Repeated exposure to amphetamine (AMPH) induces sensitization to its behavioral-activating effects. The development of sensitization depends on (1) the direct actions of AMPH in the ventral tegmental area (VTA), the cell body region of the mesocorticolimbic DA system, and (2) AMPH-induced glutamatergic neurotransmission in this region. Moreover, sensitization is accompanied by morphological changes in mesocorticolimbic DA circuitry. During development, the DA system is organized, at least in part, by the netrin-1 family of guidance cues. Both netrin-1 and its DCC and UNC-5 receptors continue to be expressed in the mesocorticolimbic DA system of the adult brain. Importantly, netrin-1 receptor deficient mice do not develop sensitization to AMPH, implicating an involvement of netrin-1 signaling in AMPH-induced plasticity of the DA system. To explore this possibility, adult rats were pretreated with repeated AMPH or saline, and DCC and UNC-5 receptor expression was examined in DA cell body and terminal regions using western blot. Striking AMPH-induced increases in the expression of DCC and UNC-5 were observed in the VTA only. Remarkably, these changes depended on NMDA-mediated glutamatergic neurotransmission. This is the first demonstration that repeated AMPH pretreatment regulates netrin-1 receptor expression in the adult brain and suggests that netrin-1 receptor regulation may be involved in the development of AMPH-induced sensitization.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.101874 |
| Date | January 2007 |
| Creators | Yetnikoff, Leora. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Psychiatry.) |
| Rights | © Leora Yetnikoff, 2007 |
| Relation | alephsysno: 002652756, proquestno: AAIMR38443, Theses scanned by UMI/ProQuest. |
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