Effects of disconnection of amygdala dopamine and nucleus accumbens N-methyl-d-aspartate receptors on ethanol-seeking behavior in mice

There is a strong interest in harnessing the genetic manipulations that are possible in mice to investigate the functional neural mechanisms modulating the associative processes that control drug-seeking behavior. However, it is unknown whether intracranial techniques, such as the disconnection procedure commonly used in rats to examine serial connectivity between implicated areas, can be successfully applied to mice. We have previously demonstrated that the expression of ethanol-seeking behavior in mice is dependent upon amygdala (Amy) dopamine and nucleus accumbens (Acb) N-methyl-d-aspartate (NMDA) receptor activation (Gremel & Cunningham, 2009). Here, we used a neuropharmacological disconnection procedure to investigate whether dopamine activation of the Amy directly leading to increases in Acb glutamate release and binding of NMDA receptors modulates the expression of ethanol-seeking behavior. Immediately before testing the expression of an ethanol-induced conditioned place preference, mice were given an Amy infusion of flupenthixol and either an ipsilateral or contralateral Acb infusion of AP-5. Although both ipsilateral and contralateral manipulations reduced the expression of ethanol conditioned place preference, in a separate experiment we demonstrated that a unilateral Acb infusion of AP-5, but not Amy flupenthixol, is sufficient to disrupt preference. The finding of a significant blockade by unilateral AP-5 into the Acb precludes any conclusions about a unique role for the Amy/Acb neuroanatomical connection in this model of ethanol-seeking behavior. Further, the current results suggest potential limitations in transferring techniques from rats to mice in order to study serial interactions between neural areas underlying motivated behaviors. Nevertheless, these findings provide evidence showing that Acb NMDA receptors play an important role in the expression of ethanol-conditioned behavior.