National Institute on Drug Abuse
Meeting Summary: Wired for Addiction
On June 22, 1998, Wired for Addiction was presented as
part of NIDA's Frontiers in Neuroscience seminar series.
The theme of these presentations centered on the neuronal remodeling that
emerges after repeated substance use and withdrawal, with particular emphasis
on the possibility of altered cognitive function as a consequence of the
neural remodeling. Presentations were made by Drs. Ann Graybiel, Tony Grace,
John Marshall, Janet Neisewander, and Regina Carelli, and a summary and
discussion was presented by Dr. Steve Grant of NIDA. Brief summaries of
their presentations follow.
Ann Graybiel, Ph.D., Massachusetts Institute of Technology: Chronic
exposure to psychomotor stimulants may rewire your brain
Exposure to amphetamine and cocaine induces gene expression in cortico-basal
ganglia circuits. Chronic intermittent exposure to the same drugs down-regulates
some of the inducible change. After a course of chronic intermittent treatment
and withdrawal of the drug, a subsequent challenge with the drug induces
new patterns of gene expression in cortico-basal ganglia circuits. The
repeated administration and withdrawal of cocaine induces both immediate
early gene (IEG) expression after drug challenge in neurons that are not
activated acutely, and an increase in the size of the area in which this
response is observed. These findings raise the possibility that prolonged
exposure to psychomotor stimulants produces enduring changes in brain wiring.
Anthony Grace, Ph.D., University of Pittsburgh: Neuronal interactions
within the limbic system of rats: Alteration during amphetamine sensitization
Amphetamine exerts differential actions on neurons in the nucleus accumbens
when given acutely versus repeatedly. Our studies show that repeated amphetamine
administration causes an increase in electrical coupling among nucleus
accumbens neurons, which appears to be driven by an increase in prefrontal
corticoaccumbens afferent activation. We propose that such a condition
would lead to alteration of information flow within this system, resulting
in a perseverance of behavioral action that may contribute to drug-seeking
behavior in humans.
John Marshall, Ph.D., University of California at Irvine: Cortical
and striatal circuits influenced during repeated methamphetamine administration
Repeated administration of methamphetamine (m-AMPH) can induce long-lasting
changes in brain function, including (I) regulatory events related to the
phenomena of tolerance, sensitization, and craving, and (II) injurious
effects associated with prolonged exposure to this stimulant drug. The
ability of repeated m-AMPH administration to injure the dopamine terminals
of the neostriatum is well characterized; this injury is a consequence of
the drug-induced overflow of both glutamate and dopamine within the caudate-putamen.
The involvement of striatal glutamate in these effects of repeated m-AMPH
treatments suggests a progressive recruitment of the corticostriatal projections
during repeated drug exposure. Evidence that cerebral cortical neurons
are activated, and that some of them degenerate, during the course of repeated
m-AMPH administration is provided by studies of immediate early gene expression,
quantification of glutamate receptors, and cellular markers for cortical
neuron degeneration. Degenerating cortical neurons include pyramidal and
stellate cells in layers III and IV of parietal cortex. As the neuronal
degeneration occurs in concert with the intense stimulant-induced stereotypical
behaviors, it is possible that the behavior itself may drive the circuits
that trigger the injured neurons, promoting further damage. The implications
of this progressive alteration in cortical and striatal circuits for the
progress of amphetamine self-administration was discussed.
Janet Neisewander, Ph.D., Arizona State University: Neurochemical
Correlates of Cocaine-Seeking Behavior
Imaging studies in humans suggest that the amygdala plays an important
role in craving elicited by cocaine and cocaine-conditioned environmental
stimuli. Our research examined the relationship between neurochemical changes
in the amygdala and cocaine-seeking behavior following exposure to a cocaine-paired
environment or a cocaine priming injection. We measured cocaine-seeking
behavior by assessing the persistence of lever-pressing in the absence of
cocaine reinforcement in animals previously trained to press a lever for
cocaine infusions. Lever-pressing under these conditions is thought to
reflect the incentive motivational properties of cocaine and cocaine-associated
stimuli. We first investigated whether the pattern of changes in cocaine-seeking
behavior corresponded with changes in concentrations of dopamine in dialysates
obtained from the amygdala during the course of cocaine withdrawal. There
were concomitant changes in cocaine-seeking behavior and dialysate dopamine
following the cocaine priming injection, but not following exposure alone
to the cocaine self-administration environment. We next investigated changes
in Fos protein expression as a general marker for neuronal activation.
Exposure to the cocaine self-administration environment, but not the cocaine
priming injection, elicited Fos expression in the basolateral nucleus of
the amygdala, nucleus accumbens shell, and cingulate cortex. In contrast,
the cocaine priming injection, but not the environmental stimuli, elicited
Fos expression in the central nucleus of the amygdala and dorsolateral caudate-putamen.
The findings suggest that different neural mechanisms mediate cocaine-seeking
behavior elicited by cocaine-conditioned environmental stimuli and those
elicited by a priming injection of cocaine. Increases in extracellular
dopamine may be critical for the induction of cocaine-seeking behavior elicited
by cocaine but may not be elicited by cocaine-conditioned environmental
stimuli.
Regina Carelli, Ph.D., University of North Carolina: The Nucleus
Accumbens and Reward: Electrophysiological Studies in Behaving Animals
Numerous investigations indicate that the nucleus accumbens (NA) is
a neural substrate crucially involved in mediating the reinforcing properties
of "natural" rewards such as food and water, and drugs of abuse
such as cocaine. Despite overwhelming evidence linking the NA with reinforcement-related
events, we do not yet understand the underlying cellular mechanisms mediating
this process in the behaving animal. We used multi-neuron recording procedure
in which NA neurons (16-32 cells) are recorded simultaneously in rats trained
to press a lever for water reinforcement, or for intravenous infusion of
cocaine (ie, self-administration). The data show that although water and
cocaine both activate cells that recognize reward, cocaine also uniquely
activates a set of neurons that may be part of a specialized reward circuit.
We found three types of activity patterns that occurred in response to
presentation of either cocaine or water. Some neurons fired in anticipation
of cocaine or water, others were activated only during the time the reinforcement
was present, and a third group became quiescent in the period of time when
the reinforcement was present. A fourth pattern in which the neuronal
activity was increased just prior to and after the presentation of cocaine
occurred. No similar responses to water reinforcement were observed. In
addition, NA neurons exhibit very dynamic firing properties which are explicitly
coupled to the behavioral state of the animal, and are markedly influenced by
the environmental context in which the drug was self-administered. These
studies provide insight into the neurobiological mechanisms underlying the
rewarding properties of natural rewards such as water, and how drugs of
abuse such as cocaine may affect this system and lead to drug addiction.
Steve Grant, Ph.D., National Institute on Drug Abuse: Summary and Discussion:
Implications for Humans
How can we best exploit these advances to stimulate translational research
in humans? The correspondences between data obtained in animals and man
are striking. Presentation of drug-associated cues to humans and animals
activates the similar regions in the brains of men and animals, exemplified
by the convergence of the orbitofrontal projections to the basal ganglia.
It may be fruitful to think of the brain as a collection of "modules"
in which each module is more responsive to particular kinds of information.
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