Drug overdose now exceeds car accidents as the leading cause of accidental death in the U.S. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in brain. That said, it is not known if alterations in the expression of these proteins relates to drug exposure and/or to the “addiction-like” behavior exhibited for drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater “addiction-like” behavior for heroin, in general, and with a greater willingness to work for drug, in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled non-availability of drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for drug, rather than to differences in total drug intake, per se.