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Electroacupuncture prevents cocaine-induced conditioned place preference reinstatement and attenuates ΔFosB and GluR2 expression.

ABSTRACT: Acupuncture has been used for treating drug addiction since the 1970s, but little is known about the mechanisms by which acupuncture affects drug cue-induced relapse. The transcription factor delta-FosB (ΔFosB) plays a critical role in behavior and pathology after chronic use of cocaine. ΔFosB regulates glutamate receptor signaling and dendritic spine morphology in animal models. This experimental study compared the effects of electroacupuncture (EA) at acupoints LI4 and LI11 with those of another potentially beneficial intervention, gabapentin (GBP), alone or in combination, on reinstatement of cocaine-induced conditioned place preference (CPP) and levels of ΔFosB and glutamate receptor subunit 2 (GluR2) expression in the nucleus accumbens (NAc). EA at LI4 and LI11 significantly prevented cue-induced cocaine CPP reinstatement, whereas needle insertion without electrical stimulation at these acupoints had no such effect. EA also significantly attenuated cocaine-induced increases in ΔFosB and GluR2 expression in the NAc. Unexpectedly, these effects were reversed when GBP was combined with EA. Treatment with EA at LI4 and LI11 prevented cocaine-induced increases in dendritic spine density in the NAc core and shell. Our results suggest that EA at LI4 and LI11 may prevent cocaine relapse by modulating ΔFosB and GluR2 expression, as well as dendritic spine density.

SUBMITTER: Nguyen ATM

PROVIDER: S-EPMC8249658 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.

Project description:Parvalbumin (PV)-positive cells are GABAergic fast-spiking interneurons that modulate the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and their output to brain areas associated with learning and memory. The majority of PV cells within the mPFC are surrounded by a specialized extracellular matrix structure called the perineuronal net (PNN). We have shown that removal of PNNs with the enzyme chondroitinase-ABC (Ch-ABC) in the mPFC prevents the consolidation and reconsolidation of cocaine-associated conditioned place preference (CPP) memories. Here we examined the extent to which retrieval of a CPP memory during cocaine-primed reinstatement altered the levels and function of PV neurons and their surrounding PNNs during the reconsolidation period. We further determined the extent to which PNN removal prior to reinstatement altered PV intensity levels and PV cell function. Male Sprague-Dawley rats were trained for cocaine-induced conditioned place preference (CPP) followed by extinction training, microinjection of Ch-ABC in the prelimbic PFC, and cocaine-induced reinstatement. Rats were sacrificed immediately prior to reinstatement or at 2 h, 6 h, or 48 h after reinstatement for immunohistochemistry or 2 h later for electrophysiology. Our findings indicate that PNN removal only partially diminished reinstatement. Cocaine-primed reinstatement produced only minor changes in PNN or PV intensity in vehicle controls. However, after PNN removal, the intensity of remaining PNN-surrounded PV cells was decreased at all times except at 2 h post-reinstatement, at which time cocaine increased PV intensity. Consistent with this, in vehicle controls, PV neurons naturally devoid of PNNs showed a similar pattern to Ch-ABC-treated rats prior to and after cocaine reinstatement, suggesting a protective effect of PNNs on cocaine-induced changes in PV intensity. Using whole-cell patch-clamp, cocaine-primed reinstatement in Ch-ABC-treated rats decreased the number of elicited action potentials but increased excitatory synaptic transmission, which may have been compensatory. These findings suggest that without PNNs, cocaine-induced reinstatement produces rapid changes in PV intensity and PV cell excitability, which may in turn regulate output of the mPFC post-memory retrieval and diminish the maintenance of cocaine memory during reconsolidation.

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Electroacupuncture prevents cocaine-induced conditioned place preference reinstatement and attenuates ΔFosB and GluR2 expression.

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