Effects of nicotine and mecamylamine on rat dorsal raphe neurons

Abstract

This study investigates the hypothesis that serotonin mediates certain nicotine effects, such as mood improvement and the suppression of the ponto-geniculo-occipital spikes of rapid eye movement sleep. The influence of nicotine (10–300 μM) on the firing rate of dorsal raphe neurons and on serotonin release was therefore, studied in rat midbrain slices. Nicotine increased the firing rate, 10–90%, in 67.5% recorded neurons and decreased it, 8–100%, in the remaining 32.5%. Serotonin release increased 2–7 times after nicotine administration, regardless of firing frequency, but the absolute value of serotonin release was 3 times higher during the decreases than during the increases in firing rate. Mecamylamine (1–20 μM) transiently stimulated the dorsal raphe neurons and competitively antagonized the nicotine-induced serotonin release. The results support the working hypothesis and additionally show that mecamylamine also stimulates dorsal raphe neurons.

Introduction

Recent results obtained in our laboratory showed that transdermally applied nicotine improves mood (Salı́n-Pascual and Drucker-Colı́n, 1998) and suppresses the ponto-geniculo-occipital spikes of rapid eye movement (REM) sleep in cats (Vazquez et al., 1996). These same events appear to be serotonin-dependent, since electrical stimulation of the dorsal raphe nucleus, the largest pool of serotonergic neurons of the brain, suppresses the ponto-geniculo-occipital spikes (Brooks and Bizzi, 1963; Mc Ginty and Harper, 1976; Simon et al., 1973) and blockers of serotonin re-uptake have major antidepressant actions (Wilner, 1985; Blier et al., 1987). Another similarity between nicotine and serotonin actions was observed in the regulation of appetite since both systemic nicotine (Schwid et al., 1992) and serotonin re-uptake blockers (Wurtman and Wurtman, 1979) cause weight loss by decreasing food intake and especially carbohydrate intake.

These serotonin like effects of nicotine may be explained by a nicotine-induced serotonin release, especially in the dorsal raphe nucleus. This hypothesis is supported by the presence of numerous nicotinic receptors on dorsal raphe neurons of mice (Marks et al., 1992), rats (Segal et al., 1978; Deutch et al., 1987), cats (Pin et al., 1968) and humans (Benwell et al., 1988) and by the well-documented role of nicotinic pre-synaptic receptors in facilitating neurotransmitter release (for review see Wonnacott, 1997).

Studies performed in brain slices showed that nicotine releases serotonin in striatum (Westfall et al., 1983) and hypothalamus (Hery et al., 1977), whereas microdyalisis studies demonstrated that systemic nicotine increases serotonin release in the frontal cortex (Ribeiro et al., 1993). However, to this date there are practically no studies concerning the effects of nicotine on dorsal raphe neurons (Li et al., 1998). In the present study, rat midbrain slices were used to examine nicotine's effects on firing rates of dorsal raphe neurons and in serotonin release.