Diurnal variation in nicotine sensitivity in mice: Role of genetic background and melatonin

Abstract

Despite the evidence that there is a daily rhythm in smoking behavior and that the effects of drugs of abuse exhibit diurnal variations, very few studies have explored the extent to which sensitivity to the effects of nicotine vary over the course of the day. In the studies described in this report, the melatonin proficient mouse strain C3H/Ibg and the melatonin deficient mouse strains C57BL/6J and DBA/2J were assessed for diurnal variations in sensitivity to the effects of nicotine. Results indicated that there is significant variation in sensitivity to both activity and body temperature depressant effects of nicotine in the melatonin proficient C3H/Ibg strain with maximal sensitivity occurring during the latter third of the light period of the light cycle and minimal sensitivity taking place during the last third of the dark phase of the light cycle. The melatonin deficient strains did not exhibit diurnal differences in sensitivity to the effects of nicotine suggesting a potential role for melatonin in modulating the effects of nicotine. Experiments with knockout mice lacking both the Mtnr1a and Mtnr1b melatonin receptors confirmed that the reduced sensitivity observed during the dark phase is melatonin dependent. Diurnal variation in nicotinic receptor expression also was measured in cortex, hippocampus, hypothalamus and striatum using [125I] α-bungarotoxin and [125I]-epibatidine. [125I] α-bungarotoxin binding in hypothalamus of C3H mice exhibited a diurnal pattern with maximal binding observed in the latter third of the light portion of the light cycle. No other significant differences in binding were detected.

The β3 subunit of the nicotinic acetylcholine receptor: Modulation of gene expression and nicotine consumption

“…Locomotor activity and body temperature were examined using a test battery developed at the Institute for Behavioral Genetics for measuring the behavioral effects of nicotine (Marks et al , 1985; Marks et al , 1989; Mexal et al , 2012). Briefly, locomotor activity was examined in a symmetrical Y-maze, consisting of three red Plexiglas arms (26 L X 6.1 W X 10.2 H; cm).…”

“…Following activity testing, the mice were returned to the holding cages before being tested for rectal body temperature 13 minutes after the nicotine injection. Nicotine doses and testing times were based on published methods (Marks et al , 1985; Marks et al , 1989; Mexal et al , 2012). Two primary dependent variables were evaluated: nicotine-induced locomotor activity (beam crosses) and change in body temperature (°C).…”

Melatonin administration alters nicotine preference consumption via signaling through high-affinity melatonin receptors

“…Importantly, melatonin supplementation at the doses sufficient to reduce nicotine intake does not alter gross daily patterns in activity. Previous literature has suggested a role for melatonin in drug-related behavior by comparing melatonin producing vs non-melatonin producing mouse strains (Akhisaroglu et al, 2004; Mexal et al, 2012; Uz et al, 2002), or by ablating the source of melatonin, the pineal gland (Kurtuncu et al, 2004; Uz et al, 2003). However, these methods have confounds and are only suggestive of a role of melatonin in drug-related behaviors.…”

“…Furthermore, day-night differences in cocaine-induced conditioned place preference and locomotor sensitization are abolished if the pineal gland (the major source of circulating melatonin) is ablated (Uz et al, 2003; Kurtuncu et al, 2004). Time-of-day differences in sensitivity to the hypothermic effects of several drugs including nicotine, ethanol and apomorphine have also been shown (Morley and Garner, 1990; Russell, 1993; Mexal et al, 2012). Moreover, recent reports demonstrate that the daily variation in sensitivity to the hypothermic effects of nicotine (Mexal et al, 2012) and the sensitizing effect of methamphetamine (Hutchinson et al, 2014) are dependent upon melatonin signaling.…”

“…Time-of-day differences in sensitivity to the hypothermic effects of several drugs including nicotine, ethanol and apomorphine have also been shown (Morley and Garner, 1990; Russell, 1993; Mexal et al, 2012). Moreover, recent reports demonstrate that the daily variation in sensitivity to the hypothermic effects of nicotine (Mexal et al, 2012) and the sensitizing effect of methamphetamine (Hutchinson et al, 2014) are dependent upon melatonin signaling. In addition, melatonin can modulate the function of neuronal nicotinic receptors (Markus et al, 2003; Lax, 2008).…”