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RSA 2003 Abstracts
Oregon Health & Science University
AN ALCOHOL SELF-ADMINISTRATION PARADIGM THAT INDUCES INTOXICATON IN C57BL/6J MICE
K. Cronise; K.L. Best; D.A. Finn; J.C. CrabbePortland Alcohol Research Center, Dept. Veterans Affairs Medical Center & Dept. Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97201
Mice typically will not consistently self-administer doses of alcohol that produce behavioral intoxication. Recently, this lab demonstrated that a modified fluid restriction paradigm produced high and stable levels of alcohol consumption. Thus, this study assessed whether the alcohol intake in this paradigm produced behavioral signs of intoxication. Female C57BL/6J mice were allowed 3 hours of fluid daily with unlimited access to food for 12 days. On days 1 and 2, mice received 3 hours of water. On day 3, mice received 30 minutes access to ethanol (5% w/v) followed by 2.5 hours access to water. The alcohol access periods were repeated every 3rd day, for a total of 4 pairings. A control group had access to water only each day. Intoxication was assessed using 4 measures of motor incoordination: accelerating rotarod (AR), fixed speed rotarod @ 6.5 RPM (FR), balance beam (BB) and screen test (ST). One group was tested on the AR and FR, while separate groups were tested on the BB and ST. The control mice were also tested on the AR, FR and BB. Testing was done immediately after access to ethanol on days 3, 6, 9 and 12. The results revealed alcohol consumption in the range of ~2 to 2.5 g/kg and blood alcohol concentrations of ~1.5 mg/ml, both of which are comparable to previous studies. Alcohol-exposed mice had shorter latencies to fall from the FR and more footslips on the BB than the control group. Also, alcohol exposed mice tended to perform more poorly across days on both the AR and ST. These results suggests that: 1) C57BL/6J mice will self-administer alcohol sufficient to produce intoxication in this restricted access paradigm; and, 2 ) that this paradigm may mimic the loss of self-control seen in the human alcoholic condition. Supported by AA13478, AA07468, & a grant from the Dept. of Veterans Affairs.
CHRONIC ETHANOL SELF-ADMINISTRATION IN FEMALE LONG EVANS RATS IMPARTS NEUROADAPTIVE CHANGES IN HYPOTHALAMIC GENE EXPRESSION PROFILES
M.M. Ford1, J. Hashimoto1, K.M. Wiren1, W.M. Freeman2, K.E. Vrana3, J.C. Eldridge3, H.H. Samson3, and D.A. Finn1
1Dept. of Behavioral Neuroscience &
2Vollum Institute, Oregon Health & Science University, Portland, OR 97239;
3Center for the Neurobehavioral Study of Alcohol, Dept. of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
The hypothalamus is an integral neuroendocrine substrate that orchestrates several homeostatic processes that include reproduction, feeding, fluid balance, stress response, and thermoregulation. Ethanol interactions with these processes have been extensively documented, thereby suggesting that the hypothalamus is a vulnerable CNS target for the manifestations of ethanol’s effects. The purpose of this study was to characterize the expression profile of hypothalamic genes in a model of excessive chronic ethanol self-administration to gain a better understanding of the neuroadaptive changes that occur with prolonged use of this drug. Following an initial two-bottle (water and 10% ethanol) preference test, adult female Long-Evans rats were initiated to consume 10% sucrose + 20% ethanol (10S/20E) in a continuous access procedure. Daily consumption of 10S/20E (8.98±1.33 g/kg) led to significantly greater intake than that initially observed with 10E (2.93±0.40 g/kg). Ethanol-naïve (control) rats were run in parallel and given daily doses of 10S (isocaloric equivalents of the 10S/20E solutions consumed by the ethanol-drinking rats) for ten weeks. The hypothalamus was dissected when each rat exhibited a diestrus-like vaginal smear. Total RNA was reverse transcribed in the presence of 33P-nucleotide and hybridized to membrane-based cDNA microarrays. Post-hoc confirmation of expression differences was carried out using quantitative real time RT-PCR. Ethanol-induced suppression of integrin and intracellular signaling molecule transcripts associated with glutamatergic neurotransmission were most notable. These findings suggest that excitatory neurotransmission within the hypothalamus is compromised by excessive ethanol intake, and that these changes may underlie the establishment of an altered homeostatic set-point in response to a chronic ethanol challenge. This study also demonstrated that a model of excessive self-administration is useful in delineating neuroadaptive processes in the CNS that occur during chronic ethanol exposure.
Supported by grants AA11997, AA06845, AA07565, AA13478, DA07246, and DA07262.
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