Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57B1/6 mice

The route of drug delivery is an important consideration in studies that ev aluate the long-term biobehavioral adaptations that occur in response to ch ronic drug administration. Continuous infusions (intravenous or subcutaneou s) or intermittent intraperitoneal (or subcutaneous) injections are the mos t commonly utilized routes of chronic drug delivery in these studies. The p urpose of the present study was to determine the effects of chronic oral ni cotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57B1/6 mice. Mice were randomized to different treatme nt groups that received 2% saccharin, containing 0-200 mu g/ml nicotine (fr ee base). In preliminary experiments, radiotelemetry devices were implanted in the mice, consumption of the nicotine-containing drinking solution caus ed a significant increase in home-cage nocturnal (but not diurnal) activity and also altered circadian alterations in body temperature. Oral nicotine exposure resulted in dose-related elevations in plasma levels of cotinine, a primary nicotine metabolite. Continuous exposure (30 days) to oral nicoti ne (200 mu g/ml) resulted in the expression of significant tolerance to the locomotor depressant and hypothermic actions of acute nicotine challenge. This tolerance was accompanied by a significant increase in brain nicotinic receptor number assessed by quantitative autoradiography using [H-3]-cytis ine (alpha 4 nAChr) and [I-125]- alpha-bungarotoxin (alpha 7 nAChr) as radi oligands. These results suggest that chronic oral nicotine delivery to fema le C57B1/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery.