Cocaine and the Changing Brain
The Brain Is Not The Same After Chronic Cocaine:
Network-Level Changes In Basal Ganglia Circuits
Ann Graybiel, Ph.D.
Massachusetts Institute of Technology
Cambridge, MA
The ventral striatum, the ventral pallidum, and
the dopaminergic and serotonergic inputs to
these regions are thought to be critical to the
expression of the behavioral and rewarding
effects of cocaine. Such expression occurs
under the modulating influence of complex
mechanisms that involve cue stimuli and
stimuli related to reward. One can think of
such a modulating neurocircuit as consisting
of the dorsally lying basal ganglia, the
thalamus, and the frontal cortex. This circuit
seems to act as a cognitive pattern generator
(analogous to the motor pattern generators of
the brainstem) that can evaluate the cognitive
aspects of stimulation and eventually activate
other brain circuits wired in with the ventral
striatum and pallidum to produce behavioral
activation. We know that the neurocircuitry
of the dorsal striatum, with its dopamine
inputs, falls into two broad categories
connected with the striosome and the matrix
compartments. We also know that this
neurocircuitry is strongly linked to both the
limbic system via the striosomes and the
sensory-motor circuitry of the striatum via the
matrix. An emphasis on the circuitry is
instructive because chronic treatment with
cocaine or amphetamine, in contrast to acute
administration of these drugs, presents a
compelling model of neuroplasticity: We
believe different neural circuits become
activated in response to cocaine as a result
of chronic exposure to the drug. This
presentation emphasizes data supporting this
view for circuits involving the dorsal striatum.
The acute administration of cocaine or
amphetamine induces striking increases in the
expression of immediate early genes (IEGs)
that serve as markers of neural activation.
We assessed the activation of c-Fos, JunB,
and ARC (a cytoplasmic gene related to the
cytoskeleton). Acutely, cocaine activated
many regions, particularly the matrix
component of both the ventral and dorsal
striatum. The degree of activation was not
dose dependent, and we obtained similar
results for a variety of genes. When we
conducted precisely the same experiments
using amphetamine instead of cocaine, we
found that the pattern of activation was very
different. We observed that, in the entire
front end of the caudate-putamen, the
predominant activation was in the striosomes,
instead of in both compartments as had been
seen after cocaine.
When cocaine is administered repeatedly, its
effects are remarkably long-lasting. For
example, in the rat, behavioral sensitization
persists for as long as 87 days after a short
period of repeated cocaine administration; it is
thought that the central effects of repeated
psychostimulant administration can
essentially last a lifetime in an animal.
Therefore, we asked what the effects of
chronic cocaine treatment would be on gene
induction in the striatum. We varied the
number of days that rats were given cocaine
and then probed for the expression of the
IEGs. As others have found, after acute
treatment with cocaine followed by a survival
time of 2 or 18 hours, we could see the
induction both of IEGs such as Fos and JunB
and of chronic FRAs (Fos-related antigens).
With 7 days of treatment (with 2-hour
survival time withdrawal), we observed a
downregulation of c-Fos and JunB and an
upregulation of chronic FRAs, monitored by
Western blot analysis.
When we analyzed the anatomic
compartments in the caudate-putamen
showing the gene activation, we were
surprised to find that, after only 4 days of
chronic cocaine treatment, a shift had begun
to occur in the anatomic localization of the
activation relative to that seen after acute
cocaine or amphetamine treatment. We found
that the IEG expression shifted toward a
striosomal pattern, which is what we had
seen with acute amphetamine treatment but
not with acute cocaine treatment. We traced
changes in levels of expression in these
gene products over the course of 7 days,
when Fos and JunB were clearly
downregulated. But what happened during
withdrawal of cocaine? We plotted the
recovery of gene expression to a challenge
by giving an injection of cocaine after
different lengths of withdrawal and
measuring how much IEG induction occurred.
After a week of withdrawal that followed a
week of repeated cocaine treatment, the
previously suppressed c-FOS had recovered
by at least half. There was a striking lateral
and anterior pattern of patchiness of JunB
and of FRAs in the striatum. Even more
important, when the Fos response
reappeared, it appeared heightened in the
striosomes, with much less expressed in the
matrix. These results suggested that we
were seeing a change in the inducibility of
genes and the expression of their gene
products that had some real circuit pattern to
it-possibly a very important aspect of the
effects of chronic exposure to cocaine. Our
results suggest that the brain circuits
responding to the drug after chronic use are
different from the circuits responding to the
first acute dose.
Double-staining Fos-expressing cells for
dynorphin showed that most responding
(Fos-positive) cells were dynorphin-positive.
These findings show an interesting
correlation with those of Yasmin Hurd and
Miles Herkenham, who published a
single-case report of striatal prodynorphin
mRNA in situ hybridization in a sudden-death
cocaine user. They found a marked increase
of prodynorphin in striosomes, relative to
control levels. Thus, both in this (single)
human case and in our animal studies, the
results suggest that cocaine tends to activate
the striosomal system after chronic use.
In primates, the only regions known to project
selectively to striosomes are the anterior part
of the anterior cingulate gyrus (or caudal
medial prefrontal cortex) and the caudal
orbital frontal cortex. These areas are
strongly implicated in psychiatric disorders
such as obsessive-compulsive disorder.
These regions of the cortex are tightly linked
to the amygdala, the hippocampus, and the
mediodorsal thalamus by circuits involved in
learning and memory and to limbic circuits that
relate, for example, to the locomotor behavior
mediated by the nucleus accumbens.
This neural circuit, linked to the striosomal
subsystem within the striatum, in certain
ways resembles the ventral tegmental area in
that nondopaminergic cells appear to enjoy a
special relationship with dopamine-containing
neurons of the midbrain. These special
striatal compartments may instruct the
reward-related neurons of the nigral/ventral
tegmental area complex. One of the things
that may occur at the systems level by virtue
of repeated exposure (of an animal or
person) to cocaine is some shift in the normal
balance between the context and evaluation
of stimuli, heavily influenced by reward
signals.
Dopamine and glutamate are key coplayers in
many neuroplastic systems within the basal
ganglia. Glutamatergic cortical afferents
project to the striatum, perhaps bearing
presynaptic dopamine receptors. They
synapse on the spines of the medium spiny
neurons. Many dopamine-containing
afferents terminate on the very same spines
that receive cortical inputs, suggesting that
dopamine can fine-tune the inputs to the
spiny neurons. Both dopamine and glutamate
strongly affect plasticity in the corticostriatal
system, perhaps by LTP and LTD. Therefore,
we wanted to be able to look at the effects of
dopamine on glutamate transmission in the
striatum.
We stimulated the somatomotor cortex in
monkeys and rats, looked for striatal
activation of IEGs as a measurable population
response, and found that activation of c-Fos
and JunB occurred in the matrix, in projection
neurons that express enkephalin. To look at
the effects of dopamine on this corticostriatal
system, we concentrated on studying cortical
activation in the rat. We first developed a
method for stimulating the cortex in awake
rats. We implanted chronic wells over the
somatomotor cortex and removed local
GABAergic inhibition in the cortex by applying
picrotoxin (or CSF, for the control studies)
epidurally over the somatomotor cortex via
the chronically implanted wells. We were
able to activate striatal IEGs using this
methodology.
To study the effects of dopamine
transmission on this activation, we first
systemically injected the broad-spectrum
dopamine D2 antagonist haloperidol and then
applied the local picrotoxin activation to the
cortex. This combination produced a strong
synergistic IEG activation, as if there were
enhanced input signaling from the cortex
when D2 receptors were blocked.
Intrastriatal injections of the dopamine D2
receptor antagonist sulpiride also enhanced
corticostriatal transmission as measured by
gene induction. Thus, dopamine receptors
inside the striatum (which are targets of
cocaine) can have a dramatic effect on
corticostriatal transmission. We further found
that this activation of striatal IEGs was
dependent on NMDA receptor activation, as it
was inhibited by application of the antagonist
MK801.
How would chronic cocaine exposure affect
corticostriatal transmission? To study this
issue, we administered cocaine or saline i.p.
to rats for 1 week to downregulate Fos and
then locally stimulated the cortex by epidural
application of picrotoxin to see whether the
cocaine exposure would influence cortically
evoked gene expression in the striatum. In
control experiments we found, as expected,
that Fos remained downregulated after the
combination of repeated cocaine plus
systemic saline or after repeated cocaine
plus acute cocaine. Repeated saline plus
picrotoxin also produced the expected robust
corticostriatal induction of Fos, but repeated
cocaine led to a dramatic decrease in the
ability of the corticostriatal stimulation to
activate IEGs in the striatum in the repeated
cocaine plus picrotoxin group. This
experiment shows that it is possible to look at
circuit-level changes that go beyond inducing
genes merely by giving drug. We can use the
cortical stimulation to probe the effects of
cocaine on corticostriatal circuit function.
It is clear that cocaine is a major activator of
basal ganglia loops and that cocaine can lead
to massive neural activation at the circuit
level. If we look at the full circuit diagram of
outflow of the basal ganglia, including
pathways leading to the neocortex, it is
striking that the basal ganglia outflow leads
not only to the somatomotor cortex or
premotor cortex but also to the prefrontal
cortex. This pattern of connectivity suggests
that some of the circuit-level changes found
after even a week of cocaine treatment could
influence not only downstream circuits that
involve locomotion and the development of
stereotypy but also upstream circuits leading
to what we have called cognitive pattern
generators in the cortex. This may be one
way in which cocaine can influence cognitive
activity after chronic exposure to this drug.
Acknowledgment
This research was supported by National
Institute on Drug Abuse Grant No. DA-08037.
Selected References
Berretta, S.; Parthasarathy, H.B.; and
Graybiel, A.M. Local release of GABAergic
inhibition in the motor cortex induces
immediate-early gene expression in indirect
pathway neurons of the striatum. J Neurosci
17:4752-4763, 1997.
Graybiel, A.M. Building action repertoires:
Memory and learning functions of the basal
ganglia. Curr Opin Neurobiol 5:733-741,
1995.
Graybiel, A.M. The basal ganglia and
cognitive pattern generators. Schizophr Bull
23:459-469, 1997.
Hillegaart, V.; Berretta, S.; and Graybiel, A.M.
Effects of chronic cocaine exposure on
corticostriatal transmission in the rat. Soc
Neurosci Abstr 22:410, 1996.
Hurd, Y.L., and Herkenham, M. Molecular
alterations in the neostriatum of human
cocaine addicts. Synapse 13:357-369, 1993.
Moratalla, R.; Elibol, B.; Vallejo, M.; and
Graybiel, A.M. Network-level changes in
expression of inducible Fos-Jun proteins in
the striatum during chronic cocaine treatment
and withdrawal. Neuron 17:147-156, 1996.
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