Unconditioned and learned morphine tolerance influence hippocampal-dependent short-term memory and the subjacent expression of GABA-A receptor alpha subunits

Abstract

Background ɣ-aminobutyric acid (GABA) facilitator valproic acid may be able to curb memory disruption induced by morphine exposure. Objective The effects of the GABA facilitator valproic acid on the behavioral tolerance induced by morphine were investigated. Then hippocampal-dependent tasks named spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Finally, the changes in the expression of hippocampal GABA-A receptors underlying morphine tolerance were also examined. Methods Rats were treated with daily morphine injections, with or without distinct contextual pairing. To examine the effect of valproic acid on morphine tolerance expression, valproic acid was pretreated an hour before morphine. Spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Afterwards the changes in the expression of hippocampal GABAα receptors using the quantitative real-time PCR and western blot techniques to detect GABArα subunits mRNAs and protein level were studied. Results Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of GABArα mRNAs and protein level. Despite its attenuating effects on the development and expression of both learned and non-associative morphine tolerance, only associative morphine tolerance-induced memory dysfunction was ameliorated by valproic acid pretreatment. We also found that the expression of GABArα1, α2, α5 subunits mRNAs and GABAα protein level were affected heavier in associative morphine tolerant rats. Conclusion Our data supports the hypothesis that unconditioned and learned morphine tolerance influences short-term memory and the expression of GABArα 1, α2, α5 mRNAs and GABArα protein level differently, and adds to our understanding of the behavioral and molecular aspects of the learned tolerance to morphine effects.

A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral‐CA1, temporoammonic‐CA1, and perforant pathway‐dentate gyrus synapses along the longitudinal axis of the hippocampus

“…We found that RME increased GABA A α1 and α5 mRNA levels in the DH. The findings of our previous study also indicate an increase in the mRNA level of hippocampal GABAα1 during non-associative morphine tolerance development in rats (Ghamkharinejad et al, 2021). Others have reported significant mRNA up-regulation of the epsilon subunit of the GABA A receptor in locus coeruleus neurons during morphine withdrawal (Heikkilä et al, 2001).…”

Conditioned morphine tolerance promotes neurogenesis, dendritic remodelling and pro‐plasticity molecules in the adult rat hippocampus

“…Learning can contribute to opiate tolerance and the conditioning analysis of morphine tolerance indicates the occurrence of context-specific tolerance. [4][5][6] The hippocampus is perhaps the most iconic brain region associated with learning and memory (Kutlu et al, 2016) and it has been hypothesized that the dH and vH may have distinct roles in the different forms of learning and memory. By measuring neurogenesis and dendritic plasticity in the dH and vH, our study shows that morphine tolerance is associated with hippocampus subregion specific changes in neurogenesis and dendritic remodelling.…”

“…Neurobiological mechanisms underlying the initiation and development of opiate tolerance remain still elusive, which prevents the discovery of effective and sustained pain relief methods. Learning can contribute to opiate tolerance and the conditioning analysis of morphine tolerance indicates the occurrence of context‐specific tolerance 4–6 . The hippocampus is perhaps the most iconic brain region associated with learning and memory (Kutlu et al, 2016) and it has been hypothesized that the dH and vH may have distinct roles in the different forms of learning and memory.…”

“…Learning can contribute to opiate tolerance and the analysis of conditioned morphine tolerance indicates the occurrence of context‐specific tolerance 4–6 . In fact, it can be argued that drug addiction is increasingly viewed as a maladaptive form of learning and memory 7 .…”

“…Learning can contribute to opiate tolerance and the analysis of conditioned morphine tolerance indicates the occurrence of context‐specific tolerance. 4 , 5 , 6 In fact, it can be argued that drug addiction is increasingly viewed as a maladaptive form of learning and memory. 7 Repeated administration of an opioid in the presence of specific environmental cues (as conditioned stimuli) can induce tolerance specific to that setting (associative tolerance).…”