1996 |
Matthews, Douglas B |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Prenatal Ethanol--Spatial Memory and Place Cell @ Miami University Oxford |
0.957 |
1998 |
Matthews, Douglas B |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Gabaergic Adaptations to Ethanol Self Administration @ University of North Carolina Chapel Hill
Research suggests that ethanol self-administration involves GABA neurotransmission via GABAA receptors in the mesolimbic system (i.e., the nucleus accumbens [NAC], amygdala [AMG] and ventral tegmental area [VTA]). GABAA receptor modulators systematically administered or infused directly into these brain regions alter ethanol self- administration. Moreover, the effects of GABAA agonists in the amygdala differ in ethanol dependent compared to non-dependent animals. However, the role of GABAA receptor in ethanol self-administration is not known. Prolonged ethanol consumption produces dependence as seen by rebound central nervous system hyperexcitability upon the removal of ethanol. Prolonged ethanol consumption alters GABAA receptor gene expression and GABAA receptor function in the cerebral cortex and hippocampus. Consequently, alterations in NAC, AMG or VTA GABAA receptor function and gene expression may be a critical factor in the regulation of ethanol self-administration. The purpose of this proposal is to investigate if chronic ethanol self-administration 1) produces ethanol dependence, 2) alters GABAA receptor function in the NAC, AMG and VTA and 3) alters GABAA receptor gene expression in the NAC, AMG and VTA. Ethanol dependence will be determined by measuring bicuculline seizure threshold following removal of ethanol in rats that self- administer an ethanol/Polycose solution compared to control rats that self-administered a Polycose solution without ethanol. GABAA receptor function will be determined in the NAC, AMG and VTA using single-cell microinotrophoresis of GABAA and ethanol from rats that self-administer the ethanol/Polycose solution compared to control rats. GABAA receptor gene expression will be measured using semi-quantitative immuno- histochemistry from rats that self-administer an ethanol/Polycose solution compared to control rats. These studies will fill a major gap concerning the role of GABAergic mechanisms on ethanol self- administration.
|
0.952 |
2002 — 2006 |
Matthews, Douglas B |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inia: System Mechanisms in Stress-Alcohol Interactions
DESCRIPTION (provided by applicant): The neurobiological mechanisms that underlie the transition from controlled to uncontrolled, or excessive, drinking are not completely understood. Excessive drinking has been demonstrated following several different ethanol exposure paradigms in monkeys, rats and mice. Furthermore, the initiation and maintenance of ethanol self-administration involves several brain regions including the nucleus accumbens, amygdala and hippocampus. In addition, specific neurotransmitter receptor subtypes and/or transporters within these brain regions have been implicated in excessive ethanol self-administration. Recently, it has been demonstrated that acute stress administration can result in high levels of ethanol self-administration and reinstatement of ethanol self-administration in drug free animals. However, it is currently unknown if the initiation of excessive drinking is influenced by interactions between stress, specific brain regions, and specific genes. The current proposal will 1) investigate the neurobiological relationship between stress, anxiety and excessive drinking in knockout mice; 2) investigate the neurobiological relationship between chronic ethanol administration, stress and ethanol self-administration in knockout mice; and 3) identify significant neurobiological abnormalities in the relationship between stress and acute ethanol administration in knockout mice. These studies will fill a major gap in understanding the relationship between stress, brain regions, genetics and the development of excessive drinking.
|
1 |
2004 — 2006 |
Matthews, Douglas B |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Gabaa Receptor G[2] Knockout: Ethanol and Spatial Memory
DESCRIPTION (provided by applicant): Acute ethanol administration impairs spatial memory in both rats and mice. Specifically, ethanol administration impairs the use of spatial memory, spatial learning and blocks spatial contextual learning. Furthermore, the cellular mechanism underlying acute ethanol's impairment of spatial memory has been identified. Namely, acute ethanol administration degrades the spatial specificity of hippocampal place cells recorded in awake freely behaving rats. However, the biochemical mechanism by which acute ethanol administration impairs spatial memory is unknown. Ethanol potentiates GABA-mediated inhibition in a variety of brain regions including brain regions in the hippocampal system. Hence, ethanol might impair spatial memory by potentiating GABA-mediated inhibition in these brain regions thereby altering hippocampal function. However, it is still controversial if ethanol interacts directly with GABAA receptors in brain. The goal of this proposal is to directly investigate if targeted genetic alteration in the gamma2 subunit of the GABAA receptor alters ethanol degradation of spatial memory. GABAA receptor gamma2 heterozygous knockout mice (expressed on the hybrid C57B1/6J - 129/SvJ strain) will be trained a variety of spatial tasks prior to having 1) their spatial memory tested or 2) the spatial specificity of hippocampal place cells determined following administration of one of three doses of ethanol (saline control, 1.25 g/kg, 1.75 g/kg or 2.25 g/kg) or diazepam (1.0 mg/kg, 1.5 mg/kg or 2.0 mg/kg). These studies will directly determine if alterations in GABAA receptor composition via targeted genetic alteration in the gamma2 subunit of the GABAA receptor alter ethanol impairment of spatial memory.
|
1 |