A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice.

AIM: We have reported that a selective dopamine D3 receptor antagonist YQA14 attenuates cocaine reward and relapse to drug-seeking in mice. In the present study, we investigated whether YQA14 could inhibit methamphetamine (METH)-induced locomotor sensitization and conditioned place preference (CPP) in mice. METHODS: Locomotor activity was monitored in mice treated with METH (1 mg/kg, ip) daily on d 4-13, followed by a challenge with METH (0.5 mg/kg) on d 21. CPP was examined in mice that were administered METH (1 mg/kg) or saline alternately on each other day for 8 days (METH conditioning). YQA14 was injected intraperitoneally 20 min prior to METH or saline. RESULTS: Both repetitive (daily on d 4-13) and a single injection (on the day of challenge) of YQA14 (6.25, 12.5 and 25 mg/kg) dose-dependently inhibited the acquisition and expression of METH-induced locomotor sensitization. However, repetitive injection of YQA14 (daily during the METH conditioning) did not alter the acquisition of METH-induced CPP, whereas a single injection of YQA14 (prior to CPP test) dose-dependently attenuated the expression of METH-induced CPP. In addition, the repetitive injection of YQA14 dose-dependently facilitated the extinction and decreased the reinstatement of METH-induced CPP. CONCLUSION: Brain D3 receptors are critically involved in the reward and psychomotor-stimulating effects of METH. Thus, YQA14 deserves further study as a potential medication for METH addiction.

Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia.

AIM: To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. METHODS: A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein-coupled receptors. [(35)S]GTPγS-binding assays and Ca(2+) imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. RESULTS: In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT1A receptor partial agonist and α1A adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors (100-fold lower than for the D3 receptor). In vivo, Y-QA31 (10-40 mg/kg, po) significantly inhibited MK-801-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose (1 mg/kg, po). Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. CONCLUSION: Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder.

Recently, the translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR) and both the starting point and an important rate-limiting step in neurosteroidogenesis, has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD) because it affects the production of neurosteroids, reinforcing the hypothesis that selective TSPO ligands could potentially be used as anti-PTSD drugs. As expected, we showed that chronic treatment with YL-IPA08 [N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl)-7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, caused significant suppression of enhanced anxiety and contextual fear induced in the inescapable electric foot-shock-induced mouse model of PTSD and the time-dependent sensitization (TDS) procedure. These effects were completely blocked by the TSPO antagonist PK11195. Furthermore, YL-IPA08 could increase the level of allopregnanolone in the prefrontal cortex and serum of post-TDS rats, and these effects were antagonized by PK11195. In summary, the findings from the current study showed that YL-IPA08, a potent and selective TSPO ligand, had a clear anti-PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.

The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a ß-secretase inhibitor.

(2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of ß-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen ß-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of ß-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive ß-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the ß-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit ß-secretase cleavage activity. Overall this study illustrates that EGCG is not a ß-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.

YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice.

The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with K(i-High) (0.68 × 10(-4) nM) and K(i-Low) (2.11 nM), and displays > 150-fold selectivity for D3 over D2 receptors and > 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25-25 mg/kg) or SB-277011A (12.5-25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development.

Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively-active STAT3.

STAT3 protein has an important role in oncogenesis and is a promising anticancer target. Herein, we demonstrate that a novel small molecule fluacrypyrim (FAPM) inhibits the growth of leukemia cells by a predominant G1 arrest with significant decrease of the protein and mRNA levels of cyclin D1. As cyclin D1 is transcriptionally regulated by STAT3, FAPM is then shown to markedly inhibit the STAT3 phosphorylation with marginal effect on the other signal transducers and activators of transcription, and without effect on phosphoinositide-3-kinase and mitogen-activated protein kinase pathways. Further analysis shows that FAPM significantly increases the protein tyrosine phosphatases (PTPs) activity in a dose-dependent manner, and the inhibition of PTP activation by sodium pervanadate reverses FAPM-induced suppression of STAT3 tyrosine phosphorylation, indicating an important role of PTP in the action of FAPM. Finally, FAPM treatment results in selective suppression of STAT3-mediated transcriptional activity and its downstream effectors, and subsequent induction of growth arrest and apoptosis in STAT3-dependent cancer cell lines. This study therefore identifies FAPM as a potent STAT3 activation inhibitor with possible therapeutic potential against malignancies with constitutive STAT3 activation.

[Application of reversed-phase ion-pair chromatography for universal estimation of octanol-water partition coefficients of acid, basic and amphoteric drugs].

This paper is to establish a reversed-phase ion-pair chromatography (RP-IPC) method for universal estimation of the octanol/water partition coefficients (logP) of a wide range of structurally diverse compounds including acidic, basic, neutral and amphoteric species. The retention factors corresponding to 100% water (logk(w)) were derived from the linear part of the logk'/phi relationship, using at least four isocratic logk' values containing different organic compositions. The logk(w) parameters obtained were close to the corresponding logP values obtained with the standard "shake flask" methods. The mean deviation for test drugs is 0.31. RP-IPC with trifluoroacetic acid as non classic ion-pair agents can be applicable to determine the logP values for a variety of drug-like molecules with increased accuracy.

Inhibitory effect of linomide on lipopolysaccharide-induced proinflammatory cytokine tumor necrosis factor-alpha production in RAW264.7 macrophages through suppression of NF-kappaB, p38, and JNK activation.

Linomide is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models. Previously, linomide was shown to influence macrophage function, although the mechanism was elusive. In this study, we investigated the effect of linomide on the macrophage inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), production induced by lipopolysaccharide (LPS) in vitro on the murine macrophage cell line, RAW264.7. Linomide exposure reduced LPS-evoked TNF-alpha production in a dose-dependent manner. Gel shift and reporter gene analyses revealed linomide inhibited LPS-induced NF-kappaB binding to the NF-kappaB consensus oligonucleotide and NF-kappaB-mediated reporter gene expression. Immunoblot analysis showed that linomide inhibited phosphorylation of p38 kinase and c-jun N terminal kinase (JNK) in LPS-stimulated RAW264.7 cells. Taken together, these results suggest that linomide inhibits TNF-alpha production by suppressing the activation of NF-kappaB and mitogen-activated protein kinase (MAPK), which might, at least in part, contribute to the beneficial effects of linomide in the treatment of autoimmune diseases.

Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production.

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Antidepressant-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in chronically stressed rats.

The present study aimed to examine the molecular and cellular mechanisms underlying the antidepressant-like effect of YL-IPA08, a novel TSPO ligand designed and synthesized at our institute. We firstly used the chronic unpredictable stress (CUS) procedure of rats, a well validated stress-related animal model of depression, to further determine the antidepressant-like of YL-IPA08. And we found that YL-IPA08 caused significant suppression of inhibiting of locomotor activity, reducing the sucrose preference and increasing the latency to eat induced by CUS. In addition, YL-IPA08 treatment increased the levels of progesterone and allopregnanolone in the hippocampus and prefrontal cortex of post- CUS rats. Furthermore, long-term YL-IPA08 administration reversed dendritic shrinkage, down-regulation of neurotrophic signaling pathway within the hippocampus, as well as HPA dysfunctions simultaneously observed in the CUS rats. Collectively, the evidence presented above supports the notion that binding to TSPO and the subsequent synthesis of neurosteroid, maintenance of hippocampal morphologic and functional plasticity, and preventing HPA axis dysfunction, may account for the profound molecular and cellular mechanism underlying the antidepressant-like effect of YL-IPA08.

Succinate ester derivative of δ-tocopherol enhances the protective effects against 60Co γ-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice.

α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required.

Neurochemical and behavioural effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor and partial 5-HT1A agonist.

BACKGROUND AND PURPOSE: Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A receptor agonist properties, exerts a significant antidepressant effect in various animal models. The aim of present research was to further investigate the pharmacology of YL-0919. EXPERIMENTAL APPROACH: We first investigated the target profile of YL-0919 using [35 S]-GTPγS binding and microdialysis. To determine whether the 5-HT or noradrenergic systems are involved in the antidepressant-like effect of YL-0919, the 5-hydroxytryptophan (5-HTP)-induced head-twitch test and antagonism with a high dose of apomorphine were performed. Using the learned helplessness paradigm, the novelty suppressed feeding test, the Vogel-type conflict and elevated plus-maze test, we further verified the antidepressant-like and anxiolytic-like effects of YL-0919. The effects of YL-0919 on hippocampal long-term potentiation (LTP) and sexual behaviour were also evaluated. KEY RESULTS: Data from the present study demonstrated that YL-0919 displays partial 5-HT1A receptor agonist properties, producing a greater impact on extracellular 5-HT levels than a conventional SSRI (fluoxetine), as well as significant antidepressant and anxiolytic effects. Furthermore, YL-0919 treatment rapidly influenced the synaptic plasticity (enhancing LTP) of rats. Finally, at doses close to those producing antidepressant-like effects, YL-0919 did not result in a marked inhibition of sexual function. CONCLUSIONS AND IMPLICATIONS: These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.

[Synthesis and bioactivity of substituted alpha-aminobenzylphosphonate].

AIM: To search for some substituted alpha-amino phosphonates as leading compounds with the vasodilator effects. METHODS: Target compounds were prepared from benzyl aldehyde, piperazine and diethyl phosphite using alcohol as solvent via Mannich-type reaction. In isolated rat aorta and in isolated guinea pig ileum, the vasodilator effects of compounds were investigated and evaluated whether they activated muscarine receptor. RESULTS: Seven compounds of substituted alpha-amino phosphonates have been synthesized and identified by IR, 1H NMR and elemental analysis. Three of them, compound 2a, 2b and 2c have vasodilator activity and do not activate M receptor. CONCLUSION: Two (2b and 2c) of them were found to have the notable vasodilator effect, and the rates of relaxing are (67 +/- 21) % and (82 +/- 18)%, separately. But they did not activate M receptors on ileum.

Involvement of allopregnanolone in the anti-PTSD-like effects of AC-5216.

Cholesterol import into mitochondria through the translocator protein (18 KDa) (TSPO) is the starting point and an important rate-limiting step in neurosteroidogenesis. For this reason TSPO has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD). In an effort to explore the role of TSPO in mediating the anti-PTSD effect, we first assessed the effects of the TSPO ligand AC-5216 in alleviating the enhanced anxiety and fear response in a time-dependent sensitization (TDS) procedure, a rat PTSD animal model. In the present study, we showed that chronic treatment with AC-5216 caused significant suppression of the enhanced anxiety and contextual fear induced in post-TDS rats; these effects were blocked by PK11195. Furthermore, AC-5216 treatment increased the levels of allopregnanolone in the serum, prefrontal cortex, and hippocampus of post-TDS rats, and these effects were antagonized by PK11195. These results demonstrate that AC-5216 has a clear anti-PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.

A novel dopamine D3 receptor antagonist YQA14 inhibits methamphetamine self-administration and relapse to drug-seeking behaviour in rats.

Growing preclinical evidence suggests that dopamine D3 receptor antagonists are promising for the treatment of addiction. We have previously reported a novel dopamine D3 receptor antagonist YQA14 with better pharmacokinetic behaviours and pharmacotherapeutic efficacy than other tested compounds in attenuating the reward and relapse of cocaine. In the present study, we investigated whether YQA14 can similarly inhibit methamphetamine self-administration and cue- or methamphetamine-trigged reinstatement of drug-seeking behaviour. The research illustrated that systemic administration of YQA14 (6.25-25mg/kg, i.p. 20min prior to methamphetamine) failed to alter methamphetamine (0.05mg/kg) self-administration under fixed-ratio 2. However, YQA14 (6.25-25mg/kg, i.p. 20min prior to methamphetamine) significantly and dose-dependently reduced methamphetamine self-administration under fixed-ratio 2 by a low dose (0.006, 0.0125, 0.025mg/kg) of methamphetamine and shifted the dose curve right and down. Further, YQA14 also lowered the break point under progressive-ratio reinforcement conditions in rats. Finally, YQA14 also significantly inhibited cue- or methamphetamine-triggered reinstatement of extinguished drug-seeking behaviour. Overall, our findings suggest that blockade of the dopamine D3 receptor by YQA14 attenuated the rewarding and incentive motivational effects of methamphetamine in rats and may have pharmacotherapeutic potential in the treatment of methamphetamine addiction. Thus, YQA14 deserves further investigation as a promising medication for the treatment of addiction.

The role of activation of the 5-HT1A receptor and adenylate cyclase in the antidepressant-like effect of YL-0919, a dual 5-HT1A agonist and selective serotonin reuptake inhibitor.

This study aimed to explore the possible mechanisms underlying the antidepressant-like effect of YL-0919, a novel antidepressant candidate with dual activity as a 5-HT1A receptor agonist and a selective serotonin reuptake inhibitor. The animal models commonly used to evaluate potential antidepressants, i.e., tail suspension (TST) in mice and forced swimming test (FST) in mice were used to evaluate the antidepressant effect of YL-0919. The activity of adenylate cyclase (AC) on the synaptic membrane was determined by the homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. The results indicated that YL-0919 (1.25-2.5mg/kg, i.g.) significantly decreased the immobility time in both the tail suspension test and the forced swim test in a dose-dependent manner, demonstrating the antidepressant-like effect of YL-0919. Furthermore, this effect was completely antagonized by the co-administration of WAY-100635 (0.3mg/kg, s.c.), a 5-HT1A selective antagonist. YL-0919 (10(-9)-10(-5)mol/L) was also shown to activate AC in vitro in a dose-dependent manner in synaptic membranes extracted from the rat prefrontal cortex, and this effect (10(-7)-10(-5)mol/L) was antagonized by WAY-100635 (10(-7)mol/L). Finally, the antidepressant-like effect of YL-0919 (2.5mg/kg, i.g.) was also blocked by the co-administration of H-89 (3 µg/site, i.c.v.), a protein kinase A (PKA) selective inhibitor. These results indicate that the activation of 5-HT1A receptors and the subsequent activation of the AC-cAMP-PKA signaling pathway in the frontal cortex play a critical role in the antidepressant-like effect of YL-0919.

Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats.

Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone did not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.

Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa).

It has been demonstrated that the translocator protein (18 kDa) (TSPO) plays an important role in stress-response and stress-related disorders, such as anxiety and depression, by affecting the production of neurosteroids, supporting the potential use of selective TSPO ligands as antidepressant or anxiolytic drugs. N-ethyl-N-(2-pyridinylmethyl)- 2-(3,4-ichlorophenyl)- 7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride (YL-IPA08), a novel TSPO ligand that has been synthesized at our institute, exerted a high affinity for TSPO in a crude mitochondrial fraction prepared from rat cerebellum but exhibited only a negligible affinity for the central benzodiazepine receptor. As expected, YL-IPA08 incubation with the cultured rat astrocyte cells increased the pregnenolone and progesterone concentration from the cultured medium. Moreover, YL-IPA08 produced significant antidepressant-like and anxiolytic-like effects in a series of mouse and rat behavior models. In addition, the antidepressant-like behavior of YL-IPA08 was totally blocked by the TSPO antagonist PK11195 in a tail suspension test, and the anxiolytic effect was blocked by PK11195 but not by a CBR antagonist in the elevated plus-maze test. Furthermore, compared with the CBR agonist diazepam, YL-IPA08 had no myorelaxant effects and did not affect the motor coordination, memory or hexobarbitone-induced sleep in mice. Overall, these results indicate that YL-IPA08 is a more potent and selective TSPO ligand, which exerts antidepressant-like and anxiolytic-like effects on behaviors that are mediated by TSPO but does not cause the side effects that are typically associated with conventional benzodiazepines.

Dopamine D(3) receptor deletion or blockade attenuates cocaine-induced conditioned place preference in mice.

The dopamine (DA) D3 receptor (D3R) has received much attention in medication development for treatment of addiction. However, the functional role of the D3R in drug reward and addiction has been a matter of debate. We recently reported that D3 receptor-knockout (D3(-/-)) mice display increased vulnerability to cocaine self-administration, which we interpret as a compensatory response to attenuated cocaine reward after D3R deletion. Here we report that D3(-/-) mice displayed attenuated cocaine-induced conditioned place response (CPP) compared to wild-type mice. Similarly, blockade of brain D3Rs by YQA-14, a novel DA D3 receptor antagonist, significantly and dose-dependently inhibits acquisition and expression of cocaine-induced CPP in WT mice, but not in D3(-/-) mice. These findings suggest that: 1) D3Rs play an important role in mediating cocaine's rewarding effects; and 2) YQA-14 is a highly potent and selective D3R antagonist in vivo, which deserves further study as a candidate for treatment of cocaine addiction.