Cross-tolerance between ethanol and neurotensin in mice selectively bred for ethanol sensitivity

Neurotensin (NT), a tridecapeptide that satisfies criteria as a neurotransmitter, mimics many actions of ethanol, and evidence indicates that some of the acute effects of ethanol are mediated in part by NT. Recent studies have shown that chronic ethanol treatment produced a downregulation of NT receptors in mesolimbic brain regions of long sleep (LS) mice and that reduced NT binding capacity was associated with acquisition and decay of tolerance to ethanol-induced locomotor inhibition and hypothermia in these mice. The present study was undertaken to determine whether cross-tolerance develops between NT and ethanol and whether chronic NT infusion produces NT receptor downregulation. Animals chronically treated with ethanol were tolerant to NT-mediated locomotor inhibition at a dose of 1.8 pmol NT, ICV, and were tolerant to NT-induced hypothermia at 1.8 and 6.0 pmol NT. Following repeated injections or continuous infusion of NT ICV, LS mice showed tolerance to both NT- and ethanol-induced hypothermia and locomotor inhibition. Indeed, ethanol doses that are hypnotic in control mice (2.8 g/kg) were not effective in abolishing locomotor activity following chronic NT administration. Results with chronic saline infusion ICV indicate that stress alters sensitivity to ethanol-induced hypothermia. Chronic infusion of NT ICV produced a region-specific downregulation of high-affinity NT receptors in the striatum. The results demonstrate that cross-tolerance develops between NT and ethanol, and further support a role for neurotensinergic systems in the actions of ethanol.