Intracranial self-stimulation (ICSS) is a unique and direct measure of brain reward characterized by elicited operant (i.e. lever pressing) behavior. The mesolimbic pathway is believed to mediate many brain reward functions, including those towards natural (i.e. food, sex, etc.) as well as drug (i.e. cocaine, alcohol, etc.) rewards. In addition, ICSS is sensitive to rewarding and aversive affective states. It has been shown that increased glutamate transmission in the ventral tegmental area (VTA) and nucleus accumbens (NAc), two key brain regions in the mesolimbic pathway, are associated with increased reward. In particular, drugs such as cocaine have resulted in elevations in glutamate receptor (GluR) subunits in the VTA. The goal of this proposal is to examine how direct manipulation of GluRs affects brain reward.
The first aim of this proposal is to use herpes simplex viral (HSV) vectors to artificially increase GluR subunits in the VTA and determine if brain reward values are changed as measured by ICSS.
The second aim will examine HSV vectors injected directly into the NAc to determine if brain reward values are changed as measured by ICSS.
The final aim i s to examine alterations in gene expression in target brain regions after ICSS alone, as well as in the animals that were treated with HSV vectors (from the first and second aims) using semi-quantitative real time RT-PCR. Since genes (particularly in the NAc) such as CREB (cAMP response element binding protein), the immediate early gene c-Fos, and prodynorphin have been shown to regulate both rewarding and aversive states, the artificial upregulation of GluRs may affect gene expression in target brain regions within the mesolimbic pathway.
| Todtenkopf, Mark S; Parsegian, Aram; Naydenov, Alipi et al. (2006) Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell. J Neurosci 26:11665-9 |
