br Introduction Addiction to opioids such
Introduction Addiction to opioids such as morphine is a chronic disorder that affects the mesocorticolimbic dopaminergic pathway in the brain. Activation of the pathway ultimately leads to dopamine release in the nucleus accumbens (NAc) (Di Chiara et al., 1998) and stimulation of dopamine receptors. These receptors are considered as two main categories: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors, each of which is generated from a different gene (Sibley et al., 1993). Activation of D1-like and D2-like dopamine receptors decreases motivation to seek reward or facilitate the reinforcing properties of addictive drugs, respectively (Li et al., 2006). Both GANT 58 to and environmental factors are involved in an individual\'s vulnerability to addiction (Cloninger et al., 1981). It is estimated that genetic variation accounts for nearly half of a person\'s risk to develop substance abuse disorders (Goldman et al., 2005). Besides, aggregation of drug addiction among family members may develop as far as fifth-degree relatives (Tyrfingsson et al., 2010). In addition to genetics, epigenetic factors also contribute to the inheritance of a variety of disorders, including drug addiction. In fact, epigenetics may provide the missing link between environmental stimuli and genetic heritability of the disorders (Bohacek and Mansuy, 2013; Danchin et al., 2011). Data indicate that approximately 50% of addicted parents\' children are hospitalized for psychiatric disorders. Besides, parental alcohol abuse could lead to some long-term concerns for their 15- to 27-years-old kids such as augmented mortality and self-destructive actions (e.g. suicide or drug abuse) (Christoffersen and Soothill, 2003). In animal studies, exposure of female rats to morphine in the adolescent period could alter the response of their offspring to morphine (Byrnes, 2005). At the molecular level, histone acetylation and DNA methylation as two major epigenetic events have been shown to occur in the NAc and striatum after drug exposure (Anier et al., 2010; Maze et al., 2010; Sheng et al., 2011). In almost all the researches that have investigated the effect of parental morphine addiction on their offspring, the female rat was exposed to morphine either during the adolescent period (Byrnes et al., 2011, 2013) or in pregnancy (Riley and Vathy, 2006; Szutorisz et al., 2014; Chen et al., 2015; Shen et al., 2016). Adolescent period could affect the development of neural and endocrine systems, and pregnancy studies make the researcher unable to exclude the direct effects of morphine on the fetus. Thus, an important question was remained to be answered: does the induction of opioid addiction in adult rats (which excludes the effects of morphine on developmental events) several days before gestation (which means that animals are abstinent at the time of mating, and fetus is not directly exposed to the drug) influences the behavior and addiction vulnerability of their offspring? Therefore, here we have evaluated the effect of parental morphine exposure before gestation on anxiety behavior and morphine preference in F1 and F2 male generations. Besides, in order to investigate the involved mechanisms, we have assessed the gene expression of dopamine receptors in different parts of the reward pathway in the rat brain.
Discussion Both genetic and environmental factors are involved in drug addiction. Recent evidence has shown that epigenetics may potentially influence the trans-generational effects of drug abuse. Hypermethylation of mu opioid receptors in the sperm samples of opioid-addicted individuals may be an example of the effects of drugs that could be transferred to the next generation and influence their addiction susceptibility (Chorbov et al., 2011). Besides, mu, kappa and delta opioid receptors are found in oocytes, which may be involved in the trans-generational inheritance of addiction (Yohn et al., 2015). Furthermore, previous studies have shown that altered response to morphine is transmittable to the next generation of morphine administered rats (Akbarabadi et al., 2018; Byrnes, 2005; Byrnes et al., 2013). Physiological and organic alterations in the brain of the progeny of morphine exposed parents have also been reported (Cicero et al., 1991; Sarkaki et al., 2008).