumbens and layer III pyramidal neurons
in the prefrontal cortex, the major output neurons in these brain
regions.
MATERIALS AND METHODS
Male Sprague Dawley rats weighing 255-355 gm were housed
individually with food and water available ad libitum. Half
of the animals (n = 5) were pretreated with
D-amphetamine sulfate using an escalating-dose regimen
similar to that described previously (Paulson et al., 1991). Each rat
received two intraperitoneal injections per day, ~8 hr apart, for 5 consecutive days, followed by 2 drug-free days for a total of 5 weeks,
beginning with 1 mg/kg (weight of the salt) and escalating to 8 mg/kg
for the last 4 d of treatment. Control animals (n = 5) received 0.9% saline. All injections were given in the home cage.
The animals were then left undisturbed for 38 d.
This treatment regimen was used because we have characterized its
behavioral effects and some of its neurochemical effects in a series of
previous studies (Robinson and Camp, 1987; Paulson et al., 1991;
Paulson and Robinson, 1995, 1996). This treatment regimen produces very
robust behavioral sensitization that persists for up to 1 year after
the discontinuation of drug treatment. It is also important to note
that it is not neurotoxic to dopamine neurons, as is the case with
continuous amphetamine administration or with much higher dose
regimens. As might be expected, amphetamine neurotoxicity is associated
with signs of cellular degeneration (Ricaurte et al., 1982; Ryan et
al., 1990).
Thirty-eight days after the last treatment with amphetamine or saline,
the rats were deeply anesthetized with sodium pentobarbital and then
were perfused intracardially with 0.9% saline. The brains were removed
and prepared for Golgi-Cox staining. Traditional Golgi-Cox methods
provide capricious staining of spines, but the modified method used
here allows consistent visualization of spines (Kolb and McClimans,
1986; Kolb et al., 1997a). Briefly, the brains were first placed in
Golgi-Cox solution for 14 d followed by 3 d in 30% sucrose.
They then were cut into 200 µm coronal sections using a vibratome and
stained (Kolb and McClimans, 1986). To be included in the analysis, the
dendritic tree of a cell had to be well impregnated and not obscured
with stain precipitations, blood vessels, or astrocytes, and the
dendritic fields had to appear primarily intact and visible in the
plane of section. The relevant brain regions were identified at low
power (100×), and five layer III pyramidal cells from each hemisphere
were drawn using a camera lucida (at 250×) in cortical areas Cg 3 (prefrontal), Par 1 (parietal), and Oc 1 (occipital), as defined by
Zilles (1985). Medium spiny neurons in the core and shell of the
nucleus accumbens were identified and drawn in the same manner.
A Sholl analysis (Sholl, 1981) of ring intersections was used to
estimate dendritic length, and for cortical cells, dendritic length was
also estimated using the branch order method (Greenough and Chang,
1985). Spine density was quantified by counting spines on one
third-order terminal tip from the basilar and apical dendrites of each
pyramidal cell and on one terminal tip of each accumbens cell. A length
of dendrite (>10 µm) was traced (1000×), and the exact length of
the dendritic segment was calculated. In a second analysis to examine
the frequency of branched spines on nucleus accumbens cells, this
procedure was repeated, but dendritic segments were drawn at 2000×,
and both total spines and spines with more than one head were counted.
Branched spines were defined as described by Comery et al. (1996), that
is, spines with more than one head clearly connected to a common shaft.
Thus, this analysis represents both a replication of the initial
analysis, because different dendritic segments were drawn, and an
extension to determine whether amphetamine had a disproportionate
effect on the number of branched spines (i.e., those with multiple
heads), as reported recently for rats raised in a complex environment
(Comery et al., 1996).
Cell selection and drawing were done by a person blind to treatment
conditions. Statistical analyses were performed by averaging across
cells per hemisphere, and group differences were assessed using
Student's t tests.
RESULTS
Figure 1 shows camera lucida
drawings of representative medium spiny neurons in the core and shell
regions of the nucleus accumbens from saline- and
amphetamine-pretreated rats. It is evident from inspection of Figure 1
that there was an increase in dendritic length and spine density in
amphetamine-pretreated rats, an impression that was verified by
quantitative analyses (Fig.
2A). Dendritic length
was increased by 16.5% in the core of the accumbens (t = 8.77; p = 0.0083) and by 8.2% in the shell of the
accumbens (t = 4.37; p = 0.051). Spine
density was increased by 19.6% in the core (t = 108.8;
p < 0.0001) and by 25.9% in the shell
(t = 179.3; p < 0.0001). Figure
3 shows camera lucida drawings of
representative dendritic segments from shell and core cells magnified
2000×. These were used to examine the frequency of branched spines.
This analysis replicated the initial one, because, as shown in Figure
3, total spine density was increased in amphetamine-pretreated rats by
32.1% in the shell of the accumbens (t = 241;
p < 0.0001) and by 27.8% in the core
(t = 287; p < 0.0001). More
interestingly, there was a disproportionate increase in the number of
branched spines (Fig. 3). In amphetamine-pretreated rats, the number of branched spines was increased by 203.6% in the shell of the accumbens (t = 157; p < 0.0001) and by 117.6%
in the core (t = 124; p < 0.0001).
Thus, in saline-pretreated rats, branched spines comprised 6.9 and
8.9% of total spines in the shell and core regions, respectively, whereas in amphetamine-pretreated rats, branched spines comprised 16 and 15.2% of total spines in these regions.
Fig. 1.
Camera lucida drawings of medium spiny neurons in
the shell (top) and core (bottom) regions
of the nucleus accumbens of saline- and amphetamine-pretreated
rats. These cells were selected for illustration because their values
were closest to the group average of any cells studied. The drawing to
the right of each cell represents a dendritic segment
used to calculate spine density. Coronal drawing is adapted from
Paxinos and Watson (1997).
[View Larger Version of this Image (22K GIF file)]
Fig. 2.
Quantitative analysis of dendritic length
(left) and spine density (right) in the
nucleus accumbens shell and core subregions (A),
the prefrontal cortex (B), the parietal cortex
(C), and the occipital cortex
(D) of rats treated with saline (indicated by S) or amphetamine (indicated by A). The
bars represent the values of mean plus SEM. Dendritic
length was estimated using a Sholl analysis, and therefore the
numbers indicate ring intersections. Spine density
refers to the mean total number of spines per 10 µm of dendrite.
Asterisks indicate a significant difference between saline- and amphetamine-pretreated groups (see Results).
[View Larger Version of this Image (24K GIF file)]
Fig. 3.
Left, Camera lucida drawings of
representative dendritic segments from medium spiny neurons in the core
(top) and shell (bottom) subregions of
the nucleus accumbens of rats pretreated with saline (S) and amphetamine (A).
These drawings were magnified 2000× and were used to count branched
spines. Enlarged examples of different forms of branched spines that
were observed in amphetamine-pretreated animals are shown in the
third column from the left.
Right, Bar graphs showing the results of the
quantitative analyses. Asterisks indicate that in
amphetamine-pretreated rats there was a significant increase in total
spines per 10 µm of dendrite and in the number of spines with
multiple heads (branched spines).
[View Larger Version of this Image (25K GIF file)]
Another effect that is obvious from Figure 3 is that the dendritic
segments from amphetamine-pretreated rats were thicker than those from
saline-pretreated rats. This effect was not quantified, but it was
clearly evident in all of the accumbens cells examined.
The only other region examined in which amphetamine pretreatment
altered dendritic length was the prefrontal cortex (Figs. 2B, 4), and only apical
dendrites were altered. Amphetamine pretreatment increased apical
dendritic length of layer III prefrontal cortical neurons by 12.4%
(t = 4.57; p = 0.048), whereas basilar
dendritic length was unchanged (Fig. 2B;
t = 0.15). Similarly, spine density was increased on
apical dendrites (t = 80.8; p < 0.0001) but not on basilar dendrites (t = 1.41) of
prefrontal cortex cells (Fig. 2B).
Fig. 4.
Camera lucida drawings of representative layer III
pyramidal cells in the prefrontal cortex (area Cg 3) of saline- and
amphetamine-pretreated rats. The drawing to the right of
each cell represents an apical or basilar dendritic segment used to
calculate spine density. Coronal drawing is adapted from Paxinos and
Watson (1997).
[View Larger Version of this Image (23K GIF file)]
In the two other cortical regions examined, there was no effect of
amphetamine pretreatment on dendritic length for either apical or
basilar dendrites (Fig. 2C,D; for the parietal
cortex, t values < 0.3; for the occipital cortex,
t values < 0.5). There was, however, a significant
decrease in spine density in both the parietal and occipital
cortices (Fig. 2C,D; for parietal apical, t = 197.0 and p < 0.0001; for parietal
basilar, t = 73.25 and p < 0.0001; for
occipital apical, t = 140.7 and p < 0.0001; for occipital basilar, t = 41.14 and
p < 0.0001).
A branch order analysis on cortical cells in all three regions yielded
the same pattern of results as seen with the Sholl analysis reported
above (data not shown).
DISCUSSION
Repeated exposure to psychostimulant drugs results in many
neurobehavioral adaptations that outlast the acute effects of the drug.
Some of these are relatively transient, such as those associated with
withdrawal syndromes, and others are remarkably persistent, such as
those associated with behavioral sensitization. The amphetamine treatment regimen used here has been shown many times both to produce a
withdrawal syndrome (nocturnal hypoactivity) and to produce behavioral
sensitization (Robinson and Camp, 1987; Paulson et al., 1991; Paulson
and Robinson, 1995, 1996). Withdrawal symptoms subside ~1 week after
the discontinuation of drug treatment, at which time animals begin
to express hypersensitivity to a drug challenge (Paulson et al.,
1991). Sensitization is fully evident 2 weeks to 1 month after the
last drug treatment and can persist at least 1 year (Paulson et
al., 1991).
Relatively transient behavioral sequelae associated with withdrawal may
be caused by transient adaptations in those neurochemical processes
involved in mediating acute drug effects. However, very persistent
experience-dependent changes in behavior are thought to involve a
different class of adaptations, changes in synaptic connectivity
(Greenough, 1984). Consistent with this hypothesis, we found that 1 month after the last treatment with amphetamine there was an increase
in dendritic surface and in the number of dendritic spines on medium
spiny neurons located in the shell and core subregions of the nucleus
accumbens and on the apical (but not basilar) dendrites of layer III
pyramidal cells in the prefrontal cortex.
Changes in dendritic structure reflected in Golgi material are
considered strong evidence of changes in synaptic connectivity. It has
been estimated that >90% of all excitatory synapses are on dendritic
spines, and in adult animals, as the amount of dendritic surface
increases so does the number of synaptic contacts (Harris and Kater,
1994). A strong relationship between measures of dendritic structure
and synaptic input has been confirmed in studies using electron
microscopy (EM) to quantify directly synaptic density. For example,
Greenough and colleagues have shown that in rats raised in complex
environments, or subjected to various learning experiences, increases
in the dendritic surface of cortical neurons assessed using
Golgi-stained material are accompanied by increases in the number of
synapses per neuron assessed with EM (Greenough and Bailey, 1988;
Greenough et al., 1990). More recently, Purves (1994) and colleagues
have shown a direct relationship between the number of dendritic
branches and the number of synapses in sympathetic and parasympathetic
ganglia. Of course, without ultrastructural studies we cannot be
certain that the increase in dendritic surface and spines found here is
accompanied by an increase in synaptic contacts, but normally in adult
rats nearly all spines in the cortex and striatum have a synaptic
contact (Gray, 1959; Peters and Feldman, 1976; Wilson et al., 1983). If
this is also true for amphetamine-sensitized rats, it would seem that
repeated exposure to amphetamine produces fundamental alterations in
the pattern and number of synaptic connections on the major output
neurons of the nucleus accumbens and prefrontal cortex.
The increase in the number of branched spines is especially intriguing,
because this may provide a very effective mechanism to enhance synaptic
efficacy (Trommald et al., 1990). Very little is known about branched
spines (Harris and Stevens, 1988; Chicurel and Harris, 1992), but an
increase in branched spines has been reported in dentate granule cells
after long-term potentiation (Trommald et al., 1990) or kindling
produced by medial perforant path stimulation (Geinisman et al., 1989)
and in the dorsolateral striatum after rearing in a complex environment
(Comery et al., 1996). Trommald et al. (1990) reported that after
long-term potentiation both branches of a branched spine were always
associated with normal-appearing presynaptic active zones, and in all
cases each branch was innervated by a different axon. Whether this will
be the case here remains to be tested, but as pointed out by Trommald et al. (1990), the addition of a second spine head to an existing spine
may provide a very efficient way to double the input effect at a
specific location.
The increase in spine density and the number of branched spines
produced by past exposure to amphetamine was found on the terminal
dendrites of medium spiny neurons and pyramidal cells. We need to
consider, therefore, the nature of the synaptic inputs onto this
portion of the dendritic tree. For medium spiny neurons, the most
complete information is for cells in the dorsal striatum. The distal
dendrites of medium spiny neurons receive inputs primarily from two
structures extrinsic to the striatum (Smith and Bolam, 1990). The heads
of spines are innervated by boutons that form an asymmetric contact;
these boutons are thought to arise in the neocortex and to use an
excitatory amino acid (EAA), probably glutamate, as their transmitter.
Approximately 50% of these spines also receive a dopaminergic input
that forms a symmetric contact with either the neck of the spine or an
area nearby on the shaft of the dendrite (Smith and Bolam, 1990;
Groenewegen et al., 1991). Thus, a fundamental unit on the distal
portion of medium spiny neuron dendrites is a "triad" consisting of
a spine that receives both an excitatory (asymmetric) input from the
cortex and an inhibitory (symmetric) input from dopamine-containing
cells in the tegmentum (Smith and Bolam, 1990; Groenewegen et al.,
1991). More proximal portions of the dendrites and the cell body
receive inputs that arise primarily intrinsic to the striatum.
This triad structure is also found in the nucleus accumbens and the
prefrontal cortex (Goldman-Rakic et al., 1989, 1992; Smith and Bolam,
1990; Berger et al., 1991; Groenewegen et al., 1991). In the nucleus
accumbens, asymmetric (presumed EAA) inputs arise from structures such
as the prefrontal cortex and hippocampus (Totterdell and Smith, 1989;
Sesack and Pickel, 1990, 1992; Smith and Bolam, 1990; Groenewegen et
al., 1991). Similarly, in the prefrontal cortex, spines on pyramidal
cells that have presumed dopaminergic synapses also have asymmetric
(presumed EAA) synapses (Berger et al., 1991; Goldman-Rakic et al.,
1992). It has been suggested, therefore, that in both the striatum and
neocortex, triads provide the structural means by which dopamine
modulates or gates the major excitatory drive produced by EAA inputs
onto output neurons (Smith and Bolam, 1990; Berger et al., 1991;
Groenewegen et al., 1991; Goldman-Rakic et al., 1992). This convergence
of dopaminergic and presumed glutaminergic inputs at the site of morphological adaptation reported here is especially intriguing, because both of these neurotransmitter systems have been prominently implicated in amphetamine sensitization. Psychomotor sensitization to
amphetamine is prevented by cotreatment with either dopamine or
glutamate antagonists (Kalivas and Stewart, 1991; White and Wolf,
1991). Furthermore, psychostimulant sensitization is associated with
alterations in the responsiveness of nucleus accumbens neurons to both
dopamine and glutamate agonists (Henry and White, 1991; White et al.,
1995). Thus, changes in triads, the sites of convergence of dopamine
and glutamate inputs onto medium spiny neurons, may provide the
structural basis for sensitization-related alterations in the
responsiveness of nucleus accumbens neurons to both dopamine and
glutamate inputs. The structural adaptations reported here would
require new protein synthesis, so it is also important to note that
sensitization is prevented by cotreatment with protein synthesis
inhibitors (Robinson, 1991; Karler et al., 1993).
Figure 5 summarizes one proposed site of
morphological plasticity associated with repeated amphetamine
treatment, the triad found on the distal dendrites of medium spiny
neurons and prefrontal pyramidal cells. Amphetamine pretreatment
increased dendritic length, increased spine density, and increased the
number of branched spines in those regions in which triads are
prevalent. These latter two modifications are represented
diagrammatically in Figure 5B. Figure 5 also indicates that
the relationship between these postsynaptic modifications and presumed
new patterns of synaptic connectivity is not known, and there are a
number of ways the triad arrangement could be altered (for discussion,
see Fig. 5). Of course, there could also be structural changes in the
presynaptic boutons (e.g., Uranova et al., 1989) or other changes in
dendritic structure (Harris and Kater, 1994). Whatever the case, the
present results suggest that repeated amphetamine treatment can produce
persistent morphological adaptations in the basic "processing unit"
associated with distal dendritic branches of output neurons in the
nucleus accumbens and prefrontal cortex, the synaptic triad.
Fig. 5.
A schematic illustration of the effect of
amphetamine pretreatment on spine density in the nucleus accumbens.
A, Two spines on a distal dendrite of a medium spiny
neuron are illustrated. In the striatum, spine heads on distal
dendrites are innervated by presumed EAA inputs from the cortex (e.g.,
prefrontal cortex or hippocampus in the case of the accumbens) that
form asymmetric contacts. Approximately half of these spines also
receive a dopaminergic (DA) input onto the neck of the
spine or nearby onto the dendritic shaft (Smith and Bolam, 1990;
Groenewegen et al., 1991). The lower spine in
A illustrates one of these triads. After amphetamine treatment, there was an increase in dendritic surface and spine density
in the regions occupied by triads. B, Amphetamine
treatment produced an especially large increase in the number of
branched spines. What is not known, of course, is the relationship
between this altered postsynaptic surface and patterns of synaptic
connectivity (indicated by the dashed terminals). There
are a number of possibilities. It is possible, of course, that the
additional spines are unoccupied. This seems unlikely because previous
studies on experience-dependent plasticity suggest that in adult
animals spines are not typically vacant. Alternatively, the heads of
the additional spines could receive new asymmetric contacts
(dashed terminal 1 in B). If normal proportions were maintained, it would be expected that approximately half of these new spines would receive both a symmetric dopaminergic input onto their neck and an asymmetric EAA input onto the spine head.
The other half of the new spines would receive only an asymmetric contact. But there are a number of ways the DA inputs could be arranged. One very interesting possibility is that the original DA
input would remain near the base of the common spine neck, near or on
the dendritic shaft (dashed terminal 2), where it could modulate both EAA inputs onto the spine heads. This might provide a
mechanism by which DA could exert greater modulatory control over the
excitatory drive onto medium spiny neurons without any "sprouting"
of additional DA terminals. This idea is consistent with observations
that nucleus accumbens cells in sensitized rats are more sensitive to
DA agonists (Henry and White, 1991) but less sensitive to glutamate
(White et al., 1995). Alternatively, the DA input on the original spine
could move out to the neck of the original branch (dashed
terminal 3). If there was no additional DA terminal added to
the neck of the new branched spine (dashed terminal
4), this could result in a decrease in dopaminergic
control over EAA inputs at this location because the asymmetric input onto the new spine head would be "unopposed" by a symmetric input onto the same spine. An unlikely possibility is that there is an
increase in the number of dopaminergic synapses onto spines that have
no EAA input. This would be unusual, because in normal animals
symmetric contacts are almost always accompanied by an asymmetric
contact (Smith and Bolam, 1990; Groenewegen et al., 1991). Finally,
some spines on the distal dendrites could become occupied by inputs
that normally are not found there, for example, from sources intrinsic
to the nucleus accumbens. To determine which of these, or other,
scenarios is correct will require detailed ultrastructural studies.
Whatever the new pattern of synaptic connectivity, it is obvious that
there are many ways by which the structural modifications reported here
could produce enduring changes in the effects of DA and glutamate
neurotransmitters on the excitability of nucleus accumbens medium spiny
neurons (and prefrontal pyramidal neurons).
[View Larger Version of this Image (24K GIF file)]
In closing, it is interesting to speculate about what role these
structural adaptations might play in some of the long-term behavioral
consequences of repeated exposure to psychomotor stimulant drugs in
humans. One consequence of repeated amphetamine use is amphetamine
psychosis, a syndrome characterized by paranoid schizophrenic-like symptoms (Segal and Schuckit, 1983; Robinson and Becker, 1986). It has
been suggested that aberrant dopamine-glutamate interactions in
corticostriatal thalamocortical loops play a role in the
pathophysiology of schizophrenia (Carlsson and Carlsson, 1990);
therefore, amphetamine-induced changes in dopamine-glutamate triads in
the prefrontal cortex and striatum could contribute to the development
of amphetamine psychosis. Another consequence of repeated exposure to
psychostimulant drugs is addiction. Sensitization-related
neuroadaptations in brain reward systems may be important in the
development of addiction (Robinson and Berridge, 1993; Berridge and
Robinson, 1995), and the medium spiny neurons have been proposed to
"serve as the final common path of opiate and psychostimulant
reward" (Carlezon and Wise, 1996, p 3120). It is possible, therefore,
that the compulsive pattern of drug-taking behavior that characterizes
addiction may develop in part because of the ability of some drugs to
alter patterns of synaptic connectivity in the very brain regions that mediate drug reward. Of course, how they do so, what role structural modifications actually play in mediating behavioral change, including sensitization, and whether other drugs of abuse produce similar adaptations will require further study. Although we are left with many
unanswered questions, the results reported here suggest a promising new
avenue for exploring drug-dependent plasticity in the nervous
system.
FOOTNOTES
Received June 23, 1997; revised Aug. 5, 1997; accepted Aug. 13, 1997.
This work was supported by grants from the National Institute on Drug
Abuse and from the National Science and Engineering Research Council of
Canada. We thank G. Gorney and R. Gibb for excellent technical
assistance and K. C. Berridge, K. Browman, and K. M. Harris
for helpful comments on an earlier draft of this manuscript.
Correspondence should be addressed to Dr. Terry E. Robinson,
Biopsychology Program, Department of Psychology, The University of
Michigan, 525 East University (East Hall), Ann Arbor, MI 48109.
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M. V. Solbrig, G. F. Koob, L. H. Parsons, T. Kadota, N. Horscroft, T. Briese, and W. I. Lipkin
Neurotrophic Factor Expression After CNS Viral Injury Produces Enhanced Sensitivity to Psychostimulants: Potential Mechanism for Addiction Vulnerability
J. Neurosci.,
November 1, 2000;
20(21):
RC104 - RC104.
[Abstract]
[Full Text]
[PDF]
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