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  • Our study showed that parental


    Our study showed that parental morphine exposure in the adulthood is associated with an increased tendency toward morphine consumption in F1 but not F2 male offspring. Thus, it seems that trans-generational effects of parental morphine consumption disappear in the second generation. In support of our data, it has been suggested previously that exposure of adolescent female rats to opioids may increase the risk of substance use in their offspring (Vassoler et al., 2014). Furthermore, studies have shown that offspring of alcohol-preferring rats shows greater nicotine consumption and reinstatement after extinction compared to the offspring of alcohol-non preferring animals (He et al., 2006). In the addicted subjects’ children, higher rates of psychopathologic disorders such as depression, substance abuse, and suicidal behaviors have also been observed (Corte and Becherer, 2007). The reasons for the above-mentioned effects are not much understood; However, it has been shown that morphine exposure during the adolescent period may change maternal care (Johnson et al., 2011). Furthermore, both female and male adolescence opiate exposure may lead to neurodevelopmental alterations that increase the risk of substance abuse in the offspring (Byrnes et al., 2013). Here we found that in the first generation of morphine-exposed parents (F1-MEP), open arm time and total locomotion were decreased while open arm entry was not altered in the EPM test. Thus, it seems that anxiety-like behavior is increased in the male offspring of morphine-exposed parents. In support of our data, previous studies have demonstrated that prenatal morphine exposure increases anxiety in EPM test in the F1 offspring (Chen et al., 2015). In order to clarify the possible mechanisms involved in morphine preference in the offspring of morphine exposed parents, we evaluated the pattern of gene expression of dopamine receptors in four important reward sites of the kv1.3 inhibitor (PFC, NAc, hippocampus, and striatum). Gene expression study was not performed in the F2 offspring because their morphine preference and anxiety level were not different from their control group. We found that D1-like dopamine receptors were significantly increased in the NAc and PFC of the F1-MEP group. D1 dopamine receptor is found in all dopaminergic neurons projecting areas of the nigrostriatal and mesocorticolimbic pathways (Fremeau et al., 1991). The receptor modulates opioid-induced neuroadaptations, reward, and reinforcement. Polymorphisms of D1 dopamine receptor gene may affect susceptibility to opioid dependence (Zhu et al., 2013). Alcohol consumption and preference and similarly self-administration of cocaine are reduced in D1-like dopamine receptors knockout mice (El-Ghundi et al., 1998). Thus, the up-regulation of D1 dopamine receptors in the brain reward pathway of the F1-MEP group may be a mechanism for higher preference to morphine in these animals. D5 dopamine receptors are mostly expressed in the thalamus, hippocampus, and on the dopaminergic neurons in the ventral tegmental area (Ciliax et al., 2000). The role of these receptors in the brain is not completely determined. However, D5 receptors may participate in emotion regulation, memory, and response to novel stimuli (Knight, 1996). It has been shown that intra-NAc injection of D5 receptor antisense oligonucleotide could lead to the selective defeat of cocaine recognition (Filip et al., 2000). Lack of LTP development in DRD5 +/- mice proposes that the receptor is needed for the normal formation of synaptic plasticity (Swant et al., 2010). We found that D5 dopamine receptor was increased in the NAc, PFC, and striatum that was significant in the NAc and PFC. Besides, the receptor was considerably down-regulated in the hippocampus. Clinical studies have suggested that D5 dopamine receptor may be a candidate gene for the beginning of smoking and development to nicotine addiction (Sullivan et al., 2001). A very limited genetic association and linkage studies propose that D5 receptor gene may be a candidate gene for drug abuse (Li et al., 2006; Straub et al., 1999; Vanyukov et al., 1998). Thus, the overexpression of D5 receptor in our F1-MEP rats may be another mechanism for increased morphine preference in these animals that needs to be further evaluated in the future.