Cocaine and the Changing Brain
Agenda
9:00 a.m. - 9:05 a.m. Welcome
Nancy S. Pilotte, Ph.D.
National Institute on Drug Abuse
National Institutes of Health
9:05 a.m. - 9:40 a.m. Cocaine Targets in Primate Brain: Liberation from Prosaic
Views
Bertha Madras, Ph.D.
Harvard Medical School and
New England Regional Primate Center
Substantial evidence supports the view that the dopamine
transporter is a principal target of cocaine in the brain. The
drug-binding domain on the transporter, however, is more complex
than previously viewed. Cocaine congeners that contain no amine
nitrogen are as effective as monoamine drugs in blocking the
transporter and in producing pharmacological effects. The dopamine
transporter does not have an exclusive grip on cocaine. Cocaine
also binds to other targets in brain, in regions with low levels of
dopamine and at sites that appear distinct from monoamine
transporters.
9:40 a.m. - 10:15 a.m. The Brain Is Not the Same After Chronic Cocaine:
Network-Level Changes in Basal Ganglia Circuits
Ann Graybiel, Ph.D.
Massachusetts Institute of Technology
The chronic administration of cocaine leads to changes in immediate
early gene expression in the striatum that has been associated
previously with the administration of a single dose of amphetamine.
These changes persist during cocaine withdrawal and may occur in
concert with the development of behavioral sensitization.
10:15 a.m. - 10:50 a.m. Changes in Human Brain Systems After Long-Term Cocaine
Use
Nora Volkow, M.D.
Brookhaven National Laboratory
Studies discussed involve those done with PET and [11C]-cocaine for
the investigation of the regional distribution, the pharmacokinetics,
and the efficacy of cocaine at the dopamine transporter directly in
the human brain and the relationship of these characteristics to
cocaine's behavioral effects.
10:50 a.m. - 11:25 a.m. Cocaine Causes Long-Term Synaptic Modulation in the
Ventral Tegmental Area
John T. Williams, Ph.D.
Oregon Health Sciences University
Dopamine cells show intrinsic spontaneous firing, but the rate and
pattern of activity are shaped by afferent inputs. Thus afferent input
to the ventral tegmental area plays a role in determining the
behavioral state of the animal. The acute and chronic effects of
cocaine on the afferent inputs to dopamine cells in the ventral
tegmental area involve several neurotransmitter systems, including
dopamine, serotonin, GABA, adenosine, and glutamate. The effects
of these endogenous transmitters and the mechanism by which
cocaine alters their function are discussed.
11:25 a.m. - 12:00 p.m. Regulation of the Dopamine Transporter and Cocaine
Sensitization
Nancy R. Zahniser, Ph.D.
University of Colorado School of Medicine
Functional measures of activity of the dopamine transporter are
addressed in this presentation, which presents new data on the
concurrent measurement of dopamine clearance, using in vivo
voltammetry, and behavior in freely moving rats. This addresses the
nagging question of whether changes in activity of the dopamine
transporter occur only in rats that become behaviorally sensitized to
cocaine.
12:00 p.m. - 1:30 p.m. Lunch
1:30 p.m. - 2:05 p.m. Whole-Cell Plasticity in Cocaine Addiction: Current
Perspectives
Francis J. White, Ph.D.
Finch University of Health Sciences
The Chicago Medical School
Our recent studies have identified alterations in whole-cell currents
in the nucleus accumbens neurons after repeated cocaine
administration. Both voltage-sensitive sodium and calcium currents
are reduced during the early period of withdrawal from cocaine (3
days after the last cocaine). Reductions in the calcium current
appear primarily to involve N-type channels and appear to result from
alterations in the basal state of channel phosphorylation. These
effects greatly diminish the excitability of nucleus accumbens
neurons, thereby reducing the ability of these neurons to respond to
salient motivational and cognitive commands from cortical and limbic
structures. These alterations may underlie some of the anhedonic
and anergic features of the cocaine withdrawal syndrome.
2:05 p.m. - 2:40 p.m. Cocaine Dependence and Withdrawal: Neuroadaptive
Changes in Brain Reward and Stress Systems
Friedbert Weiss, Ph.D.
The Scripps Research Institute
Neuroadaptation theories predict that the development of drug
dependence involves changes in the function of neuronal systems
that oppose the pharmacological actions of substances of abuse.
This results in the emergence of withdrawal symptoms that could
promote continued consumption of the drug. Examination of the
effects of long-term cocaine self-administration and withdrawal on
the functional status of brain reward and stress systems suggests
that withdrawal and abstinence after chronic cocaine are
associated with a dysfunction in limbic monoamine systems that
includes deficiencies in the extracellular dopamine and serotonin
concentrations as well as an altered sensitivity of 5-HT1b receptors.
Repeated cocaine and its withdrawal were also associated with
distinct changes in the release of corticotropin-releasing factor in the
central nucleus of the amygdala. Together, the data suggest that
neuroadaptive processes in brain reward and stress systems are
important factors in the development and maintenance of cocaine
dependence.
2:40 p.m. - 3:00 p.m. Break
3:00 p.m. - 3:35 p.m. Sensitization to Cocaine Is Associated With Modified
Calcium Transduction and Gene Expression in the Nucleus Accumbens
Peter W. Kalivas, Ph.D.
Washington State University
Behavioral sensitization that is induced by repeated cocaine
administration is associated with long-term alterations in
neurotransmission in the nucleus accumbens. Notably, both
presynaptic and postsynaptic dopamine transmissions are enhanced
in cocaine-sensitized rats. Data are presented that demonstrate that
the enhanced releasability of presynaptic dopamine arises from
induction of a calcium transduction pathway involving CaM-KII. We
have also recently characterized a novel gene, NAC-1, with
characteristics of an immediate early gene. NAC-1 mRNA is
upregulated in the nucleus accumbens of rats sensitized to cocaine,
and an antisense knockout of NAC-1 reveals that expression of this
gene can regulate the behavioral response to cocaine.
3:35 p.m. - 4:10 p.m. CART: A Novel Addiction Peptide
Michael J. Kuhar, Ph.D.
Emory University
CART (cocaine- and amphetamine-regulated transcription factors)
peptides are novel putative neurotransmitters/cotransmitters. They
have psychostimulant-like effects in that they alter locomotor activity
and feeding behaviors. They are localized to regions in the brain that
are associated with these behaviors, as well as other regions,
suggesting involvement in a variety of physiologic functions.
4:10 p.m. - 4:30 p.m. Closing Remarks
Alan I. Leshner, Ph.D.
National Institute on Drug Abuse
National Institutes of Health
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