Harry L June
Howard University
Project start date: 2008-12-15
Project end date: 2013-11-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Harry L June
GABA RECEPTOR MECHANISMS IN ALCOHOL REINFORCEMENT
Harry L June, Professor
Psychologyindiana Univ-purdue Univ At Indianapolis
620 Union Drive, Room 518
indianapolis, In 462025167
Grant 5R01AA011555-03 from National Institute On Alcohol Abuse And Alcoholism IRG: ALTX
Abstract: There is increasing evidence that GABAA-benzodiazepine (BDZ) receptors are involved in the regulation of EtOH-self- administration. The goal of this proposal is to identify specific neurobiological substrates of GABAA-BDZ neurotransmission which mediate EtOH reinforcement. To accomplish this goal, the selectively bred high alcohol drinking (HAD) 1 and 2 rat lines will be used. The main hypothesis to be tested is that GABAA-BDZ neuroanatomical circuits in two extended amygdala loci [e.g., central nucleus of the amygdala, bed nucleus of the stria terminalis], mediate in part, activation of underlying neuroanatomical substrates contributing to the reinforcing properties of EtOH. First, dose-effect and time course studies will examine the capacity of site-specific microinjections of high affinity BDZ inverse agonists, a BDZ antagonist and the GABAA antagonist SR 95531 in the central nucleus of the amygdala and bed nucleus of the stria terminalis to attenuate EtOH intake using scheduled controlled responding (i.e., operant methodology). It is hypothesized that inverse agonists and antagonists with similar binding affinity should be equally effective as EtOH antagonists. Effective antagonists (i.e., inverse agonists) of EtOH-maintained responding should be antagonized by competitive BDZ antagonist, since their suppression should be mediated by a direct action at the BDZ component of the GABAA complex. Second, to systematically evaluate the selectivity of the agents to suppress EtOH-motivated responding, a 4-stage behavioral analysis will be employed. It is hypothesized that agents (e.g., inverse agonists, BDZ antagonist, SR 95531) which specifically affect the reinforcing aspects of EtOH should not alter responding of alternative reinforcers with similar reinforcing efficacy (i.e., saccharin), or similar post-ingestional caloric properties (i.e., sucrose). Finally, it is hypothesized that interactions at GABAA-BDZ sites may modulate the function of monoaminergic neurons sustaining EtOH-seeking behaviors. These studies should contribute to a scientific understanding of the role of GABAA-BDZ receptor complex plays in regulating EtOH seeking behavior
Keywords: GABA receptor, benzodiazepine receptor, ethanol, neural transmission, neurotransmitter antagonist, reinforcer, substance abuse related behavior alcoholic beverage consumption, gamma aminobutyrate, neuroanatomy, receptor binding, sucrose, sweetening agent behavioral /social science research tag, laboratory rat, microinjection
Project start date: 1999-09-14
Project end date: 2003-05-31
5R01AA011555-03 (2001): $170004
5R01AA011555-02 (2000): $165094
1R01AA011555-01A2 (1999): $177227
GABAa Receptor Subunits In Alcohol Reinforcement
Harry L June, Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 5R01AA012407-04 from National Institute On Alcohol Abuse And Alcoholism IRG: ALTX
Abstract: The goal of this proposal is to evaluate the role of the alphal and alpha5 GABAA receptor subunits in EtOH reinforcement. To accomplish this, the high alcohol drinking (HAD) rat lines, the alphal knock out (KO) mice and their wild type counter part (WT) will be used. The first hypothesis to be tested is whether postsynaptic alpha1 receptors in the ventral pallidum (VP) of HAD rats contribute to the reinforcing properties of EtOH. Site-specific microinjection of selective alphal antagonists in the VP will be evaluated for their capacity to attenuate EtOH-maintained responding. It is hypothesized that the alphal antagonist will selectively decrease EtOH responding since the alphal subunit is present in very high levels throughout the VP. The second hypothesis will evaluate the degree to which complete deletion of the alphal subtype modulates acquisition of alcohol-seeking behaviors using the KO and WT mice. It is hypothesized that the KO mice will initiate alcohol-maintained responding because alcohol reward has been shown to be regulated by multiple neurotransmitter systems; however, the drinking in the KO mice is predicted to be significantly lower than the WT. Moreover, we hypothesize that the magnitude of reduction with alphal antagonists in the KOs will be less than that seen in the WT because the KOs will be devoid of a functional alphal subunit. The third specific aim will test the hypothesis that enhanced alphal binding selectivity, longer lived in vivo and more water soluble ligands will result in a more optimal alcohol antagonist. Finally, the fourth hypothesis will assess whether alpha5 receptors in the hippocampus (CA1 and CA3) modulate putative GABAergic EtOH reward substrates (e.g., nucleus accumbens, basal amygdala, bed nucleus of the stria terminalis). To accomplish this, microinjection of selective alpha5 inverse agonists in the hippocampus to attenuate EtOH-maintained responding will be evaluated. We hypothesized that the alpha5 ligands will selectively decrease EtOH responding in the hippocampus since the alpha5 containing receptors are primarily localized in the hippocampus. In contrast, the selective alpha5 ligands infused in the VP will not alter EtOH responding, since this locus is completely devoid of alpha5 subunits, and the ligands have a very low affinity for the alphal receptor subtype. These studies should further our understanding of the GABAA receptor mechanisms in EtOH-seeking behavior and may possibly identify agents which may have potential in reducing alcohol drinking in humans.
Keywords: GABA receptor, alcoholism /alcohol abuse, ethanol, neuropharmacology, receptor sensitivity, hippocampus, psychological reinforcement, receptor binding, receptor expression, substance abuse related behavior, genetically modified animal, laboratory mouse, laboratory rat, microinjection
Project start date: 2002-05-01
Project end date: 2007-04-30
5R01AA012407-04 (2005): $228257
5R01AA012407-03 (2004): $229237
5R01AA012407-02 (2003): $230180
1R01AA012407-01A2 (2002): $243337
THE ALPHA-1 GABAA RECEPTOR REGULATES ALCOHOL-DRINKING BEHAVIORS
Harry L June
Department/ Educational Institution Type:
Grant 5R21AA016933-02 from National Institute On Alcohol Abuse And Alcoholism
Abstract: It is well established that the rewarding properties of ethanol [EtOH] are mediated in part by GABAA-receptor mechanisms; however, only recently has research demonstrated that the a1 receptor subunit, particularly those within the ventral pallidum [VP], may be the critical GABAergic receptor regulating EtOH reinforcement. The primary objective of this proposal will be to further evaluate the role of the GABAA a1-containing receptor subunit in regulating EtOH-seeking behaviors by employing a combination of neuropsychopharmacological and molecular biology techniques. To accomplish this goal, the selectively-bred high alcohol-drinking [HAD-1] rats will be used. The primary hypothesis to be tested is that a selective inhibition of the GABAA a1 receptor containing subunit within the VP of HAD-1 rats will lead to selective reductions in EtOH-motivated behavior, with little or no effect on sucrose-motivated behaviors. The inhibition of the GABAA a1 subunit will be accomplished by constructing a herpes simplex virus [HSV] vector, which will utilize the siRNA sequence specific, posttranscriptional gene silencing mechanism. This vector will then be infused directly into the VP of HAD-1 rats via bilateral guide cannulae. It is hypothesized that a selective reduction in EtOH-maintained responding will be observed following infusion of the vector-mediated siRNA amplicon into the VP. Specifically, reinforcer and neuroanatomical specificity will be expected, as neither suppression on sucrose maintained responding following infusion of the active virus in the VP, nor suppression on alcohol responding infusion of the active virus into the neuroanatomical control locus [e.g., caudate putamen] will be expected. In subsequent studies, a combination of in situ reverse transcriptase-PCR, immunohistochemistry, and Western analyses [immunoblotting] will be used to determine the success of the HSV-siRNA viral vector manipulations. These studies should extend our understanding of the role of the GABAA a1 receptor subtype in the regulation of alcohol-drinking behaviors
Keywords: Absolute ethanol; Alcohol consumption; Alcohol Drinking; alcohol ingestion; alcohol intake; alcohol product use; alcohol use; Alcohol, Ethyl; alcoholic beverage consumption; alcoholic drink intake; Alcohols; alpha-D-Glucopyranoside, beta-D-fructofuranosyl; Behavior; Bilateral; Breeding; Cannulas; Cell/Tissue, Immunohistochemistry; Chemical Class, Alcohol; Control Locus; drinking behavior; Ethanol; ethanol consumption; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ETOH; EtOH drinking; etoh use; Fostering; Genetics, in situ Hybridization; Globus Pallidus; Goals; Grain Alcohol; heavy metal lead; heavy metal Pb; Herpes labialis Virus; Herpes Simplex Virus; Herpes Simplex Virus Vector; herpesvirus; Herpesvirus hominis; HSV; HSV vector; human herpesvirus 1 group; IHC; Immunoblotting; Immunohistochemistry; Immunohistochemistry Staining Method; In Situ; In Situ Hybridization; in situ Hybridization Staining Method; In Vitro; in vivo; Infusion; Infusion procedures; Investigators; Lead; Ligands; Mediating; Method LOINC Axis 6; Methodology; Methods and Techniques; Methods, Other; Methylcarbinol; Mice, Mutant Strains; Molecular Biology Techniques; motivated behavior; mouse mutant; Mutant Strains Mice; N, N, 6-trimethyl-2-(4-methylphenyl)imidazo(1, 2a)pyridine-3-acetamide hemitartrate; neurobehavioral; novel; pallidum; Pb element; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Property; Property, LOINC Axis 2; Psychological reinforcement; Putamen; putamen; Quelling; Rat-1; Rat-1 Cells; receptor; Receptor Protein; Regulation; Reinforcement; Reinforcement (Psychology); reinforcer; Research; Research Personnel; Researchers; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; Rewards; RNA Interference; RNA Silencing; RNA Silencings; RNA, Small Interfering; RNAi; Role; RT-PCR; RTPCR; Saccharose; Sequence-Specific Posttranscriptional Gene Silencing; Simplexvirus; siRNA; Small Interfering RNA; social role; Specificity; Structure of putamen; success; Sucrose; Techniques; Testing; vector; Viral Vector; Virus; Viruses, General; zolpidem
Project start date: 2008-04-01
Project end date: 2011-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2011
PFA/PA: PA-06-181
5R21AA016933-02 (2009): $178125
EFFICACY OF NOVEL TRIPLE UPTAKE INHIBITORS IN TREATING ALCOHOLISM AND DEPRESSION
Harry L June, Professor
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 5R01AA017461-02 from National Institute On Alcohol Abuse And Alcoholism
Abstract: Alcoholism and depression often co-occur in humans, but it has been difficult to find a single treatment which is effective against both conditions. This comorbid condition is frequently observed following impulsive binge alcohol consumption, as well as in compulsive drinking in humans. The primary objective of the present proposal is to identify effective compounds at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating the comorbid condition. To accomplish this, a series of triple monoamine uptake inhibitors [TUIs] [e.g., DOV 216,303, DOV 21,947, and DOV 102,677], which have been successfully tested in Phase I studies for depression with published preclinical-antidepressant [AD] efficacy, will be evaluated. The first aim will test the hypothesis that orally-administered TUIs can effectively attenuate excessive alcohol drinking in the binge and prolonged repeated alcohol deprivation [PRAD] models using the alcohol-preferring [P] rat. Initial studies will employ DOV 102,677 [our lead compound], recently shown to reduce limited alcohol responding for six days after a single administration. It is hypothesized that acute treatment for binge drinking, and chronic treatment for PRAD drinking, will selectively reduce intake in both models. The second aim will test the hypothesis that TUIs will effectively attenuate the negative affective states [e.g., withdrawal symptomatology], characterized by reductions in pleasure [i.e., anhedonia] and increased immobility [i.e., indicative of depressive-like behaviors] following alcohol-induced abstinence from binge and PRAD drinking. Negative affective states will be inferred using the intracranial self-stimulation [ICSS] and forced swim test [FST] models. We hypothesize that both acute and chronic DOV treatments will attenuate the negative affective states associated with alcohol-induced abstinence from the two heavy drinking models. Aim 3 will test the hypothesis that similar neurobiological substrates mediate alcohol dependence and the negative affective states associated with binge drinking within the extended amygdala [EA] [i.e., bed nucleus of the stria terminalis (BST); central nucleus of the amygdala (CeA); shell of the nucleus accumbens (nAcc)]; and medial prefrontal cortex (mPfc). To evaluate this hypothesis, site-specific microinjection of our lead TUI [DOV 102, 677] will be given in the EA loci and mPfc. However, because little if any data are available on the precise brain substrates which regulate the actions of TUIs, we will initially employ the c-fos technology in naove P rats to delineate multiple CNS loci which may mediate the actions of DOV 102, 677. These studies should identify effective compounds at the preclinical level which may serve as prototypes for further evaluation of clinical efficacy in treating comorbid alcoholism and depression, as well as shed light on the neurobiological commonalities which regulate the two conditions. PUBLIC HEALTH RELEVANCE The present proposal will evaluate a series of novel antidepressant medications for their capacity to reduce excessive alcohol drinking and alcohol abstinence effects in a rodent model of alcohol abuse. The primary objective of the proposal will be to successfully identify agents that may be used to treat both depression and alcohol addiction in humans
Keywords: Abstinence; Acute; Affective; Alcohol Drinking; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anhedonia; Antidepressant Agent; Antidepressant Drugs; Antidepressant Drugs, Tricyclic; Antidepressants; Antidepressants, Tricyclic; Antidepressive Agents; Antidepressive Agents, Tricyclic; Attenuated; Bed Nucleus of Stria Terminalis; Behavior; Brain; Cell Nucleus; Chemical Class, Alcohol; Chronic; Clinical Trials, Phase I; Common Rat Strains; DOV 216, 303; DOV 216303; Data; Dependence; Drugs; Early-Stage Clinical Trials; Emotional Depression; Encephalon; Encephalons; EtOH drinking; Ethanol dependence; Evaluation; FOS gene; G0S7; Heavy Drinking; Human; Human Volunteers; Human, General; Individual; Intake; Lead; Light; Mammals, Rats; Man (Taxonomy); Man, Modern; Medial; Mediating; Medication; Microinjections; Modeling; Nervous System, Brain; Neurobiology; Nucleus; Nucleus Accumbens; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Photoradiation; Pre-Clinical Model; Preclinical Models; Prefrontal Cortex; Property; Property, LOINC Axis 2; Protooncogene FOS; Publishing; Rat; Rattus; Rodent Model; SCHED; SSRI; Schedule; Selective Serotonin Reuptake Inhibitor; Selective serotonin re-uptake inhibitor; Self Stimulation; Series; Site; Stria Terminalis Nucleus; Structure of terminal stria nuclei of preoptic region; Swimming; Symptoms of depression; Technology; Testing; Tricyclic Antidepressive Agents; Volunteers, Human; Withdrawal; abstaining from alcohol; abstaining from ethanol; abstinence from alcohol; abstinence from ethanol; ing; alcohol abstinence; alcohol addiction; alcohol dependency; alcohol ingestion; alcohol intake; alcohol problem; alcohol product use; alcohol use; alcohol-dependent; alcoholic beverage consumption; alcoholic drink intake; amygdaloid nuclear complex; binge alcohol consumption; binge drinking; c fos; c-fos Gene; c-fos Proto-Oncogenes; clinical efficacy; depression; depressive; depressive symptoms; deprivation; drink heavily; drinking; drug/agent; episodic drinking; ethanol abstinence; ethanol abuse; ethanol addiction; ethanol consumption; ethanol dependency; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol-dependent; etoh use; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; extreme drinking; hazardous alcohol use; heavy alcohol use; heavy metal Pb; heavy metal lead; inhibitor; inhibitor/antagonist; monoamine; neurobiological; neurobiological mechanism; novel; phase 1 study; phase 1 trial; phase I trial; pleasure; pre-clinical; preclinical; problem drinking; protocol, phase I; prototype; serotonin reuptake inhibitor; uptake; v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog
Relevance: The present proposal will evaluate a series of novel antidepressant medications for their capacity to reduce excessive alcohol drinking and alcohol abstinence effects in a rodent model of alcohol abuse. The primary objective of the proposal will be to successfully identify agents that may be used to treat both depression and alcohol addiction in humans
Project start date: 2008-12-15
Project end date: 2013-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2010
PFA/PA: PA-07-070
5R01AA017461-02 (2010): $352688
Sponsored Links Excellgen http://Excellgen.com
ANXIETY AND ALCOHOLISM: NOVEL BENZODIAZPINE TREATMENTS
Harry L June
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 5R01AA017963-02 from National Institute On Alcohol Abuse And Alcoholism
Abstract: Alcoholism and anxiety frequently co-occur in humans; however, it has been difficult to find a single treatment which is effective against both conditions. Substantial evidence suggests that the motivational aspects of alcohol withdrawal (e.g., increased anxiety and anhedonia) referred to as negative affective states play an important role in the maintenance of excessive alcohol drinking, and may also be associated with relapse. Evidence also suggests a salient role for GASAergic mechanisms in regulating excessive alcohol drinking and the negative affective states associated with abstinence. The initial objective of the present proposal is to identify novel a1 GASAA subtype-preferring ligands at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating both excessive alcohol drinking and the negative affective states associated with abstinence. To accomplish this, Aim 1 will employ our established pharmacophore/receptor model of SDl binding sites to synthesize novel a1 subtype-preferring ligands with reduced efficacies at diazepam sensitive (DS) subtypes (e.g., a1,2,3,5)´ Once the two agents (e.g., I3CCt, 3-PSC) have been synthesized, Aim 2 will test the hypothesis that their chronic oral administration for 30 consecutive days can effectively attenuate excessive binge alcohol drinking in the high alcohol drinking (HAD) rats using the drinking-in-the-dark-multiple-scheduled-access [DIDMSA] model. We hypothesize that chronic SDl treatments will attenuate excessive binge drinking. Aim 3 will test the hypothesis that chronic SDl treatment will attenuate negative affective states (e.g., increased anxiety and anhedonia) associated with abstinence. The second objective will be to identify select GASAA receptor subunits which may playa role in the regulation of excessive alcohol drinking and the negative affective states associated with abstinence. Aim 4 will test the hypothesis that inhibition of the a1 receptor subunits within the ventral´ pallidum (VP) will lead to selective time-dependent reductions in binge alcohol responding. To down regulate the a1 subunit, a novel siRNA sequence will be delivered into the VP by bilateral microinfusion using a herpes simplex virus-1 (HSV-1) amplicon vector. These studies should identify novel pharmacotherapies for further evaluation of clinical efficacy in treating comorbid alcoholism and anxiety at the preclinical level. In addition, they should shed light on the salient neuronal mechanisms in the regulation of comorbid alcoh.olism and anxiety, which could be important inultimately leading to a successful treatment for the comorbid condition
Keywords: 7-Chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one; Abstinence; Administration, Oral; Affective; Alcohol Drinking; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anhedonia; Anxiety; Attenuated; Benzodiazepine Compounds; Benzodiazepines; Bilateral; Binding Sites; Chemical Class, Alcohol; Chronic; Combining Site; Common Rat Strains; Development; Diazepam; Drug Administration, Oral; Drug Therapy; EtOH drinking; Ethanol dependence; Evaluation; GABA Receptor; Genes; Globus Pallidus; HHV-1; HSV-1; HSV1; Heavy Drinking; Herpes Simplex Virus 1; Herpes Simplex Virus Type 1; Herpesvirus 1 (alpha), Human; Herpesvirus 1, Human; Human; Human herpes simplex virus type 1; Human herpesvirus 1; Human herpesvirus type 1; Human, General; Individual; Lateral; Lead; Ligands; Light; Maintenance; Maintenances; Mammals, Rats; Man (Taxonomy); Man, Modern; Modeling; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; Oral Administration; Pb element; Pharmacotherapy; Phase; Photoradiation; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Procedures; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNA, Small Interfering; RNAi; Rat; Rat-1; Rat-1 Cells; Rattus; Reactive Site; Receptor Protein; Receptors, gamma-Aminobutyric Acid; Regulation; Relapse; Role; SCHED; Schedule; Seizures; Sequence-Specific Posttranscriptional Gene Silencing; Small Interfering RNA; Technology; Testing; Time; Tremor; Valium; Withdrawal; abstaining from alcohol; abstaining from ethanol; abstinence from alcohol; abstinence from ethanol; alcohol abstinence; alcohol addiction; alcohol dependency; alcohol ingestion; alcohol intake; alcohol product use; alcohol use; alcohol withdrawal; alcohol-dependent; alcoholic beverage consumption; alcoholic drink intake; amygdaloid nuclear complex; chronic EtOH drinking; chronic alcohol consumption; chronic alcohol drinking; chronic alcohol ingestion; chronic alcohol use; chronic ethanol consumption; chronic ethanol drinking; chronic ethanol ingestion; clinical efficacy; deprivation; drink heavily; drinking; effective therapy; ethanol abstinence; ethanol addiction; ethanol consumption; ethanol dependency; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol withdrawal; ethanol-dependent; etoh use; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; extreme drinking; heavy alcohol use; heavy metal Pb; heavy metal lead; herpes simplex i; herpes virus 1, human; human alphaherpesvirus 1; intraoral drug delivery; neuronal; novel; pallidum; pharmacophore; pre-clinical; preclinical; prototype; receptor; siRNA; social role; stem; vector; withdrawal from alcohol
Relevance: Narrative Alcoholism and anxiety frequently co-occur in humans; however, it has been difficult to find a single treatment which is effective against both conditions. In the present application, we propose to use novel benzodiazepine compounds to treat both alcohol dependence and the anxiety which is often seen following attempts to reduce chronic drinking. The second phase of the application will employ a gene reduction procedure referred to as RNAi to identify which GABA receptor may be important in regulating chronic alcohol drinking and anxiety. By identifying the receptors that play a role in regulating alcoholism and anxiety, it may be possible to develop more optimal treatments for the comorbid condition
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PAR-07-048
5R01AA017963-02 (2010): $406854
1R01AA017963-01A1 (2009): $384386
BENZODIAZEPINE ACTIONS ON ALCOHOL REINFORCEMENT
Harry L June, Professor
Psychologyindiana Univ-purdue Univ At Indianapolis
620 Union Drive, Room 518
indianapolis, In 462025167
Grant 5R01AA010406-05 from National Institute On Alcohol Abuse And Alcoholism IRG: ZRG4
Abstract: Adapted from S ) The overall goal of this proposal is to identify and systematically examine benzodiazepine (BDZ) receptor ligands which attenuate the reinforcing properties of ethanol (ETOH). To accomplish this goal, the high alcohol drinking (HAD) rat and measures of ETOH reinforcement will be used. Quantitative receptor autoradiography (QAR) will also be used to determine if the binding affinity of effective BDZ ligands at central nervous system (CNS) sites correlates with the magnitude of behavioral effects. The main hypothesis to be tested is whether certain BDZ inverse agonist and antagonist ligands can selectively attenuate measures of ETOH reinforcement; this may be related to their binding at diazepam sensitive (DS), and to a lesser degree at diazepam insensitive (DI) conformations of GABAA-BDZ receptors. Initial dose-effect and time course studies will examine the ability of agents to attenuate ETOH intake using operant methodology. It is hypothesized that agents with high affinity for DS sites will be effective ETOH antagonists; however, agents with high affinity at both DS and DI sites should produce more potent and prolonged antagonism. In a second series of experiments, the threshold for electrical brain stimulation reward (BSR) will be compared in naive HAD and low alcohol drinking (LAD) rats. The role of oral (contingent) ETOH administration will also be tested for comparison with intra gastric (IG) (noncontingent) infusions in HAD rats. In addition, HAD and LAD rats will be compared for sensitivity to BSR following noncontingent ETOH administration. It is hypothesized that HAD rats will evidence a lower threshold and higher rate of responding for BSR compared with LAD rats under naive and following noncontingent ETOH. Contingent ETOH administration is expected to yield a more positive (euphoric) action on BSR compared with the noncontingent route in HAD rats. Studies of effective anti-ETOH agents using the optimal ETOH BSR threshold route will then be conducted in HAD rats. Using QAR, a third series of experiments will examine both inhibition and time course profiles of agents found effective as ETOH antagonists at CNS sites. It is hypothesized that highly effective ETOH antagonists should evidence greater binding at DS and DI sites hypothesized to mediate ETOH reinforcement, and that interactions at these sites may mediate in part (indirectly influence) activation of underlying neuroanatomical substrates contributing to the reinforcing properties of ETOH. It is further hypothesized that the behavioral and binding time course profiles will not be parallel. These studies should advance our understanding of the role the GABAA-BDZ receptor complex plays in mediating ETOH reinforcement, and may lead to the development of treatments for alcohol abuse and alcoholism
Keywords: GABA receptor, alcoholic beverage consumption, benzodiazepine receptor, ethanol, neuropharmacology, psychological reinforcement alcoholism /alcohol abuse, disease /disorder model autoradiography, laboratory rat
Project start date: 1997-04-01
Project end date: 2003-03-31
5R01AA010406-05 (2001): $121521
5R29AA010406-04 (2000): $104199
5R29AA010406-03 (1999): $101964
5R29AA010406-02 (1998): $99818
1R29AA010406-01A3 (1997): $107570
EFFICACY OF NOVEL TRIPLE UPTAKE INHIBITORS IN TREATING ALCOHOLISM AND DEPRESSION
Harry L June
Department/ Educational Institution Type:
Grant 5R01AA017461-03 from National Institute On Alcohol Abuse And Alcoholism
Keywords: abstaining from alcohol; abstaining from ethanol; Abstinence; abstinence from alcohol; abstinence from ethanol; ing; Acute; Affective; alcohol abstinence; Alcohol abuse; alcohol addiction; Alcohol consumption; Alcohol dependence; alcohol dependency; Alcohol Drinking; alcohol ingestion; alcohol intake; alcohol problem; alcohol product use; alcohol use; alcohol-dependent; alcoholic beverage consumption; alcoholic drink intake; Alcoholism; Alcohols; Amygdala; Amygdaloid Body; amygdaloid nuclear complex; Amygdaloid Nucleus; Amygdaloid structure; Anhedonia; Antidepressant Agent; Antidepressant Drugs; Antidepressant Drugs, Tricyclic; Antidepressants; Antidepressants, Tricyclic; Antidepressive Agents; Antidepressive Agents, Tricyclic; Attenuated; Bed Nucleus of Stria Terminalis; Behavior; binge alcohol consumption; binge drinking; Brain; c fos; c-fos Gene; c-fos Proto-Oncogenes; Cell Nucleus; Chemical Class, Alcohol; Chronic; clinical efficacy; Common Rat Strains; Data; Dependence; Depression; depressive; depressive symptoms; deprivation; DOV 216, 303; DOV 216303; drink heavily; drinking; drug/agent; Drugs; Emotional Depression; Encephalon; Encephalons; episodic drinking; ethanol abstinence; ethanol abuse; ethanol addiction; ethanol consumption; Ethanol dependence; ethanol dependency; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol-dependent; EtOH drinking; etoh use; Evaluation; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; extreme drinking; FOS gene; G0S7; hazardous alcohol use; heavy alcohol use; Heavy Drinking; heavy metal lead; heavy metal Pb; Human; Human Volunteers; Human, General; Individual; inhibitor; inhibitor/antagonist; Intake; Lead; Light; Mammals, Rats; Man (Taxonomy); Man, Modern; Medial; Mediating; Medication; Mental Depression; Microinjections; Modeling; monoamine; Nervous System, Brain; neurobiological; neurobiological mechanism; Neurobiology; novel; Nucleus; Nucleus Accumbens; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; phase 1 study; Photoradiation; pleasure; pre-clinical; Pre-Clinical Model; preclinical; Preclinical Models; Prefrontal Cortex; problem drinking; Property; Property, LOINC Axis 2; Protooncogene FOS; prototype; Publishing; Rat; Rattus; Rodent Model; SCHED; Schedule; Selective serotonin re-uptake inhibitor; Selective Serotonin Reuptake Inhibitor; Self Stimulation; Series; serotonin reuptake inhibitor; Site; SSRI; Stria Terminalis Nucleus; Structure of terminal stria nuclei of preoptic region; Swimming; Symptoms of depression; Technology; Testing; Tricyclic Antidepressive Agents; uptake; v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog; Withdrawal
Relevance: The present proposal will evaluate a series of novel antidepressant medications for their capacity to reduce excessive alcohol drinking and alcohol abstinence effects in a rodent model of alcohol abuse. The primary objective of the proposal will be to successfully identify agents that may be used to treat both depression and alcohol addiction in humans
Project start date: 2008-12-15
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01AA017461-03 (2011): $317419
GABAa Receptor Subunits In Alcohol Reinforcement
Harry L June
Indiana Univ-purdue Univ At Indianapolis
5R01AA012407-05 (2006): $221898