Association of contextual cues with morphine reward increases neural and synaptic plasticity in the ventral hippocampus of rats

Abstract

Drug addiction is associated with aberrant memory and permanent functional changes in neural circuits. It is known that exposure to drugs like morphine is associated with positive emotional states and reward-related memory. However, the underlying mechanisms in terms of neural plasticity in the ventral hippocampus, a region involved in associative memory and emotional behaviors, are not fully understood. Therefore, we measured adult neurogenesis, dendritic spine density and brain-derived neurotrophic factor (BDNF) and TrkB mRNA expression as parameters for synaptic plasticity in the ventral hippocampus. Male Sprague Dawley rats were subjected to the CPP (conditioned place preference) paradigm and received 10 mg/kg morphine. Half of the rats were used to evaluate neurogenesis by immunohistochemical markers Ki67 and doublecortin (DCX). The other half was used for Golgi staining to measure spine density and real-time quantitative reverse transcription-polymerase chain reaction to assess BDNF/TrkB expression levels. We found that morphine-treated rats exhibited more place conditioning as compared with saline-treated rats and animals that were exposed to the CPP without any injections. Locomotor activity did not change significantly. Morphine-induced CPP significantly increased the number of Ki67 and DCX-labeled cells in the ventral dentate gyrus. Additionally, we found increased dendritic spine density in both CA1 and dentate gyrus and an enhancement of BDNF/TrkB mRNA levels in the whole ventral hippocampus. Ki67, DCX and spine density were significantly correlated with CPP scores. In conclusion, we show that morphine-induced reward-related memory is associated with neural and synaptic plasticity changes in the ventral hippocampus. Such neural changes could underlie context-induced drug relapse.

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

“…Increasing evidence suggests that the hippocampus and its dentate gyrus subregion are important in reward‐associated behavior. On a correlative level, the reward‐context associations produced by morphine conditioned place preference (CPP; Bardo & Bevins, ; Tzschentke, ) modify indices of hippocampal plasticity (Zheng, Zhang, Li, Loh, & Law, ; Portugal et al, ; Rivera et al, ; Zhang, Xu, Zheng, Loh, & Law, ; Alvandi, Bourmpoula, Homberg, & Fathollahi, ), and after psychostimulant or opiate CPP dentate gyrus neurons are activated by re‐exposure to the drug‐paired context (Barr & Unterwald, ; Rivera et al, ). Notably, during CPP testing, entrance to the drug‐paired context is preceded by phase‐locked hippocampal theta rhythm (Takano, Tanaka, Takano, & Hironaka, ), suggesting the involvement of the hippocampus in reward memory retrieval of contextual cues.…”

“…ABGCs are implicated in many aspects of hippocampal‐dependent function, including stages of context‐associated learning and memory, such as retrieval, forgetting, extinction, reinstatement (Akers et al, ; Deng, Aimone, & Gage, ; Kitamura & Inokuchi, ; Saxe et al, ; Suárez‐Pereira, Canals, & Carrión, ). ABGCs have also begun to be examined for their potential role in reward‐associated learning and memory (Canales, ; Eisch et al, ; Deschaux et al, ; Castilla‐Ortega et al, ; Zhang et al, ; Alvandi et al, ; Barr, Bray, & Forster, ). For example, ABGC deletion via image guided, hippocampal‐targeted X‐ray irradiation (IG‐IR) directed at the hippocampus results in increased subsequent intravenous (i.v.)…”

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…In this study, we analyzed epigenetic changes in response to acute and chronic morphine induction in 10 regions of the rat brain reported to be implicated in response to opiates and the formation of addiction: the midbrain contains the VTA that has been consistently implicated in addiction 23,24 ; the pons contains the locus coeruleus that is key in the integration of opioid and stress signalling and which is served by innervation from the paraventricular nucleus of the hypothalamus 25 ; the inferior and superior colliculus regulate response to opiate withdrawal through reduced activation of mu-opioid receptor signalling 26,27 ; the cerebral cortex (containing the dorsomedial prefrontal cortex), hippocampus and cerebellum are implicated in reinforcement of drug-seeking beheaviors [28][29][30] ; the medulla oblongata is crucial in pain modulation and opiate withdrawal behaviors 31 ; and the thalamus whose function is disrupted in opiate dependence 32,33 . We measured global 5-methylcytosine and 5-hydroxymethylcytosine levels, and analyzed the DNA methylation of genes previously identified as implicated in morphine tolerance (Bdnf, Comt, Il1b, Il6, Nr3c1…”

Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA‐A Receptor δ Subunit Knockout Mice

“…The stimulants may enhance cognition by increasing vigilance, attention and response speed , while opioids may depress cognitive functions . Although opioids generally inhibit hippocampal neurogenesis and cognition , in wild‐type rodents, morphine‐induced CPP is associated with increased ventral hippocampal neurogenesis and expression of BDNF and TrkB mRNAs . While the δ‐KO mice do not have drastic alterations in general learning and memory , they do have deficits in hippocampal learning and memory, neurogenesis and inhibitory functions .…”