Conditioned aversive memory associated with morphine withdrawal increases brain‐derived neurotrophic factor in dentate gyrus and basolateral amygdala

Abstract

Morphine has been shown to increase the expression of brain‐derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of conditioned naloxone‐precipitated morphine withdrawal on BDNF and its precursor protein, proBDNF. We used the conditioned place aversion (CPA) paradigm to evaluate the role of corticotropin‐releasing factor (CRF)/CRF1 receptor signaling on the BDNF expression and corticosterone plasma levels after CPA expression and extinction. Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone‐associated compartment. The expression of BDNF and proBDNF in the dentate gyrus (DG) and basolateral amygdala (BLA) was measured in parallel with the corticosterone plasma levels with and without CRF1 receptor blockade. Mice subjected to conditioned naloxone‐induced morphine withdrawal showed an increased expression of BDNF (in DG and BLA) in parallel with an enhancement of corticosterone plasma levels. These results demonstrated that BDNF expression together with the increased activity of hypothalamic‐pituitary‐adrenocortical (HPA) axis are critical to the acquisition of aversive memory. However, we have observed a decrease in corticosterone plasma levels and BDNF expression after CPA extinction reaffirming the importance of BDNF in the maintenance of aversive memory. In addition, the pre‐treatment with the CRF1 receptor antagonist CP‐154 526 before naloxone conditioning session impaired morphine withdrawal‐induced aversive memory acquisition, the increased corticosterone plasma levels, and the expression of BDNF observed after CPA expression in the DG and BLA. Altogether, present results are suggesting a clear connection between HPA axis and BDNF in the formation and extinction of aversive memory.

Hippocampal and amygdalar increased BDNF expression in the extinction of opioid-induced place preference

“…The role of amygdalar BDNF in extinction of addictive behaviors is understudied, though it may be regulating aversive responses to withdrawal ( Heldt et al, 2014 ). Yet, opposing effects were reported for alcohol and opioids; having decreased BDNF in AMY during alcohol withdrawal ( You et al, 2014 ), but an increase during morphine-induced withdrawal ( Martínez-Laorden et al, 2020 ). However, decreased BDNF expression in alcohol withdrawal might be due to the absence of an extinction phase.…”

MicroRNA‐132 is involved in morphine dependence via modifying the structural plasticity of the dentate gyrus neurons in rats

“…In this work, we collected the brain tissue at 6 h after the last morphine injection to avoid the acute effect of single morphine exposure (the half‐life of morphine is 2–4 h) and the effect of long‐term abstinence (>24 h)‐induced emotional and mental symptoms. Third, our work focused on the hippocampal DG, which is not one of the traditional members of the reward system like LC, NAc, VTA, PFC, and hippocampal CA1, 1,21,30 but increasing evidence has shown that the DG is not only involved in morphine‐associated memory but also in morphine dependence 11–15 …”

“…[8][9][10] Moreover, recent studies reveal that the DG is activated in morphine-dependent rodents. [11][12][13][14][15] Rats receiving 10 days successive increasing doses of morphine treatment display an evident c-fos induction in the DG. 15 Brain imaging research in rats shows that Meng Jia and Xuewei Wang contributed equally.…”

“…Morphine exposure‐induced structural plasticity is observed mostly in the mesolimbic dopamine system and other pathways mediating rewarding, among which the dentate gyrus (DG) of the hippocampus, a part of the limbic system, is long thought to mediate spatial memory 7 and context‐associated memory of drug abuse 8–10 . Moreover, recent studies reveal that the DG is activated in morphine‐dependent rodents 11–15 . Rats receiving 10 days successive increasing doses of morphine treatment display an evident c‐fos induction in the DG 15 .…”