Morphine-Associated Contextual Cues Induce Structural Plasticity in Hippocampal CA1 Pyramidal Neurons

Abstract

In people with a prior history of opioid misuse, cues associated with previous drug intake can trigger relapse even after years of abstinence. Examining the processes that lead to the formation and maintenance of the memories between cues/context and the opioid may help to discover new therapeutic candidates to treat drug-seeking behavior. The hippocampus is a brain region essential for learning and memory, which has been involved in the mechanisms underlying opioid cravings. The formation of memories and associations are thought to be dependent on synaptic strengthening associated with structural plasticity of dendritic spines. Here, we assess how dendritic spines in the CA1 region of the hippocampus are affected by morphine-conditioning training. Our results show that morphine pairing with environmental cues (ie, the conditioned place preference (CPP) apparatus) triggers a significant decrease in the number of thin dendritic spines in the hippocampus. Interestingly, this effect was observed regardless of the expression of a conditioned response when mice were trained using an unpaired morphine CPP design and was absent when morphine was administered in the home cage. To investigate the mechanism underlying this structural plasticity, we examined the role of Rho GTPase in dendritic spine remodeling. We found that synaptic expression of RhoA increased with morphine conditioning and blocking RhoA signaling prevented the expression of morphine-induced CPP. Our findings uncover novel mechanisms in response to morphine-associated environmental cues and the underlying alterations in spine plasticity.

Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure

“…A recent study found that 1 day withdrawal from repeated morphine administration decreased thin spine density in hippocampal neurons, and this loss of thin spines was associated with increased expression of total RhoA in hippocampal synapses. These effects were present when morphine was administered in a novel environment (conditioning chamber) and not elicited following home cage administered morphine (Fakira et al 2016). This suggests that hippocampal synaptic RhoA induction encodes associations between environmental cues and drug exposure rather than frank morphine reward.…”

“…These effects were present when morphine was administered in a novel environment (conditioning chamber) and not elicited following home cage administered morphine (Fakira et al . ). This suggests that hippocampal synaptic RhoA induction encodes associations between environmental cues and drug exposure rather than frank morphine reward.…”

“…Notably, pharmacological inhibition of the RhoA pathway selectively in the hippocampus reduces morphine‐induced place preference, suggestive of a reduction in drug‐seeking behavior (Fakira et al . ). We found that RhoA pathway activity reduces spine density in NAc MSNs, thereby recapitulating the effects of multi‐week morphine withdrawal.…”

“…While most studies to date have focused on the Rac1, Rap1, and Ras small GTPases, recent work suggests that drugs of abuse also engage the RhoA small GTPase network. In particular (Fakira et al 2016) found that 1 day withdrawal from 4 days of escalating doses of morphine triggers an increase in the expression of RhoA in hippocampal synapses, and this RhoA induction, in turn, is essential for the formation of morphine-mediated conditioned place preference. Nevertheless, the effects of morphine withdrawal on the RhoA network in the NAc remain unclear.…”

Hippocampal Activity Dynamics During Contextual Reward Association in Virtual Reality Place Conditioning

“…Following operant water-conditioning, mice underwent a Mor-CPP protocol in the VR environment ( Fig. 2A), modified based on our previous reports Fakira et al, 2016). First, animals underwent a pre-conditioning test in which they ran freely, without reward, to establish a baseline for time spent in each compartment as a measure of any inherent bias individual animals may have for one context over the other.…”