Guo-hua Bi, M.D.

@article{Han2017,

title = {CB1 Receptor Activation on VgluT2-Expressing Glutamatergic Neurons Underlies Delta(9)-Tetrahydrocannabinol (Delta(9)-THC)-Induced Aversive Effects in Mice.},

author = {Xiao Han and Yi He and Guo-Hua Bi and Hai-Ying Zhang and Rui Song and Qing-Rong Liu and Josephine M Egan and Eliot L Gardner and Jing Li and Zheng-Xiong Xi},

doi = {10.1038/s41598-017-12399-z},

issn = {2045-2322 (Electronic); 2045-2322 (Linking)},

year  = {2017},

date = {2017-09-26},

journal = {Sci Rep},

volume = {7},

number = {1},

pages = {12315},

address = {Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA.},

abstract = {Cannabis can be rewarding or aversive. Cannabis reward is believed to be mediated by activation of cannabinoid CB1 receptors (CB1Rs) on GABAergic neurons that disinhibit dopaminergic neurons in the ventral tegmental area (VTA). However, little is known about the mechanisms underlying cannabis aversion in rodents. In the present study, CB1Rs are found not only on VTA GABAergic neurons, but also on VTA glutamatergic neurons that express vesicular glutamate transporter 2 (VgluT2). We then used Cre-Loxp transgenic technology to selectively delete CB1Rs in VgluT2-expressing glutamatergic neurons (VgluT2-CB1 (-/-)) and Cre-dependent viral vector to express light-sensitive channelrhodopsin-2 into VTA glutamatergic neurons. We found that photoactivation of VTA glutamatergic neurons produced robust intracranial self-stimulation (ICSS) behavior, which was dose-dependently blocked by DA receptor antagonists, but enhanced by cocaine. In contrast, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of cannabis, produced dose-dependent conditioned place aversion and a reduction in the above optical ICSS in VgluT2-cre control mice, but not in VgluT2-CB1 (-/-) mice. These findings suggest that activation of CB1Rs in VgluT2-expressing glutamate neurons produces aversive effects that might explain why cannabinoid is not rewarding in rodents and might also account for individual differences in the hedonic effects of cannabis in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{You2017,

title = {The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats.},

author = {Zhi-Bing You and Jun-Tao Gao and Guo-Hua Bi and Yi He and Comfort Boateng and Jianjing Cao and Eliot L Gardner and Amy Hauck Newman and Zheng-Xiong Xi},

doi = {10.1016/j.neuropharm.2017.09.007},

issn = {1873-7064 (Electronic); 0028-3908 (Linking)},

year  = {2017},

date = {2017-09-06},

journal = {Neuropharmacology},

volume = {126},

pages = {190--199},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.},

abstract = {The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4-10 mg/kg, i.p.) dose-dependently decreased oxycodone self-administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4-4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4-10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2-015 or BAK4-54) provide new lead molecules for development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yang:2017aa,

title = {Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats.},

author = {Hong-Ju Yang and Hai-Ying Zhang and Guo-Hua Bi and Yi He and Jun-Tao Gao and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28700935},

doi = {10.1016/j.celrep.2017.06.046},

issn = {2211-1247 (Electronic)},

year  = {2017},

date = {2017-07-11},

urldate = {2017-07-11},

journal = {Cell Rep},

volume = {20},

number = {2},

pages = {319--332},

address = {Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.},

abstract = {Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhang:2017aa,

title = {The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic.},

author = {Hai-Ying Zhang and Guo-Hua Bi and Hong-Ju Yang and Yi He and Gilbert Xue and Jianjing Cao and Gianluigi Tanda and Eliot L Gardner and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28266501},

doi = {10.1038/npp.2017.41},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2017},

date = {2017-03-29},

journal = {Neuropsychopharmacology},

volume = {42},

number = {9},

pages = {1871--1883},

address = {Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.},

abstract = {(+/-)Modafinil ((+/-)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (+/-)MOD analogs, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters, and enzymes. Although at a concentration of 10 muM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like, and sigma1 receptors. R-MOD was more selective, but had much lower affinity at the DAT (Ki=3 muM) than JJC8-016 (Ki=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhang2017,

title = {Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats.},

author = {Hai-Ying Zhang and Guo-Hua Bi and Xia Li and Jie Li and Hong Qu and Shi-Jian Zhang and Chuan-Yun Li and Emmanuel S Onaivi and Eliot L Gardner and Zheng-Xiong Xi and Qing-Rong Liu},

doi = {10.1038/npp.2014.297},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2015},

date = {2015-01-01},

journal = {Neuropsychopharmacology},

volume = {40},

number = {4},

pages = {1037--1051},

address = {Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.},

abstract = {The discovery of functional cannabinoid receptors 2 (CB2Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}