Cocaine and the Changing Brain
Introduction
Nancy S. Pilotte, Ph.D.
National Institute on Drug Abuse
National Institutes of Health
Rockville, MD
Recent research coupling the neurobiology of
reward with the neurochemical sequelae of
repeated cocaine administration indicates that
adaptations within the dopamine system
occur but do not alone underlie the enduring
aspects of drug abuse. This symposium was
organized to document these changes and
had three objectives. The first was to
summarize the neural remodeling (anatomical
or neurochemical) that occurs within the
mesolimbic dopamine system, after repeated
exposure to and withdrawal from cocaine,
and to link these neuroadaptations to their
functional consequences. As the
modification of one system often leads to
compensatory changes in other systems, the
second objective was to identify and
describe the functional changes that occur in
nondopaminergic neurons at various times
after the cessation of cocaine administration.
The third goal of this symposium was to aid in
identifying enduring changes in one or more
brain systems, to suggest possible
neurochemical targets for developing
therapeutic interventions for the medical
treatment of drug abuse.
The presentations encompassed the
macroscopic visions and the microscopic
details of the brain after cocaine use. Data
were presented detailing where cocaine
itself bound in the human and the nonhuman
primate brains. In addition to the expected
labeling of dopamine transporter sites in
areas rich in dopamine terminals, there was
appreciable binding in the orbitofrontal cortex,
the hippocampus, the amygdala, and the
thalamus. Within these areas, the cocaine
binding was not entirely displaced when
various monoaminergic transport inhibitors
were used as competitors.
Using imaging techniques to help define
functional changes that occur subsequent to
repeated drug use and withdrawal, data
were presented that pointed to a profound
dopamine D2 receptor deficiency in the
mesostriatal dopaminergic neurons. This
deficiency was accompanied by marked
reductions in glucose utilization in the
orbitofrontal cortex, an area sparse in
dopaminergic innervation, where cocaine is
thought to bind to nondopaminergic targets.
Neurons from the prefrontal cortex project to
striatal targets, where they may serve as
cognitive pattern generators in a manner
analogous to the well-known functions of the
motor pattern generators of the brainstem. In
this role, cortical inputs may evaluate the
cognitive aspects of stimulation, including the
environmental context, reinforcement, and
learning, and may eventually activate or even
downregulate other brain circuits that work in
concert with the ventral striatum to produce
behavioral activation. An acute cocaine
challenge given to animals after a period of
repeated cocaine treatment plus an
intervening withdrawal period produces
patterns of neural activation (marked by
induction of immediate early gene expression)
that are different from those observed after
acute administration, representing yet another
example of cocaine-induced neuroplasticity.
Repeated administration of cocaine has
functional consequences on both
dopaminergic and nondopaminergic neurons
that persist after the exposures are
terminated. For example, dopamine is
removed from the extracellular space by
uptake processes more slowly in the nucleus
accumbens than in the dorsal striatum
because there are fewer transporters in the
accumbens than in the striatum. In
behaviorally sensitized animals, uptake of
dopamine by the dopamine transporter in the
nucleus accumbens is even more inefficient,
and a challenge injection of cocaine results in
supranormal concentrations of dopamine in
the synaptic space of brain areas known to
be critical in mediating the reinforcing
properties of drugs of abuse. This
neurochemical sensitization accompanies the
behavioral sensitization.
Other data suggest that the rate of uptake
may be regulated by changes in the
membrane potential, and depolarization
decreases the rate of uptake by the
dopamine transporter. Furthermore, repeated
exposure to cocaine can alter the
mechanisms underlying transmitter release in
response to a depolarizing agent and
decreases the efficiency of sodium and
calcium channels in the plasma membrane.
Acutely, the cocaine-induced inhibition of
monoamine uptake increases synaptic
transmission and blocks the inhibitory
function of serotonergic autoreceptors by
prolonging the residence time of the
neurotransmitter in the synaptic space. At
the same time, heterosynaptic modulation (by
serotonin and dopamine) of transmitters such
as GABA is also enhanced. Intermittent
exposures to cocaine ultimately enhance the
dopamine-D1 stimulation of cAMP. One of the
metabolic products of cAMP is adenosine,
which has transmitter activities of its own
and decreases GABA release. It seems,
then, that chronic cocaine use can alter the
dynamic balance between different
neurotransmitter systems and can lead to
enduring changes in neural control. This
observation is also noticed at the systems
level, where withdrawal from cocaine can
alter basal neural tone such that basal
extracellular dopamine and serotonin
concentrations fall below the limits of
detection over a long period of time.
The final area of research discussed by the
participants of this symposium is that of
peptides and genes regulated by cocaine.
One of these, corticotropin-releasing factor
or CRF, is the well-known mediator of the
"stress response," by which hypothalamic
CRF induces the release of ACTH from the
anterior pituitary gland, which in turn elicits
the output of glucocorticoids from the adrenal
gland (to dampen the initiating stimulation by
CRF). This peptide is also found in brain
regions that have not been directly linked with
the peripheral stress response, such as the
locus coeruleus, and nuclei within the
amygdala. Acutely, the injection of cocaine
increases the extracellular concentration of
CRF in the central nucleus of the amygdala;
cocaine withdrawal similarly activates
neurons within this region. Another family of
peptides, the cocaine- and
amphetamine-regulated transcription factors
or CART, is found in brain regions that are
implicated in the rewarding properties of
drugs of abuse, as well as in centers that
control other behaviors associated with
satiety. Finally, cocaine administration
directly induces the expression of a gene, the
NAC-1, within the nucleus accumbens;
animals in which antisense has been used to
knock out this gene do not develop behavioral
sensitization to cocaine.
The variety of targets identified through these
presentations are at once encouraging and
daunting. They clearly point out that cocaine
produces enduring neural adaptations, not
only in dopaminergic systems but also in
nondopaminergic systems. The recognition
of the potential interactions between these
systems (and those that surely exist but have
not yet been identified) suggests that
neuroadaptations occur at many different
levels. Each level is a potential target for the
development of medical interventions, with
the possibilities of preventing further use and
abuse and reversing adaptations induced by
cocaine. An appreciation of the intricacies
and interrelationships among these factors is
crucial for each of us who works in this field.
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