Research ReportMorphine could increase apoptotic factors in the nucleus accumbens and prefrontal cortex of rat brain's reward circuitry
Introduction
Morphine, well known extract of opium poppy, has become one of the most potent pain relievers. Morphine also activates the brain's reward circuitry. The ability of morphine to strongly activate brain reward mechanisms and its ability to chemically alter the normal functioning of these systems can produce morphine dependency (Zhang and QCaL, 2008). Nucleus accumbens (NAc) is a critical element of the mesocorticolimbic system, a brain circuit implicated in reward and motivation. This basal forebrain structure receives glutamatergic inputs from regions including prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP) (Carlezon and Thomas, 2009), and receives the dopaminergic inputs from the ventral tegmental area (VTA) of the midbrain. Lots of evidences support the involvement of VTA dopaminergic system in drug induced reward as well as natural rewards (Nestler and Carlezon, 2006). Morphine can modulate cellular functions through modulation of molecular mechanisms. Until recently, little was known about the changes in molecular mechanisms underlying morphine effects.
Morphine may act as the modulator of cell proliferation and cell death. It has been shown that opioids can protect astrocytes from apoptosis triggered by apoptosis promoting agents (Kim et al., 2001), delay neuronal death in the avian ciliary ganglion (Meriney and Gray, 2001), and promote the growth of tumor cells (Gupta et al., 2002, Ishikawa et al., 1993, Moon, 1988). On the other hand, opioids have also been demonstrated to induce apoptosis of immunocytes (Singhal et al., 1997, Singhal et al., 1998), cancer cells (Hatzoglou et al., 1996, Tegeder et al., 2003), neuroblastoma cells such as SK-N-SH, NG108-15 and PC12 cells (Kugawa et al., 1998, Oliveira et al., 2003, Yin et al., 1997) and neuronal cells (Boronat et al., 2001, Mao et al., 2002), as well as human microglia (Hu et al., 2002). Accumulating evidence has demonstrated that opiates can cause apoptosis and cell injury of neuronal cells and other cells such as immunocytes (Singhal et al., 2001, Wang et al., 2001) and cancer cells (Yoshida et al., 2000).
In the molecular mechanisms of apoptosis various key proteins are involved in the regulation of programmed cell death (Kinloch et al., 1999, Sastry and Rao, 2000). Some members of the Bcl-2 family of proteins, such as Bcl-2 and Bcl-xL, suppress apoptosis, while the expression of others, such as the homologs Bax and Bak, are pro-apoptotic (Adams and Cory, 2007). Hochenbery et al. (1990) showed that the Bcl-2 oncoprotein, localized mainly to the mitochondrial membranes and prevents the release of cytochrome c (induced by Bax) play an important role in protecting neurons from apoptosis. Signals from either intrinsic or extrinsic agents can trigger apoptotic cascade; activation of caspases which degrade their cellular targets until cell dies (Garcia-Fuster et al., 2007, Hatzoglou et al., 1996, Singhal et al., 1999, Yin et al., 1997). The activation of effecter caspases such as caspase-3 leads to downstream cleavage of various cytoplasmic or nuclear substrates including PARP. These downstream cleavage events mark many of the morphological features of apoptotic cell death (Huppertz et al., 1999). Other studies show that different addictive drugs, such as heroin, can induce apoptosis in several cultured cell lines. Heroin induces mitochondrial malfunction, caspase activation, poly-ADP ribose polymerase (PARP) cleavage, and DNA fragmentation in PC-12 cells (Meriney and Gray (2001)).
According to the above mentioned studies, we set out to determine whether morphine would affect apoptosis in the nucleus accumbens and the prefrontal cortex by assessing the apoptotic proteins involved in the regulation of programmed cell death Bcl-2 (anti-apoptotic), Bax (pro-apoptotic), Caspase-3 and PARP in rats.
Section snippets
Behavioral test
In conditional place preference paradigm as a behavioral test, our results showed that administration of morphine in conditioning phase could induce place preference (Fig. 1). One-way ANOVA followed by Dunnett’s test [F(3,23)=15.33, P<0.0001] revealed that there were significant differences in conditioning scores among the vehicle (saline control group) and experimental groups that received morphine in 5 and 10 mg/kg. The most effective dose of morphine was 5 mg/kg (P<0.01). On the other hand,
Discussion
The present study demonstrated that administration of morphine dose-dependently induces reward and changes the level of apoptotic factors in the brain structures involved in drug reward. The major findings of this study were (i) significant increase in the amount of apoptotic factors in the NAc and PFC after application of morphine during conditioned place preference model and (ii) the most effective doses of morphine on alterations of Bax/Bcl-2 ratio, caspase-3 and PARP were 0.5 and 5 mg/kg in
Animals
Thirty-two adult male Wistar rats, (Pasteur Institute, Tehran, Iran) weighing 220–320 g, were used in these experiments. Animals were housed in groups of three per cage in a 12/12 h light/dark cycle (lights on between 7:00 AM and 7:00 PM) with free access to chow and tap water. The animals were randomly allocated to different experimental groups. Rats were habituated to their new environment and handled for 1 week before the experimental procedure was started. All experiments were executed in
Acknowledgments
This study was supported by the grant (No. 90-821-A) from Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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2021, Pharmacology Biochemistry and BehaviorCitation Excerpt :Therefore, an additional experiment should be conducted on verifying this speculation. Consistent with our findings, it has previously shown that morphine in a dose-dependent manner increased reward and the expression of apoptotic factors in the NAc and mPFC involved in drug reward (Katebi et al., 2013), and produced less dendritic arborization following extinction of morphine CPP (Leite-Morris et al., 2014). Therefore, the underlying mechanism of the increased apoptotic neuronal death in the NAc and mPFC in our study are not known.
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