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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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