CROSS-TOLERANCE BETWEEN ETHANOL AND NEUROTENSIN IN MICE SELECTIVELY BRED FOR ETHANOL SENSITIVITY

Neurotensin (NT), a tridecapeptide that satisfies criteria as a neurot ransmitter, mimics many actions of ethanol, and evidence indicates tha t some of the acute effects of ethanol are mediated in part by NT. Rec ent studies have shown that chronic ethanol treatment produced a downr egulation of NT receptors in mesolimbic brain regions of long sleep (L S) mice and that reduced NT binding capacity was associated with acqui sition and decay of tolerance to ethanol-induced locomotor inhibition and hypothermia in these mice. The present study was undertaken to det ermine whether cross-tolerance develops between NT and ethanol and whe ther chronic NT infusion produces NT receptor downregulation. Animals chronically treated with ethanol were tolerant to NT-mediated locomoto r inhibition at a dose of 1.8 pmol NT, ICV, and were tolerant to NT-in duced hypothermia at 1.8 and 6.0 pmol NT. Following repeated injection s or continuous infusion of NT ICV, LS mice showed tolerance to both N T-and ethanol-induced hypothermia and locomotor inhibition. Indeed, et hanol doses that are hypnotic in control mice (2.8 g/ kg) were not eff ective in abolishing locomotor activity following chronic NT administr ation. Results with chronic saline infusion ICV indicate that stress a lters sensitivity to ethanol-induced hypothermia. Chronic infusion of NT ICV produced a region-specific downregulation of high-affinity NT r eceptors in the striatum. The results demonstrate that cross-tolerance develops between NT and ethanol, and further support a role for neuro tensinergic systems in the actions of ethanol.