Disrupting the Interaction of nNOS with CAPON Prevents the Reinstatement of Morphine Conditioned Place Preference.

Drug abuse is a dramatic challenge for the whole society because of high relapse rate. Environmental cues are crucial for the preference memory of drug abuse. Extinction therapy has been developed to inhibit the motivational effect of drug cues to prevent the reinstatement of morphine abuse. However, extinction therapy alone only forms a new kind of unstable inhibitory memory. We found that morphine conditioned place preference (CPP) extinction training increased the association of nitric oxide synthase (nNOS) with its carboxy-terminal PDZ ligand (CAPON) in the dorsal hippocampus (dHPC) significantly and blocking the morphine-induced nNOS-CAPON association using Tat-CAPON-12C during and after extinction training reversed morphine-induced hippocampal neuroplasticity defect and prevented the reinstatement and spontaneous recovery of morphine CPP. Moreover, in the hippocampal selective ERK2 knock-out or nNOS knockout mice, the effect of Tat-CAPON-12C on the reinstatement of morphine CPP and hippocampal neuroplasticity disappeared, suggesting ERK2 is necessary for the effects of Tat-CAPON-12C. Together, our findings suggest that nNOS-CAPON interaction in the dHPC may affect the consolidation of morphine CPP extinction and dissociating nNOS-CAPON prevents the reinstatement and spontaneous recovery of morphine CPP, possibly through ERK2-mediated neuroplasticity and extinction memory consolidation, offering a new target to prevent the reinstatement of drug abuse.

Physical exercise modifies behavioral and molecular parameters related to opioid addiction regardless of training time.

Addiction is a devastating worldwide disorder that requires effective and innovative therapies. Physical exercise could be useful in addiction treatment because it shares a common neural circuit with addictive drugs. Based on this, molecular adaptations consequent to time of exercise in opioid exposed animals were evaluated. Rats were designed as sedentary (SED) or exercised (EXE). This last group was separated to perform three different periods of swimming: short-term (S-EXE), medium-term (M-EXE) and long-term (L-EXE) for 14, 28 and 42 days, respectively. On the last exercising week, one-half of the animals from SED and all animals from S-, M- and l-EXE were concomitantly exposed to morphine-conditioned place preference (CPP) paradigm and y-maze task for behavioral assessments followed by molecular assays in both Nucleus accumbens (NAc) and hippocampus. Between SED groups, morphine conditioning showed drug-CPP and increased dopamine transporter (DAT), dopamine receptor type-1 (D1R), type-2 (D2R) and glucocorticoid receptor (GR) in both brain areas in relation to saline group. Besides the small morphine-CPP in relation to SED group, all periods decreased DAT, D1R, and GR immunoreactivity in NAc, DAT and D1R in hippocampus, while D2R in both brain areas and GR in hippocampus were primarily decreased by L-EXE. Our findings show that even a short-term exercise modifies behaviors related to drug withdrawal, changing DA targets and GR, which are closely linked to addiction. Therefore, our outcomes involving physical exercise are interesting to perform a possible clinical trial, thus expanding the knowledge about drug addiction.

Epigenetic upregulation of CXCL12 expression contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

Addiction and rewarding effect is a primary side effect of morphine, which is commonly used to relieve the acute or chronic pain. Several lines of evidence have suggested that inflammation response in the VTA contributes to morphine-induced reward (conditioned place preference, CPP), while the mechanism are poorly understood. The present study showed that repeated morphine conditioning persistently increased the expression of CXCL12 mRNA and protein in VTA. Furthermore, inhibition of CXCL12 prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rodent. In addition, molecular analysis revealed that morphine conditioning increased the occupancy of p-STAT3 in the specific binding site (-1667/-1685) of CXCL12 promoter regions, and enhanced the interaction between acetyltransferase p300 and STAT3, and, hence, induced the histone H4 hyperacetylation in the promoter region and facilitated the transcription and expression of CXCL12 in VTA. Collectively, these results, for the first time, provided the evidence that persisted increase of VTA CXCL12 via epigenetic mechanism mediated the acquisition and maintenance, but not the expression, of morphine CPP.

Increased entrances to side compartments indicate incubation of craving in morphine-induced rat and tree shrew CPP models.

In humans, cues associated with the rewarding effect of drugs of abuse induce drug craving and activate drug-associated memories after prolonged abstinence. In animal studies with the self-administration (SA) paradigm, responses to drug-associated cues increase within time after extinction, a phenomenon described as incubation of craving. Conditioned place preference (CPP) is widely used to measure the rewarding effect of drugs and the reward memory thereof. However, little is known whether responses to drug associated cues progressively increase after abstinence from the drugs in the CPP paradigm. To test whether the drug-associated cues could increase specific responses over the abstinence period in the CPP paradigm, we employed the high dose morphine-induced CPP paradigms in rats and tree shrews in the present study. We examined the CPP scores and the entrances to side chambers of the CPP apparatus to check whether they would progressively increase in the CPP paradigms. Twenty-one male adult Sprague-Dawley rats and eight adult male tree shrews were used to establish morphine-induced CPP and another ten rats treated with saline were controls for the rat experiments. After morphine conditioning, rats and tree shrews showed significant higher CPP scores at the first or second post tests than at baseline but then the CPP scores in the abstinence period decreased gradually. During the abstinence period, animals with morphine-conditioning experiences entered progressively more times to both side compartments, whereas the number of entrances to side chambers of the saline group in rats had no such significant differences. These findings suggest that progressively increased entrances to the side chambers in the extended abstinence period reflect the incubation of craving in high dose morphine-induced CPP paradigms. Also, our data imply that reward memory and drug craving can be distinguished in the CPP paradigm.