Ephrins and Repeated Cocaine

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Repeated exposure to psychostimulants, such as cocaine or amphetamine, leads to a progressive and enduring augmentation of locomotor and stereotyped behaviors in rats, a phenomenon known as behavioral sensitization. It has been suggested that the neuronal plasticity underlying behavioral sensitization results in the enhancement of the incentive motivational effects of psychostimulants, which contributes to drug craving. Thus, studies examining the mechanisms underlying behavioral sensitization could provide new insight into plasticity in the central nervous system that may help elucidate the mechanisms underlying the shift to compulsive drug use among human psychostimulant addicts. Growing evidence indicates that the plasma membrane-bound ephrin ligands and their receptors, the Eph tyrosine kinases, play critical roles in synaptic remodeling both during development and in the mature nervous system. Recently, ephrins and their receptors were shown to influence plasticity in the mesotelencephalic dopamine systems, which mediate both the development and long-term expression of behavioral sensitization to psychostimulants. In mammals, eight ephrins (ephrinA1-ephrinA5; ephrinB1-ephrinB3) and thirteen Eph receptors (EphA1-EphA8; EphB1-EphB4, EphB6) have been identified to date. The goal of this grant application is to assess the influence of acute and repeated injections of cocaine on the expression of EphB1 and ephrin-B2 in the neostriatum, core and shell of the nucleus accumbens, substantia nigra and/or ventral termental area. We also will assess the influence of antisense oligonucleotide suppression of EphB1 receptor expression in these nuclei on the development of behavioral sensitization to cocaine. Rats will be used as subjects in all of these experiments.