This application is for a Senior Scientist Award (K05) to provide salary support for Terry E. Robinson to continue his ongoing studies on neuroplastic adaptations engendered by drugs of abuse and the role they play in addiction. Dr. Robinson has published extensively on the effects of psychomotor stimulants on brain monoamine systems and behavior, and especially on psychomotor stimulant sensitization, withdrawal, and neurotoxicity. Recently he has focused on the ability of environmental stimuli to modulate the induction and expression of psychomotor sensitization, as well as the neurobiological mechanisms involved. The experiments proposed in the present application represent a new research direction. Most studies on the neurobiology of sensitization have focused on biochemical adaptations in neurotransmitter systems. Drs. Robinson and Kolb have recently reported, however, that repeated treatment with amphetamine or cocaine produces persistent changes in the structure of dendrites and dendritic spines on neurons in the nucleus accumbens and prefrontal cortex, two brain regions prominently implicated in mediating drug reward. These findings suggest that exposure to psychostimulant drugs alters patterns of synaptic connectivity in these brain regions, presumably also altering their function.
The specific aim of the new research direction proposed here is to further characterize the ability of psychostimulant drugs to alter neural circuitry in brain reward regions (using the Golgi technique) and to determine the extent to which these structural adaptations are related to the development of psychomotor sensitization. In the first series of experiments a variety of procedures known to increase or decrease the strength or persistence of behavioral sensitization will be used to determine the extent to which structural adaptations co-vary with the behavioral phenomenon. In the second, it will be determined whether drug self-administration experience produces effects on dendritic structure similar to those seen with experimenter- administered drug, and the relationship between the degree of exposure to self-administered cocaine, escalation of intake and morphological adaptations. In the third, more detailed information will be acquired about the exact locus of psychostimulant drug-induced changes in spine density on medium spiny neurons and pyramidal cells (i.e., are structural changes confined to one portion of the dendritic tree), and whether other cell populations are also affected. Finally, in the fourth, it will be determined whether exposure to psychostimulant drugs at one point in life limits the ability of the affected brain regions to undergo structural adaptations later in life, as a consequence of changes in environmental condition or in association with recovery from brain damage. For Dr. Robinson these experiments involve a new approach to the study of psychomotor sensitization, and to the problem of the long-term neurobiological consequences of drug use. This is the reason for a KO5 application at this time. A KO5 Award would free his time from other departmental and university responsibilities and allow him to concentrate on developing new skills in the anatomical and molecular analysis of persistent drug effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA000473-03
Application #
6523146
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Volman, Susan
Project Start
2000-09-20
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$127,332
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ferrario, Carrie R; Robinson, Terry E (2007) Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsychopharmacol 17:352-7
Ferguson, Susan M; Fasano, Stefania; Yang, Pengwei et al. (2006) Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity. Neuropsychopharmacology 31:2660-8
Samaha, Anne-Noel; Robinson, Terry E (2005) Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci 26:82-7
Crombag, Hans S; Gorny, Grazyna; Li, Yilin et al. (2005) Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex. Cereb Cortex 15:341-8
Samaha, Anne-Noel; Yau, Wai-Ying Wendy; Yang, Pengwei et al. (2005) Rapid delivery of nicotine promotes behavioral sensitization and alters its neurobiological impact. Biol Psychiatry 57:351-60
Briand, Lisa A; Robinson, Terry E; Maren, Stephen (2005) Enhancement of auditory fear conditioning after housing in a complex environment is attenuated by prior treatment with amphetamine. Learn Mem 12:553-6
Ferguson, Susan M; Thomas, Mark J; Robinson, Terry E (2004) Morphine-induced c-fos mRNA expression in striatofugal circuits: modulation by dose, environmental context, and drug history. Neuropsychopharmacology 29:1664-74
Hu, Ming; Crombag, Hans S; Robinson, Terry E et al. (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81-5
Samaha, Anne-Noel; Mallet, Nicolas; Ferguson, Susan M et al. (2004) The rate of cocaine administration alters gene regulation and behavioral plasticity: implications for addiction. J Neurosci 24:6362-70
Ferguson, Susan M; Robinson, Terry E (2004) Amphetamine-evoked gene expression in striatopallidal neurons: regulation by corticostriatal afferents and the ERK/MAPK signaling cascade. J Neurochem 91:337-48

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