Research articleEffects of BDNF receptor antagonist on the severity of physical and psychological dependence, morphine-induced locomotor sensitization and the ventral tegmental area-nucleus accumbens BDNF levels in morphine- dependent and withdrawn rats
Introduction
Previous studies have shown that morphine dependence [8,22], either naloxone-precipitated [22] or spontaneous [1,8] morphine withdrawal can lead to a significant increase in autonomic-somatic symptoms, grooming and anxiety, depressive-like behaviors [12], hyperactivity [31]. Morphine dependence reflects plastic changes in neural circuitry including the brain reward system [14], which produces behavioral sensitization and reinforcing effects of drugs [9].
Previous studies demonstrated that brain-derived neurotrophic factor (BDNF) has a key role in the molecular and cellular adaptations of the reward-related brain areas, including the ventral tegmental area (VTA)-nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) circuits [29]. BDND could regulate the release of dopamine [27] and behavioral responses to drugs of abuse (dependence, sensitization, craving, relapse and cue-induced drug seeking) via receptor tyrosine kinase B (trk B) [10,20,32]. Previous studies have shown that infusion of BDNF into VTA-NAc enhances locomotor sensitization to cocaine [10], while the reduction of BDNF signaling in the NAc prevents cocaine induced-conditioned place preference (CPP) and behavioral sensitization [6].
On the other hand, the role of BDNF in the pathogenesis of depression and anxiety is still controversial. It has been shown that BDNF signaling in the brain stress system (the hippocampus and the hypothalamo-pituitary-adrenocortical axis) produces anxiolytic and antidepressant-like effects [21,28,30], and in the brain reward system produces anxiety, depressive-like behaviors [2,7]. Other studies have suggested that VTA BDNF may block [17] or preserve [32] morphine-induced CPP, while knockdown of TrkB and BDNF infusion into the NAc had no effect on morphine CPP [17]. However, the role of BDNF on behavioral changes resulting from chronic morphine administration is unknown.
So, given the well-known effects of BDNF in the development of drug dependence, TrkB receptor antagonists may be a valuable pharmacological tool for the development of novel therapeutic strategies. Therefore, this study examined the effects of TrkB receptor antagonist (ANA-12), which can be administered systemically, on the severity of physical and psychological dependence on morphine, morphine-induced locomotor sensitization, and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats.
Section snippets
Animals, induction of morphine dependence
Adult male Wistar rats (200 + 20 gr) were housed in cages under a 12-h light/dark cycle at 22–24 °C and had ad libitum access to food and water. All of the experimental procedures were conducted in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals. Rats were made dependent on morphine (Temad, Iran) subcutaneously at a dose of 10 mg/kg, twice per day at 12 h intervals for 10 days, as described previously [22].
Administration of ANA-12
ANA-12 is a small-molecule
Severity of physical morphine dependence
The overall Gellert–Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 injection than in those receiving saline (t18 = −6.326, P = .0001). Among the graded signs, abdominal contraction (T18 = −6.215, P = .0001) and loss weight (T18 = 2.212, P = .04) were higher in morphine-dependent rats receiving ANA-12 than in those receiving saline (Fig. 2A). There were no significant differences between groups among the checked signs (data not shown). Thus,
Discussion
This study shows that the systemic administration of ANA-12 exacerbated the severity of physical morphine dependence and partially attenuated the anxiety-like behaviors in morphine-dependent rats. Also, we found that the development of dependence on morphine enhanced levels of BDNF in the VTA of the morphine-dependent rats but not in the NAc, similarly to a previous study [32]. Nevertheless, withdrawal from morphine decreased the VTA and NAc BDNF levels in morphine-dependent rats. The elevated
Conclusion
Our study provides new evidence that the systemic administration of ANA-12 exacerbated the severity of physical morphine dependence and partially attenuated the anxiety-like behavior caused by chronic morphine via a TrkB-mediated mechanism in rats. To the contrary, ANA-12 did not affect the morphine-induced hyperlocomotion and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats. Thus, the blockade of the BDNF signaling may be a useful approach for the treatment of psychological
Conflict of interest
The authors report no conflicts of interest.
Acknowledgment
This work was supported by grants from Semnan University of Medical Sciences (Semnan, Iran).
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