Ontogeny of behavioral sensitization: associative and nonassociative processes

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DESCRIPTION (provided by applicant): Repeated exposure to psychostimulant drugs (e.g., cocaine) results in the related phenomena of behavioral sensitization and conditioned activity. In adult rats, both associative and nonassociative processes are important for these phenomena, although the brain regions that mediate these processes are uncertain. Young rats, on the other hand, do not show adult-like behavioral sensitization and conditioned activity. This fact is most evident when drug pretreatment occurs on a single day (i.e., the "one-shot" paradigm). Specifically, adult rats will exhibit conditioned activity and context-dependent, but not context-independent, sensitization after a single cocaine pretreatment; whereas, young rats show robust context-dependent and context-independent sensitization and no conditioned activity. To account for this pattern of results, we have hypothesized that a single psychostimulant exposure neither initiates an excitatory associative process in young rats (i.e., accounting for the lack of conditioned activity) nor does it initiate an inhibitory associative process (i.e., accounting for the occurrence of context-independent sensitization). The purpose of this grant proposal is to distinguish the neural mechanisms underlying context-dependent and context-independent sensitization and conditioned activity. Both adult and young rats will be studied because age-dependent differences in behavioral sensitization and conditioned activity can be used as a tool for further elucidating the neural mechanisms underlying these phenomena. The purpose of the initial experiments is to (a) determine what environmental cues, if any, are necessary for young rats to exhibit behavioral sensitization (Specific Aim 1), and (b) determine the persistence of "one-shot" behavioral sensitization and conditioned activity in young and adult rats (Specific Aim 2). The neural bases of behavioral sensitization will be examined by measuring regional differences in Fos immunoreactivity after completion of conditioned activity and sensitization testing (Specific Aim 3). The pattern of Fos immunoreactivity is hypothesized to differ according to age, with only adult rats predicted to show increased Fos immunoreactivity in brain areas mediating associative components of behavioral sensitization and conditioned activity. Second, lidocaine will be microinjected into various brain regions of adult and young rats to determine whether neural mechanisms underlying the associative and nonassociative components of behavioral sensitization and conditioned activity can be parsed apart (Specific Aim 4). Third, PKC is important for associative learning so Specific Aim 5 will determine whether a PKC inhibitor (chelerythrine) will attenuate associative and/or nonassociative components of behavioral sensitization and conditioned activity in young and adult rats. Results from these various experiments will significantly enhance our knowledge concerning the ontogeny of behavioral sensitization and provide additional insight about the neural mechanisms underlying the associative and nonassociative components of behavioral sensitization and conditioned activity. Public Health Relevance: Exposure to psychostimulant drugs (e.g., cocaine and amphetamine) produces behavioral sensitization and conditioned activity. Sensitization-related changes in various brain systems may play an important role in drug addiction. The purpose of this grant proposal is to assess the importance of associative learning, and related neural changes, involved in the development and persistence of behavioral sensitization and conditioned activity in young and adult rats.