The opioid antagonist naltrexone (NTX) reduces responding for food at similar doses as those that reduce responding for ethanol and the animals become supersensitive to NTX's effects. NTX supersensitivity may contribute to the drug's ability to decrease ethanol consumption. If we explore the behavioral and environmental factors that modulate sensitivity to NTX, then we may develop therapeutic techniques to maximize NTX's effect on ethanol drinking and minimize NTX's effect on other behaviors. The purpose of this proposal is to characterize the behavioral and environmental factors that contribute to NTX supersensitivity as it relates to ethanol consumption. The first specific aim will attempt to establish a dose effect relationship for the development of supersensitivity in rats responding for 10% ethanol. Rats responding for ethanol will receive repeated NTX injections once/week for 8 weeks. Preliminary data suggest that the naltrexone's potency to reduce responding for ethanol will increase over time. The second specific aim will determine whether NTX's effects can become associated with contextual stimuli, which may produce NTX-like effects in the absence of the drug. Rats will receive repeated NTX while responding for ethanol in the presence of an olfactory cue (CS+). A separate cue will be used on saline injection days (CS-). Following an injection procedure similar to the first specific aim, we will test whether the CS+ without NTX decreases responding and whether the CS- attenuates NTX's effect. The third specific aim will test whether repeated NTX enhances extinction of responding to an ethanol-conditioned cue and whether this experience will reduce reinstatement after an ethanol priming injection. Rats will have extended exposure to ethanol paired with a cue. NTX will be given repeatedly when rats are responding for only the cue. Later, the rats' responding will be measured after receiving a priming injection of ethanol. These studies should suggest behavioral and environmental factors that may enhance or attenuate NTX's use in treating human alcoholism ? ?
| Williams, Keith L; Harding, Kaitlyn M (2014) Repeated alcohol extinction sessions in conjunction with MK-801, but not yohimbine or propranolol, reduces subsequent alcohol cue-induced responding in rats. Pharmacol Biochem Behav 116:16-24 |
| Williams, Keith L; Broadbridge, Carissa L (2009) Potency of naltrexone to reduce ethanol self-administration in rats is greater for subcutaneous versus intraperitoneal injection. Alcohol 43:119-26 |
| Williams, Keith L; Schimmel, Jasmine S (2008) Effect of naltrexone during extinction of alcohol-reinforced responding and during repeated cue-conditioned reinstatement sessions in a cue exposure style treatment. Alcohol 42:553-63 |
