Browsing by Author "Ding, Zheng-Ming"
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Item Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats(Elsevier, 2016-10) Ding, Zheng-Ming; Ingraham, Cynthia M.; Rodd, Zachary A.; McBride, William J.; Psychiatry, School of MedicineRepeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the ‘EtOH’ than ‘Water’ groups (e.g., 150 mg% EtOH: to ~ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the ‘Water’ than ‘EtOH’ groups (e.g., 200 μM sulpiride: to ~ 190–240 vs 150–160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the ‘Water’ (to ~ 150–180% and 180–230% of baseline, respectively) but not the ‘EtOH’ groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA.Item Changes in Gene Expression within the Extended Amygdala following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats(Elsevier, 2014-02) McBride, William J.; Kimpel, Mark W.; McClintick, Jeanette N.; Ding, Zheng-Ming; Edenberg, Howard J.; Liang, Tiebing; Rodd, Zachary A.; Bell, Richard L.; Department of Psychiatry, IU School of MedicineThe objective of this study was to determine changes in gene expression within the extended amygdala following binge-like alcohol drinking by male adolescent alcohol-preferring (P) rats. Starting at 28 days of age, P rats were given concurrent access to 15 and 30 % ethanol for 3 one-h sessions/day for 5 consecutive days/week for 3 weeks. Rats were killed by decapitation 3 h after the first ethanol access session on the 15th day of drinking. RNA was prepared from micropunch samples of the nucleus accumbens shell (Acb-sh) and central nucleus of the amygdala (CeA). Ethanol intakes were 2.5 – 3.0 g/kg/session. There were 154 and 182 unique named genes that significantly differed (FDR = 0.2) between the water and ethanol group in the Acb-sh and CeA, respectively. Gene Ontology (GO) analyses indicated that adolescent binge drinking produced changes in biological processes involved with cell proliferation and regulation of cellular structure in the Acb-sh, and in neuron projection and positive regulation of cellular organization in the CeA. Ingenuity Pathway Analysis indicated that, in the Acb-sh, there were several major intracellular signaling pathways (e.g., cAMP-mediated and protein kinase A signaling pathways) altered by adolescent drinking, with 3-fold more genes up-regulated than down-regulated in the alcohol group. The cAMP-mediated signaling system was also up-regulated in the CeA of the alcohol group. Weighted gene co-expression network analysis indicated significant G-protein coupled receptor signaling and transmembrane receptor protein kinase signaling categories in the Acb-sh and CeA, respectively. Overall, the results of this study indicated that binge-like alcohol drinking by adolescent P rats is differentially altering the expression of genes in the Acb-sh and CeA, some of which are involved in intracellular signaling pathways and may produce changes in neuronal function.Item Ethanol increases glutamate neurotransmission in the posterior ventral tegmental area of female Wistar rats(Wiley, 2012-04) Ding, Zheng-Ming; Engleman, Eric A.; Rodd, Zachary A.; McBride, William J.; Department of Psychiatry, IU School of MedicineBackground— The posterior ventral tegmental area (pVTA) mediates the reinforcing and stimulating effects of ethanol (EtOH). Electrophysiological studies indicated that exposure to EtOH increased glutamate synaptic function in the VTA. The current study determined the neurochemical effects of both acute and repeated EtOH exposure on glutamate neurotransmission in the pVTA. Methods— Adult female Wistar rats were implanted with microdialysis probes in the pVTA. During microdialysis, rats received acute i.p. injection of saline or EtOH (0.5, 1.0 or 2.0 g/kg) and extracellular glutamate levels were measured in the pVTA. The effects of repeated daily injections of EtOH (0.5, 1.0, or 2.0 g/kg) on basal extracellular glutamate concentrations in the pVTA and on glutamate response to a subsequent EtOH challenge were also examined. Results— The injection of 0.5 g/kg EtOH significantly increased (120–125 % of baseline), whereas injection of 2.0 g/kg EtOH significantly decreased (80% of baseline) extracellular glutamate levels in the pVTA. The dose of 1.0 g/kg EtOH did not alter extracellular glutamate levels. Seven repeated daily injections of each dose of EtOH increased basal extracellular glutamate concentrations (from 4.1 ± 0.5 to 9.2 ± 0.5 μM) and reduced glutamate clearance in the pVTA (from 30 ± 2% to 17 ± 2%), but failed to alter glutamate response to a 2.0 g/kg EtOH challenge. Conclusion— The results suggest that the low dose of EtOH can stimulate the release of glutamate in the pVTA, and repeated EtOH administration increased basal glutamate transmission in the pVTA, as a result of reduced glutamate clearance.Item Gene expression changes in glutamate and GABA-A receptors, neuropeptides, ion channels and cholesterol synthesis in the periaqueductal gray following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats(Wiley, 2016-05) McClintick, Jeanette N.; McBride, William J.; Bell, Richard L.; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear, and anxiety. The periaqueductal gray (PAG) is involved in processing pain, fear, and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied. METHODS: Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-hour sessions/d during the dark/cycle, 5 days/wk for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 to 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression. RESULTS: Ethanol significantly altered the expression of 1,670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were found to be altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes, and 4 glycine receptor genes showed decreased expression in the alcohol-drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium, and 5 calcium ion channels were found to be differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate-limiting enzyme. Genes involved in the production of myelin also had decreased expression. CONCLUSIONS: The results demonstrate that binge alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear, and anxiety, which could contribute to excessive drinking to relieve these negative effects.Item Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking(Elsevier, 2015-02) McClintick, Jeanette N.; McBride, William J.; Bell, Richard L.; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Department of Biochemistry and Molecular Biology, IU School of MedicineAlcohol binge-drinking during adolescence is a serious public health concern with long-term consequences. We used RNA sequencing to assess the effects of excessive adolescent ethanol binge-drinking on gene expression in the dorsal raphe nucleus (DRN) of alcohol preferring (P) rats. Repeated binges across adolescence (three 1h sessions across the dark-cycle per day, 5 days per week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session) significantly altered the expression of approximately one-third of the detected genes. Multiple neurotransmitter systems were altered, with the largest changes in the serotonin system (21 of 23 serotonin-related genes showed decreased expression) and GABA-A receptors (8 decreased and 2 increased). Multiple neuropeptide systems were also altered, with changes in the neuropeptide Y and corticotropin-releasing hormone systems similar to those associated with increased drinking and decreased resistance to stress. There was increased expression of 21 of 32 genes for potassium channels. Expression of downstream targets of CREB signaling was increased. There were also changes in expression of genes involved in inflammatory processes, axonal guidance, growth factors, transcription factors, and several intracellular signaling pathways. These widespread changes indicate that excessive binge drinking during adolescence alters the functioning of the DRN and likely its modulation of many regions of the central nervous system, including the mesocorticolimbic system.Item Gene expression changes in the ventral hippocampus and medial prefrontal cortex of adolescent alcohol-preferring (P) rats following binge-like-alcohol drinking(Elsevier, 2017) McClintick, Jeanette N.; McBride, William J.; Bell, Richard L.; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of MedicineBinge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including decreased hippocampal and prefrontal cortex volume and defects in memory. We used RNA sequencing to assess the effects of adolescent binge drinking on gene expression in these regions. Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-hour sessions/d during the dark/cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 to 3 g/kg/session). Ethanol significantly altered the expression of 416 of 11,727 genes expressed in the ventral hippocampus. Genes and pathways involved in neurogenesis, long-term potentiation and axonal guidance were decreased, which could relate to the impaired memory function found in subjects with adolescent alcohol binge-like exposure. The decreased expression of myelin and cholesterol genes and apparent decrease in oligodendrocytes in P rats could result in decreased myelination. In the medial prefrontal cortex, 638 of 11,579 genes were altered; genes in cellular stress and inflammatory pathways were increased, as were genes involved in oxidative phosphorylation. Overall, the results of this study suggest that adolescent binge-like alcohol drinking may alter the development of the ventral hippocampus and medial prefrontal cortex and produce long-term consequences on learning and memory, and on control of impulsive behaviors.Item Gene expression within the extended amygdala of 5 pairs of rat lines selectively bred for high or low ethanol consumption(Elsevier, 2013-11) McBride, William J.; Kimpel, Mark W.; McClintick, Jeanette N.; Ding, Zheng-Ming; Hyytia, Petri; Colombo, Giancarlo; Liang, Tiebing; Edenberg, Howard J.; Lumeng, Lawrence; Bell, Richard L.; Biochemistry & Molecular Biology, School of MedicineThe objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line-pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol-preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line-pairs. Microarray analysis revealed up to 1772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line-pairs, but not for all 5 line-pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line-pairs indicated 1014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4-6 individual named genes that significantly differed across up to 3 line-pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line-pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line-pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line-pairs.Item Inhibitory and Excitatory Alcohol-Seeking Cues Distinct Roles in Behavior, Neurochemistry, and Mesolimbic Pathway in Alcohol Preferring (P) rats(Elsevier, 2023) Hauser, Sheketha R.; Deehan, Gerald A., Jr.; Knight, Christopher P.; Waeiss, R. Aaron; Engleman, Eric A.; Ding, Zheng-Ming; Johnson, Phillip L.; McBride, William J.; Truitt, William A.; Rodd, Zachary A.; Psychiatry, School of MedicineCues associated with alcohol use can readily enhance self-reported cravings for alcohol, which increases the likelihood of reusing alcohol. Understanding the neuronal mechanisms involved in alcohol-seeking behavior is important for developing strategies to treat alcohol use disorder. In all experiments, adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a CS0, a neutral stimulus. The data indicated that presentation of an excitatory conditioned cue (CS+) can enhance EtOH- seeking while the CS- can inhibit EtOH-seeking under multiple test conditions. Presentation of the CS+ activates a subpopulation of dopamine neurons within the interfascicular nucleus of the posterior ventral tegmental area (posterior VTA) and basolateral amygdala (BLA). Pharmacological inactivation of the BLA with GABA agonists inhibits the ability of the CS+ to enhance EtOH-seeking but does not alter context-induced EtOH-seeking or the ability of the CS- to inhibit EtOH-seeking. Presentation of the conditioned odor cues in a non-drug-paired environment indicated that presentation of the CS+ increased dopamine levels in the BLA. In contrast, presentation of the CS- decreased both glutamate and dopamine levels in the BLA. Further analysis revealed that presentation of a CS+ EtOH-associated conditioned cue activates GABA interneurons but not glutamate projection neurons. Overall, the data indicate that excitatory and inhibitory conditioned cues can contrarily alter EtOH-seeking behaviors and that different neurocircuitries are mediating these distinct cues in critical brain regions. Pharmacotherapeutics for craving should inhibit the CS+ and enhance the CS- neurocircuits.Item Microinjections of acetaldehyde or salsolinol into the posterior ventral tegmental area increase dopamine release in the nucleus accumbens shell(Wiley Blackwell (Blackwell Publishing), 2013-05) Deehan, Gerald A.; Engleman, Eric A.; Ding, Zheng-Ming; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of MedicineBACKGROUND: Published findings indicate that acetaldehyde (ACD; the first metabolite of ethanol [EtOH]) and salsolinol (SAL; formed through the nonenzymatic condensation of ACD and dopamine [DA]) can be formed following EtOH consumption. Both ACD and SAL exhibit reinforcing properties within the posterior ventral tegmental area (pVTA) and both exhibit an inverted "U-shaped" dose-response curve. The current study was undertaken to examine the dose-response effects of microinjections of ACD or SAL into the pVTA on DA efflux in the nucleus accumbens shell (AcbSh). METHODS: For the first experiment, separate groups of male Wistar rats received pulse microinjections of artificial cerebrospinal fluid (aCSF) or 12-, 23-, or 90-μM ACD into the pVTA, while extracellular DA levels were concurrently measured in the AcbSh. The second experiment was similarly conducted, except rats were given microinjections of aCSF or 0.03-, 0.3-, 1.0-, or 3.0-μM SAL, while extracellular levels of DA were measured in the AcbSh. RESULTS: Both ACD and SAL produced a dose-dependent inverted "U-shaped" response on DA release in the AcbSh, with 23-μM ACD (200% baseline) and 0.3-μM SAL (300% baseline) producing maximal peak responses with higher concentrations of ACD (90 μM) and SAL (3.0 μM) producing significantly lower DA efflux. CONCLUSIONS: The findings from the current study indicate that local application of intermediate concentrations of ACD and SAL stimulated DA neurons in the pVTA, whereas higher concentrations may be having secondary effects within the pVTA that inhibit DA neuronal activity. The present results parallel the studies on the reinforcing effects of ACD and SAL in the pVTA and support the idea that the reinforcing effects of ACD and SAL within the pVTA are mediated by activating DA neurons.Item Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats(MDPI, 2022-08-05) Katner, Simon N.; Sentir, Alena M.; Steagall, Kevin B.; Ding, Zheng-Ming; Wetherill, Leah; Hopf, Frederic W.; Engleman, Eric A.; Psychiatry, School of MedicineWith the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4−5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.