Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System / 神经科学通报·英文版

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.

Effect of Heroin on DLG4 Expression in Hippocampus, Amygdala and Frontal Cortex of Rats / 法医学杂志

OBJECTIVE@#To observe the expression of discs large homolog 4 (DLG4) protein in hippocampus, amygdala and frontal cortex of rats and evaluate postsynaptic density in heroin dependence.@*METHODS@#The rat heroin dependent model was established by increasing intraperitoneal injection of heroin. DLG4 proteins in hippocampus, amygdala and frontal cortex of heroin dependent 9, 18, 36 days rats were detected with immunohistochemical staining and compared with that in the control group.@*RESULTS@#DLG4 proteins in hippocampus, amygdala and frontal cortex were gradually reduced with extension of heroin dependent time.@*CONCLUSION@#Heroin dependence can affect postsynaptic density of hippocampus, amygdala and frontal cortex. The changes become more apparent with extension of heroin dependence time.

The suppression of c-fos in neuron apoptosis induced by heroin / 法医学杂志

OBJECTIVE@#To explore the changes of c-fos in apoptosis of cerebellar granular neuron of neonatal SD rats induced by heroin and the mechanisms of neuronal injury caused by heroin.@*METHODS@#Primary cerebellar granular neuron were cultured in vitro, the model of apoptosis induced by heroin was established. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were adopted to investigate the changes of c-fos in cell models.@*RESULTS@#Ten microg/mL of heroin was the optimal dose to induce the apoptosis of cerebellar granular neuron at 48 h. Both Western blotting and RT-PCR showed down regulation of c-fos expression.@*CONCLUSION@#Heroin could induce apoptosis of cerebellar granular neuron and down regulation of c-fos, which may be one of the apoptosis mechanisms.

The effects of heroin on intracellular free Ca2+ of rat myocardium / 法医学杂志

OBJECTIVE@#To observe the effects of heroin on intracellular free Ca2+ in rat myocardium.@*METHODS@#The effects of heroin on intracellular free Ca2+ were observed in cultured neonatal rat myocardium by measuring intracellular free Ca2+ concentration using calcium fluorescent probe Flou-3/AM and laser scanning confocal microscope.@*RESULTS@#Different doses and concentrations of heroin appeared to have different effects on intracellular free Ca2+ concentrations, with a dosage dependent short linear increase in the fluorescence intensity (i.e., Ca2+ concentration) leading to [Ca2+]i peak.@*CONCLUSION@#Heroin could affect concentrations of [Ca2+]i in myocardium and its dosage related effect needs further investigation.

Apoptosis of cultured cortical neurons of rat's brain induced by heroin / 法医学杂志

OBJECTIVE@#To investigate whether heroin can directly induce apoptosis in primary cultured cortical neurons of rat's brain.@*METHODS@#Cultured primary neurons cultures were obtained from cerebral cortex of embryo rats. After 7 days, the cells were incubated with different concentrations of heroin (purity-80%) for 24 hours. The neuronal survival was assessed by cell viability counting with fluorescent diacetate (FDA) staining. The morphological and biochemical changes were observed with Hoechst 33258 fluorescent staining and then analyzed by agarose gel electrophoresis, respectively.@*RESULTS@#After treatment with different concentrations of heroin, the neurons showed a decreased survival rate in a dose dependent manner, and there was a significant difference in the survival rate between the heroin group and the control group (P < 0.05). When exposed to different concentrations of heroin, neurons exhibited the morphological and biochemical features of apoptosis, including cell shrinkage, neurite degeneration, network disappearance, condensation and aggregation of nuclear chromatin, and the formation of DNA ladders. With the increase of heroin concentration of rat's brain more apoptotic bodies were seen.@*CONCLUSION@#Heroin can directly induce apoptosis in primary cultured cortical neurons in rat's brain.

Heroína / Heroin

O consumo de heroína se tem revelado preocupante dentro do cenário mundíal Complicações clínicas e psiquiátricas graves têm sido relatadas entre os usuários. Nos Estados Unidos da América do Norte, a prevalência de abuso de heroína é menor do que 1 porcento; entretanto, os efeitos negativos deste consumo asseguram a severidade do problema. No Brasil, o uso deste opiáceo vem despontando como um fenômeno íncipiente, porém não menos preocupante.