Yong-hui Dang

Distinct roles of dopamine D3 receptors in modulating methamphetamine-induced behavioral sensitization and ultrastructural plasticity in the shell of the nucleus accumbens

Persistent changes in behavior and psychological function that occur as a consequence of exposure to drugs of abuse are thought to be mediated by the structural plasticity of specific neural circuits such as the brains dopamine (DA) system. Changes in dendritic morphology in the nucleus accumbens (NAc) accompany drug‐induced enduring behavioral and molecular changes, yet ultrastructural changes in synapses following repeated exposure to drugs have not been well studied. The current study examines the role of DA D3 receptors in modulating locomotor activity induced by both acute and repeated methamphetamine (METH) administration and accompanying ultrastructural plasticity in the shell of NAc in mice. We found that D3 receptor mutant (D3−/−) mice exhibited attenuated acute locomotor responses as well as the development of behavioral sensitization to METH compared with wild‐type mice. In the absence of obvious neurotoxic effects, METH induced similar increases in synaptic density in the shell of NAc in both wild‐type and D3−/− mice. These results suggest that D3 receptors modulate locomotor responses to both acute and repeated METH treatment. In contrast, the D3 receptor is not obviously involved in modulating baseline or METH‐induced ultrastructural changes in the NAc shell.

Fluoride exposure during development affects both cognition and emotion in mice.

Previous studies have suggested that sodium fluoride (NaF) may have adverse effects on neurodevelopment. In the present study, we evaluated developmental neurotoxicity by assessing in cognitive function and emotional behavior in BalB/C mice treated with NaF. Mice were weaned at 4weeks, and water or different NaF concentrations (2, 5, or 10mg/L in drinking water) were provided for 4weeks. We found that exploration preference in the novel object recognition test was significantly altered in mice treated with 5 and 10mg/L NaF compared with the water-treated control animals. Furthermore, mice treated with 5 and 10mg/L NaF showed significantly longer escape latencies, less time in the target quadrant, and fewer platform-crossing numbers in the Morris water maze compared to those in the control group. In addition, mice treated with 10mg/L NaF spent a lower percentage of time in the open arms in the elevated-plus maze, while no significant changes were noted in the open and close arm entries or the total arm entries. We also found that the cumulative immobility time in the tail suspension test was longer in mice treated with 5 and 10mg/L NaF compared to the control group. Only 10mg/L NaF-treated mice showed longer immobility time compared with the control group. Collectively, our data indicate that developmental exposure to NaF induces cognitive deficits and anxiety-depression-like behaviors in mice.

Effects of immobilization stress on emotional behaviors in dopamine D3 receptor knockout mice

A central problem in understanding the dopamine system in anxiety and depression is to specify functions of different members of the dopamine receptor family. Recent studies have reported that the dopamine D2/D3 receptor agonist pramipexole exerts an antidepressant-like effect in the chronic mild stress model and in the behavioral despair model, suggesting dopamine D3 receptor may be an important target for antidepressant actions. The aim of the present study was to examine the role of dopamine D3 receptor on the anxiety-like and depression-like behaviors induced by immobilization stress. We subjected D3 receptor knockout (D3KO) mice to a series of behavioral paradigms after acute (1 h) or chronic (1 h a day for 14 days) immobilization stress. The results showed that immobilization stress significantly altered the anxiety-like behaviors (open field test and elevated plus maze) and depression-like behaviors (tail suspension test) in both D3KO mice and their wild-type littermates. Moreover, further analysis of the data indicated that the D3KO mice, but not their littermates, failed to show a change in immobility time in the tail suspension test after the acute and chronic stress as compared to intact controls, suggesting an increased resistance to the immobilization stress given before behavioral tests. Although our study did not suggest a significant role of D3 receptor in regulating basal anxiety-like and depression-like behaviors, it demonstrated the mice lacking D3 receptor might be more resistant to stressful procedure than their WT littermates.

Roles of levo-tetrahydropalmatine in modulating methamphetamine reward behavior

Levo-tetrahydropalmatine (l-THP), as an alkaloid purified from the traditional Chinese herbal medicine Corydalis and Stephania, has been widely used to produce many traditional Chinese herbal preparations. The effect of l-THP on methamphetamine-induced reward learning still remains unclear although it has been proved to be effective on treating allodynia and drug addiction. This experiment has been designed to examine the effect of l-THP on the acquisition, expression, extinction, and reinstatement of methamphetamine-induced conditioned place preference (CPP) in mice. The results show that methamphetamine (METH) could induce CPP in mice at doses of 0.5mg/kg, 1.0mg/kg and 2.0mg/kg respectively, but l-THP alone could not do so. Meanwhile, l-THP could not induce conditioned place aversion at doses of 1.25mg/kg to 20.0mg/kg in mice, but it could attenuate the acquisition and expression of METH-induced CPP and facilitate the extinction of METH-induced CPP in mice. Besides, l-THP could inhibit the reinstatement of METH-induced CPP at the dose of 10.0mg/kg whether it was given in the extinction training phase or 30min before the reinstatement. These results suggest that l-THP can globally suppress the rewarding properties of METH on all phases of the CPP task and it may have potential effects on the treatment of METH abuse.

Methamphetamine induces alterations in the long non-coding RNAs expression profile in the nucleus accumbens of the mouse

BackgroundRepeated exposure to addictive drugs elicits long-lasting cellular and molecular changes. It has been reported that the aberrant expression of long non-coding RNAs (lncRNAs) is involved in cocaine and heroin addiction, yet the expression profile of lncRNAs and their potential effects on methamphetamine (METH)-induced locomotor sensitization are largely unknown.ResultsUsing high-throughput strand-specific complementary DNA sequencing technology (ssRNA-seq), here we examined the alterations in the lncRNAs expression profile in the nucleus accumbens (NAc) of METH-sensitized mice. We found that the expression levels of 6246 known lncRNAs (6215 down-regulated, 31 up-regulated) and 8442 novel lncRNA candidates (8408 down-regulated, 34 up-regulated) were significantly altered in the METH-sensitized mice. Based on characterizations of the genomic contexts of the lncRNAs, we further showed that there were 5139 differentially expressed lncRNAs acted via cis mechanisms, including sense intronic (4295 down-regulated and one up-regulated), overlapping (25 down-regulated and one up-regulated), natural antisense transcripts (NATs, 148 down-regulated and eight up-regulated), long intergenic non-coding RNAs (lincRNAs, 582 down-regulated and five up-regulated), and bidirectional (72 down-regulated and two up-regulated). Moreover, using the program RNAplex, we identified 3994 differentially expressed lncRNAs acted via trans mechanisms. Gene ontology (GO) and KEGG pathway enrichment analyses revealed that the predicted cis- and trans- associated genes were significantly enriched during neuronal development, neuronal plasticity, learning and memory, and reward and addiction.ConclusionsTaken together, our results suggest that METH can elicit global changes in lncRNA expressions in the NAc of sensitized mice that might be involved in METH-induced locomotor sensitization and addiction.

Dopamine D3 receptor regulates basal but not amphetamine-induced changes in pain sensitivity in mice

Pain is a complex and subjective experience that involves not only the transduction of noxious stimuli by nociceptive fibers, but also the cognitive and emotional processing by the brain. Previous studies on the transmission of nociception suggest that the activation of mesolimbic dopamine (DA) system plays an important role in mediating the suppression of tonic pain. The aim of the current study was to examine the role of DA D3 receptor in modulating basal and amphetamine-induced changes in pain sensitivity in mice. We used wild-type and D3 receptor mutant mice and determined allodynia induced by both noxious heat (radiant heat) and mechanical (von Frey hair) stimuli. We show that D3 receptor mutant mice exhibit hypoalgesia in both the tail-flick test and von Frey hair test compared to wild-type mice. Amphetamine-induced hyperalgesia in both D3 receptor mutant and wild-type mice in the tail-flick test and von Frey hair test. There was no significantly difference in the relative change in pain sensitivity between wild-type and D3 receptor mutant mice in both the tail-flick test and von Frey hair test following amphetamine administration. These results suggest that the D3 receptor regulates the transmission of nociception. Moreover, amphetamine can lower pain threshold in mice.

Effect of microinjecting of 5-aza-2-deoxycytidine into ventrolateral orbital cortex on depressive-like behavior in rats.

DNA methylation and histone modification are two major epigenetic mechanisms involved in the pathophysiology of major depressive disorder (MDD) and the action of antidepressants. We and others have recently shown that epigenetic regulation through histone acetylation within ventrolateral orbital cortex (VLO) contributes to the antidepressant-like effects of histone deacetylase inhibitors [HDACi, such as valproic acid (VPA) and MS-275] observed in rats. However, there is so far no investigation focused on the effect of DNA methylation in VLO on depressive-like behaviors. Here, we examined the effects of the DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-aza) on rat forced swimming test (FST) and locomotor activity when microinjected into VLO. We found that bilateral intra-VLO injections of 5-aza increased the duration of immobility in FST in a dose-dependent manner compared to vehicle-treated controls. The effects of 5-aza observed in the FST paradigms could not be attributed to non-specific decreases in activity since the inhibition of DNA methylation in VLO did not cause general impairment in locomotor activity. These results add to the evidence that DNA hypomethylation in VLO is involved in regulating depressive-like behaviors, and suggest that the effect of DNA methylation on depressive-like behaviors appear to be brain region-dependent.

HINT1 is involved in the behavioral abnormalities induced by social isolation rearing.

Social isolation (SI) rearing has been demonstrated to induce behavioral abnormalities like anxiety, impulsivity, aggression, and learning and memory deficits which are relevant to core symptoms in patients with some certain neuropsychiatric disorders. But the underlying pathophysiological mechanisms remain unclear. Recent studies have revealed HINT1 has close relation with diverse neuropsychiatric diseases. In this present study, the SI rearing mice exhibited depression-like and aggressive behavior. Besides, HINT1 protein levels decreased in PFC but increased in HIP. Based on the data obtained, we concluded that HINT1 is involved in the behavioral abnormalities induced by social isolation and exerts distinct roles in different encephalic regions.

Intranasal Delivery of Recombinant AAV Containing BDNF Fused with HA2TAT: a Potential Promising Therapy Strategy for Major Depressive Disorder

Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD.

Antidepressant effect of recombinant NT4-NAP/AAV on social isolated mice through intranasal route

The purpose of the present study was to observe the depression-like behavior induced by social isolation; detect the antidepressant effect of a recombinant adeno-associated virus (AAV) expressing NAP on social isolation mice by intranasal delivery. After construction of NT4-NAP/AAV, expression of NAP was confirmed in vitro. 3-week-old C57/BL mice were bred individually in cages as social isolation-rearing. Six weeks later, the first subset of mice underwent behavioral tests and western blot; the second was for enzyme-linked immunosorbent assay. NT4-NAP/AAV was delivered quaque die by nasal administration for consecutive 10 days before behavioral test. Several depression-like behaviors were observed in social isolation mice, including decreased relative sucrose preference, longer immobility time in forced swimming test, lower plasma corticosterone and decreased brain-derived neurotrophic factor in hippocampus. Thus, social isolation procedure appears to be an animal model of depression with good face and construct validity. Whats more, the antidepressant effect in social isolation-rearing mice was observed after intranasal administration of NT4-NAP/AAV, suggesting that this might be a promising therapeutic strategy for depressive disorder.