Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice

Abstract

The route of drug delivery is an important consideration in studies that evaluate the long-term bio-behavioral adaptations that occur in response to chronic drug administration. Continuous infusions (intravenous or subcutaneous) or intermittent intraperitoneal (or subcutaneous) injections are the most commonly utilized routes of chronic drug delivery in these studies. The purpose of the present study was to determine the effects of chronic oral nicotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57Bl/6 mice. Mice were randomized to different treatment groups that received 2% saccharin, containing 0-200 microg/ml nicotine (free base). In preliminary experiments, radiotelemetry devices were implanted in the mice; consumption of the nicotine-containing drinking solution caused 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 nicotine (200 microg/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 auto-radiography using [3H]-cytisine (alpha4 nAChr) and [125I]-alpha-bungarotoxin (alpha7 nAChr) as radioligands. These results suggest that chronic oral nicotine delivery to female C57Bl/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery.

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

“…Accordingly, future studies on the biological bases of ethanol and nicotine interactions are necessary and the use of other strains and species may provide valuable data. Though nicotine concentration may seem high in the drinking solution, nicotine absorption from the buccal cavity yields cotinine plasma levels (Klein et al, 2003(Klein et al, , 2004Sparks and Pauly, 1999) comparable to those found in adolescent smokers (Binnie et al, 2004;Caraballo et al, 2004;Wood et al, 2004). As for ethanol, according to previous studies in adolescent rodents, even the moderate doses used in the present study result in blood levels well above the legal driving limit (Silveri and Spear, 2000).…”

“…C57BL/6 mice were chosen because prior reports demonstrate that adult and periadolescent mice from this strain consume nicotine in the concentration used in the present study. In fact, oral nicotine has also been shown to be effective in eliciting behavioral (Adriani et al, 2002(Adriani et al, , 2004Gaddnas et al, 2001) and neurochemical alterations, including nicotinic receptors upregulation (Nuutinen et al, 2005;Sparks and Pauly, 1999), altered monoamine levels, and metabolism (Gaddnas et al, 2000;Tammimaki et al, 2006;Vihavainen et al, 2006) as well as altered expression of genes implicated in synaptic plasticity induced by drugs of abuse (Marttila et al, 2006) and in Alzheimer's disease (Gutala et al, 2006) in this and other mouse strains. This strain of mice is known to present particular features, such as higher voluntary ethanol consumption (Crawley et al, 1997), which should be taken into consideration in studies that involve the administration of this substance, even though the bases underlying these strain-specific characteristics remain poorly understood (Crabbe et al, 1999).…”

“…C57BL/6 mice were chosen because prior reports demonstrate that adult and periadolescent mice from this strain consume nicotine in the concentration used in the present study (Klein et al, 2003(Klein et al, , 2004Sparks and Pauly, 1999). All mice were bred and maintained in our laboratory.…”

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine

“…In the drinking water of treatment and control groups, 2% saccharine was added (to mask the bitter flavor of nicotine) (Salas et al, 2009;Sparks and Pauly, 1999;Zhang et al, 2012). In coadministration experiments, mice received ethanol or control injections during the last 10 days of nicotine treatment.…”

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

“…Therefore, since cerebral a7 nAChRs are normally upregulated in heavy smokers (Benwell et al, 1988;Breese et al, 2000) and after chronic nicotine administration in animals (Olale et al, 1997;Sparks and Pauly, 1999), a7 nAChRs in patients appear to have an abnormally blunted reaction to excessive smoking. This could be due to a dysfunction in any of several distinct endogenous mechanisms, which normally control a7 nAChR expression and activity in the brain (Albuquerque et al, 1997;Pereira et al, 2002).…”