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.
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