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RSA 2005 ABSTRACTS
OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND
THE EFFECT OF NALTREXONE ON SCHEDULED HIGH ALCOHOL CONSUMPTION IN MICEN. Yoneyama, A.R. Murillo, J.C. Crabbe, T.J. Phillips, D.A. Finn
VAMC Research & Dept. of Behavioral Neuroscience, OHSU, Portland, OR 97239
Recent findings indicate that scheduling periods of fluid availability produces a high, stable, level of ethanol intake in male and female C57BL/6 and genetically heterogeneous (i.e. WSC) mice. Naltrexone, an opioid receptor antagonist, has helped to reduce the rate of relapse in some alcoholic patients. Data from various animal models have found that doses of naltrexone ranging from 0.25-3 mg/kg were effective at decreasing ethanol consumption. Therefore, the purpose of this experiment was to examine the effect of naltrexone on high ethanol intake in mice when periods of fluid availability had been scheduled. Male and female WSC mice were individually housed and given varying periods of access ranging from 4-10 hours per day for 21 days. Every 3rd day, mice were offered a 5% ethanol solution for 30 minutes. 15 min prior to an ethanol session, separate groups of animals were given an i.p. injection of either naltrexone (0.6 mg/kg or 1.25 mg/kg) or an equivalent volume of saline. After the ethanol session, animals had access to water for the remainder of the period of fluid availability. Consistent with previous studies, both doses of naltrexone significantly reduced ethanol consumption, with the 1.25 mg/kg dose of naltrexone completely suppressing ethanol consumption on the last day of access. The dose-dependent suppression of ethanol intake was more apparent in the female than the male mice, but significant in both. Notably, naltrexone did not significantly decrease total fluid intake due to an increase in water consumption on days which ethanol was available. Interestingly, the reduction of ethanol intake was increased over the 21-day duration of the study by both doses of naltrexone. These findings indicate that naltrexone is effective at selectively decreasing high alcohol consumption when periods of fluid availability have been scheduled.
Supported by NIAAA INIA Consortium Grants AA13478 and AA13519, PARC grant AA10760 and the Dept. of Veterans Affairs.
GENETIC AND ENVIRONMENTAL MANIPULATIONS PRODUCE HIGH ETHANOL CONSUMPTION IN MICED.A. Finn; R. Hitzemann; R. Dhaher; C. Snelling; N. Yoneyama; J. Rhodes; J.C. Crabbe
VAMC Research and Dept. Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
One goal of the INIA investigators in Portland has been to develop animal models that exhibit consistent high ethanol intake, defined as self-administration leading to a blood ethanol concentration (BEC) in excess of 100 mg% in mice. Results from three different procedures will be described. The first procedure demonstrated that scheduling periods of fluid access produced high, stable ethanol consumption and BEC in an inbred strain that exhibits high ethanol preference (i.e., C57BL/6) and in genetically heterogeneous mice and that naltrexone significantly decreased ethanol consumption. Using mass selection from genetically heterogeneous mice, we have begun selectively breeding mice for high and low ethanol intake. These selected lines are termed the Scheduled High Alcohol Consumption (SHAC) and Scheduled Low Alcohol Consumption (SLAC) mice. The second validated procedure established that non-fluid deprived C57BL/6 mice will consume intoxicating doses of alcohol when the solution was offered beginning at hour 3 of their circadian dark cycle. During the period of 4-hr limited access to the ethanol solution, C57BL/6 mice achieved high BEC (> 150 mg%). Using mass selection, we are selectively breeding mice for their propensity to drink in the dark (DID) in amounts that lead to high BEC. This selected line is termed the High-DID (HDID) line. The third procedure demonstrated that exposure to chronic intermittent ethanol vapor and multiple withdrawal episodes can produce high ethanol intake in C57BL/6 mice. Ethanol consumption was increased by 30% for one week in separate studies that examined daily 24 hr ethanol intake or 2 hr limited access intake during the circadian dark cycle. During 2 hr limited access sessions, mice achieved high BEC (> 200 mg%). Overall, these three animal models will be continued to provide animals and/or tissue to interested investigators for physiological, neuroanatomical or gene expression studies. Supported by NIAAA INIA Consortium Grants AA13478 & AA13519, Center Grant AA10760, and the Dept. of Veterans Affairs.
INDUCTION OF INCREASED ETHANOL CONSUMPTION IN C57BL/6 MICE FOLLOWING MULTIPLE WITHDRAWALSC. Snelling; A. Seymour; M.A. Tanchuck; N. Yoneyama; A.R. Murillo; J.C. Crabbe; D.A. Finn
VAMC Research and Dept. Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
Previous research investigating the relationship between alcohol dependence and alcohol drinking behavior has yielded mixed results. Based on the recent demonstration by Becker and Lopez (2004) that repeated chronic ethanol exposures and withdrawal episodes could increase ethanol intake in C57BL/6 (B6) mice, our goal was to examine the effects of a short series of withdrawal episodes on voluntary ethanol intake. In the first experiments, C57BL/6 mice were allowed unlimited access to a bottle containing a 10% v/v alcohol solution and to one containing tap water (baseline). After baseline drinking stabilized (7 days), separate groups of mice were exposed to a series of three cycles of 16-hr of ethanol vapor (or air) exposure in inhalation chambers that were separated by 8-hr withdrawal periods. Ethanol vapor exposure was adjusted to yield blood ethanol concentrations (BEC) of 1.5-2.0 mg/ml. Following the last cycle of ethanol exposure, both groups of mice were again allowed to voluntarily consume either ethanol or water for a minimum of seven days. Repeated chronic ethanol exposure and withdrawal yielded a 31% increase in consumption over baseline intake, when compared to the 21% increase over baseline consumption in the air-exposed controls. These results with 24-hr ethanol intake were consistent with studies using 2-hr limited access ethanol periods beginning at 4-hrs into the dark cycle (Dhaher et al., RSA abstract). Additional studies are examining the reproducibility of these findings in B6 and in genetically heterogeneous mice that have been acclimated to a reverse light/dark cycle (lights off at 1000). Initial findings suggest the possibility of circadian effects on BEC. Nonetheless, the collaborated results provide strong support for the conclusion that multiple withdrawals with controlled exposure rates will cause an increase in voluntary ethanol consumption in B6 mice. Supported by NIAAA INIA Consortium Grants AA13478 & AA13519 and the Dept. of Veteran Affairs
INTRAGASTRIC ETHANOL SELF-ADMINISTRATION IN SELECTIVELY BRED HAD-1 AND LAD-1 RAT LINEST.L. Fidler, S.S. Watson, A.M. Struthers, C.L. Cunningham
Oregon Health & Science University, Portland, OR, 97239
The role of heritable genetic factors in alcoholism has been investigated through selective breeding of lines that are either high (HAD) or low (LAD) alcohol drinking. Since these lines were selected based on their oral consumption of ethanol it is possible that it is their affinity for or aversion to the taste of ethanol rather than to its pharmacological properties that has been the basis of selection. If selection was based on the pharmacological effects of ethanol then the line difference in ethanol drinking should persist even when ethanol self-administration occurs in the absence of normal ethanol cues, such as taste or smell. HAD and LAD rats of the first replicate line were implanted with intragastric (IG) catheters and allowed to recover. Rats were placed in an operant chamber, attached to an IG tether, and allowed free access to two bottles of saccharin water for 3 days. In the second phase, subjects were given access to two water bottles. Half of the subjects from each line were passively infused (Ethanol Group) with 10% ethanol, everyday for 5 days, while the other half received no ethanol infusions (Control Group). Next, all animals had access to one bottle of KoolAid (CS+), and licks on this tube were paired with ethanol infusions on a FR-10 schedule for 2 consecutive days. On 4 additional days, rats had a choice between the CS+ and an additional flavor paired with water infusions (CS-). During both the no-choice and choice days, rats in the Ethanol Groups self-infused more ethanol than rats in the Control Groups regardless of line. Indeed, once a choice was available, rats in the Control groups from both lines self-infused almost no ethanol. In contrast, during a subsequent 2-bottle choice between 10% ethanol and water the HAD rats drank more ethanol than the LAD rats regardless of prior treatment. The observation that only ethanol experience influenced self-infusion of ethanol and only genetic background influenced ethanol consumption suggests that ethanol intake is controlled by different factors (e.g. taste or pharmacology) depending on route of administration. This research was supported by NIAAA U01-AA13479-INIA.
MAPPING THE CIRCUITS FOR MULTIPLE WITHDRAWAL-INDUCED EXCESSIVE ETHANOL (EtOH) CONSUMPTION
R. Dhaher, D. Finn, C. Snelling and R. Hitzemann
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239-3096 and Research Service, Veterans Affairs Medical Center, Portland, OR 97239
Becker and Lopez (2004) have described a procedure that induces excessive EtOH consumption in C57BL/6J (B6) mice. Baseline consumption of a 15% EtOH solution was measured in a 2 hour limited access two-bottle choice paradigm. Mice were divided into two groups, a multiple ethanol vapor exposure and withdrawal (MW) group and an air control (Air) group, matched for EtOH consumption levels. The MW group increased EtOH consumption levels from ~3.6g/kg to ~ 5g/kg with the Air group maintaining consumption at ~3.6g/kg, with blood EtOH concentrations (BEC)s correlating with consumption levels. We have used the c-Fos mapping strategy to detect the circuits associated with this multiple withdrawal effect (MWE). Following 5 days of post-treatment EtOH consumption, mice were further subdivided into two groups. Brains were collected on the 6th night post-treatment; one group did not receive ethanol on this night (0hr), and the other group did (2hr). Preliminary data indicates that mice in the 0hr Air group showed the highest number of c-Fos positive staining in the prefrontal cortex (PFC), the ventral pallidum, the rostral pole of the bed of the stria terminalis, and the paraventricular nucleus of the thalamus. Mice in the Air group that did consume ethanol (2hr) showed a reversal of this high level of c-Fos staining in the PFC. The 2hr MW group showed an increased c-Fos response, as compared to the other three groups, in the shell of the nucleus accumbens, the piriform cortex, and in the dorsolateral and lateral posterior portions of the bed of the stria terminalis. Overall, we conclude that specific circuits, particularly in the limbic system, are associated with MWE. This study or research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism, NIH (AA U01 13484 and 13478 - INIA Project)
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