Chronic ethanol consumption by C57BL/6 mice promotes tolerance to its interoceptive cues and increases extracellular dopamine, an effect blocked by naltrexone.
BACKGROUND
C57BL/6 (B6) mice voluntarily consume ethanol. Although preingestive factors might be accountable, the fact that B6 mice voluntarily consume sufficient ethanol to set the conditions for an ethanol-deprivation effect suggest that post-ingestive pharmacological induced changes also occur. In this study, we determined the amounts of ethanol voluntarily consumed by B6 mice and associated blood ethanol levels (BEL), the effects of this consumption on extracellular dopamine (DA) and how this was altered by naltrexone, as well as on its interoceptive discriminative cues.


METHODS
In experiment 1, the amounts of 12% ethanol consumed at 2, 4, and 6 hr into the active phase of the circadian cycle and associated BEL were determined. In experiment 2, dialysate samples were collected for 1 hr to establish basal DA levels. Mice were then injected with saline or naltrexone (6 mg/kg) and given access to water and 12% ethanol or to water only, and samples were collected at 20-min intervals for the next 2 hr. In experiment 3, mice were trained to discriminate ethanol's interoceptive cues via operant techniques, and half were given 3 weeks access to ethanol and water, the other half water only. Ethanol-consuming and water control mice were again tested for their ability to discriminate the drug's interoceptive cues.


RESULTS
Mice ingested nearly 6 g/kg of ethanol and attained BEL near 100 mg/100 mL by 6 hr into the active phase. Ethanol intake at 2-hr into the dark phase was approximately 2.5 g/kg, and increased DA to approximately 100% above basal levels. Naltrexone reduced ethanol consumption and blocked the DA increase. Ethanol consumption for 3 weeks attenuated its discriminative cues.


CONCLUSIONS
B6 mice voluntarily consume sufficient ethanol (1) to produce intoxicating BEL; (2) to increase DA levels in nucleus accumbens, an effect blocked by naltrexone; and (3) to attenuate its discriminative cues.
Middaugh
Lawrence D
LD
Center for Drug and Alcohol Programs, Alcohol Research Center, Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston 29425, USA. middauld@musc.edu
Szumlinski
Karen K
KK
Van Patten
Yancy
Y
Marlowe
Angela-Leigh Bandy
AL
Kalivas
Peter W
PW
D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D003463:Cues; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000378:metabolism* / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism
D018492:Dopamine Antagonists; D009271:Naltrexone; D004298:Dopamine