A novel aspect of this work is that our pathway analysis of the PFC transcriptome highlights a complex of genes related to dopaminergic neuroplasticity that have been implicated in addiction to ethanol and other drugs. This network has hub genes including PPP1R1B (DARPP-32), DRD2, DRD1, FOS and FOSB (Figure 4A), all of which are supported as key components of the progressive and persistent changes in synaptic plasticity that arise from chronic drug exposure [54]. In particular, DARPP-32 regulates the alcohol sensitivity of NMDA receptors [55] and contributes to genetic differences in alcohol consumption in the AA/ANA rats [56] as well as having a role in actions of many drugs of abuse [57]. This network also includes PDYN (prodynorphin) which is of interest as it regulates alcohol consumption through dopamine neurotransmission [58] and PDYN polymorphisms are linked to alcoholism [59], [60] as well as heroin and cocaine addiction in humans [61]. Genetic manipulation in PDYN or κ-opioid receptors also supports the importance of this network in regulation of alcohol consumption in mice [62], [63]. Two phosphodiesterases, PDE10A and PDE1B, are part
