Our data also showed that D dopamine receptor was down
Our data also showed that D2 dopamine receptor was down-regulated in the hippocampus, NAc and striatum of F1-MEP animals, which was only significant in the hippocampus. Both agonists and antagonists of D2 dopamine receptor are able to decrease heroin self-administration (Hemby et al., 1996; Rowlett et al., 2007). Knockout studies have suggested a critical role for D2 dopamine receptor in mediation of morphine-induced CPP (Dockstader et al., 2001; Maldonado et al., 1997) or self-administration behavior (Elmer et al., 2002). It has been reported that heroin reinforcement in rhesus monkeys is blocked by D2 receptor agonists (Rowlett et al., 2007). Thus, it seems reasonable that down-regulation of D2 dopamine receptor in the F1-MEP rat HAT Inhibitor II mass may be a risk factor toward morphine preference and dependence. In F1-MEP animals, the D3 dopamine receptor was increased in the NAc, hippocampus, and PFC and decreased in the striatum but the changes were not statistically significant. Studies have suggested that D3 dopamine receptor plays a considerable role in heroin approach behaviors motivated by conditioned stimuli (Galaj et al., 2015). The receptor up-regulates after alcohol (Vengeliene et al., 2006) and nicotine (Le Foll et al., 2003) exposure in the rat striatum and after chronic opioid consumption in human peripheral blood lymphocytes (Goodarzi et al., 2009). Researchers have reported that antagonists of D3 dopamine receptor reduce drug cue-induced reinstatement of drug seeking (Cervo et al., 2005; Galaj et al., 2014; Gilbert et al., 2005). Therefore, it is not surprising that the receptor was up-regulated (although not significantly) in our F1-MEP rats that had a higher preference for morphine compared to their control group. We also found that D4 dopamine receptor was significantly up-regulated in hippocampus and striatum and down-regulated in the PFC. The receptor is found in especially brain areas that are involved in reward and reinforcement such as striatum (Rivera et al., 2002), cerebral cortex, and hippocampus (Suzuki et al., 1995). It should be mentioned that we did not find D4 receptor expression in the NAc of study animals. This is in agreement with previous experiments reporting the lack of effect of intra-accumbal administration of L-750,667 (a selective antagonist of D4 dopamine receptor) on cocaine-seeking behavior (Anderson et al., 2006). Other experiments have also reported that the expression of D4 dopamine receptor in the NAc is too low to modify the reinforcing effects of drugs of abuse (Khan et al., 1998; Oak et al., 2000). It has been suggested that insufficient expression of this receptor in the reward system can increase the susceptibility toward drug addiction (Czermak et al., 2004). In addition, a famous polymorphism exists in the exon III of D4 dopamine receptor gene, which is expressed as a 48-bp variable number of tandem repeats (Ding et al., 2002). When the repeat number reaches 7 (7R), the response of the resulted receptor to dopamine is diminished (Rao et al., 1994). Human studies have reported that the 7R allele is a risk factor for drug addiction (Li et al., 1997; Shields et al., 1998) and is related to decrease of gene expression in human brain tissue (Simpson et al., 2010). Earlier, we have shown that the expression of D4 receptor is considerably reduced in peripheral blood lymphocytes of opioid addicts (Goodarzi et al., 2009). The reason behind the observed up- and down-regulation of dopamine receptors in the brain in the F1-MEP group may reside in epigenetic mechanisms such as DNA methylation or histone acetylation. For example, it has been shown that chronic administration of morphine increases acetylation of histone H3 lysine 14 in the NAc (Sheng et al., 2011) and basolateral amygdala in rats (Wang et al., 2015). Therefore, it is reasonable to hypothesize that histone acetylation may be involved in D1-like dopamine receptor up-regulation in F1-MEP animals. Similarly, DNA methylation may be the reason for down-regulation of dopamine receptors in reward sites of the brain. All of these hypotheses need to be examined in future studies.