Positive and negative regulators of nucleus accumbens amphetamine-produced conditioned place preference in rats.

摘要

The rewarding properties of amphetamine in rats can be demonstrated using conditioned place preference (CPP). The nucleus accumbens (NAc) plays a critical role in CPP produced by amphetamine. Three experiments explored the role of signaling molecules and metabotropic glutamate receptors in NAc amphetamine-produced CPP. The first study assessed the role of the mitogen-activated protein kinase family, including ERK, p38 and JNK. Amphetamine administration directly into NAc of anaesthetized animals resulted in ERK activation. In behavioral tests, ERK or p38 but not JNK inhibition impaired CPP. Two major groups of metabotropic glutamate receptors exist. Amphetamine-produced ERK activation depends on Group I metabotropic glutamate receptors. In a second set of studies, antagonists to Group I or Group II receptors impaired amphetamine-produced CPP.; In a third set of studies I tested whether inhibiting a molecule which downregulates signaling molecules activated by amphetamine will enhance CPR Protein kinase A (PKA) has been shown to mediate amphetamine-produced CPP. Calcineurin is a protein phosphatase activated by PKA, which negatively regulates PKA downstream targets. I predicted that a PKA activator will impair amphetamine-produced CPP, whereas a calcineurin inhibitor will enhance it. Some rats received a lower number of conditioning sessions not sufficient to produce CPP with a standard amphetamine dose. These rats showed CPP if receiving a calcineurin inhibitor after amphetamine conditioning sessions. In contrast, rats receiving a PKA activator showed impaired CPP when receiving partial conditioning sessions or the number of conditioning sessions normally sufficient to establish CPP.; My thesis explored the role of metabotropic glutamate receptors and signaling molecules in nucleus accumbens amphetamine-produced CPP. Inhibitors of ERK or p38 mitogen-activated protein kinases and antagonists to Group I or Group II metabotropic glutamate receptors impaired CPP. CPP was similarly impaired by a PKA activator. In contrast, a calcineurin inhibitor enhanced CPP. The results suggest that these signaling molecules and metabotropic glutamate receptors may regulate the establishment of nucleus accumbens amphetamine-produced CPP and may also mediate other forms of reward-related learning.