Effects of nicotine and chlorisondamine on cerebral glucose utilization in immobilized and freely‐moving rats

Abstract

1 Chlorisondamine blocks central nicotinic receptors for many weeks via an unknown mechanism. Intracerebroventricular administration of [ 3 H]-chlorisondamine in rats results in an anatomically restricted and persistent intracellular accumulation of radioactivity. The initial aim of the present study was to test whether nicotinic receptor antagonism by chlorisondamine is also anatomically restricted. 2 Male adult rats were pretreated several times with nicotine to avoid the disruptive eects of the drug seen in drug-naõÈ ve animals. They then received chlorisondamine (10 mg i.c.v.) or saline, and local cerebral glucose utilization (LCGU) was measured 4 weeks later after acute nicotine (0.4 mg kg 71 s.c.) or saline administration. During testing, rats were partially immobilized. Nicotine signi®cantly increased LCGU in the anteroventral thalamus and in superior colliculus. Chlorisondamine completely blocked the ®rst of these eects. Chlorisondamine signi®cantly reduced LCGU in the lateral habenula, substantia nigra pars compacta, ventral tegmental area, and cerebellar granular layer. 3 The second experiment was of similar design, but the rats were not pre-exposed to nicotine, and were tested whilst freely-moving. Acute nicotine signi®cantly increased LCGU in anteroventral thalamus, superior colliculus, medial habenula and dorsal lateral geniculate. Overall, however, nicotine signi®cantly decreased LCGU. Most or all of the central eects of nicotine on LCGU were reversed by chlorisondamine given 4 weeks beforehand. 4 These ®ndings suggest that chlorisondamine blocks nicotinic eects widely within the brain. They also indicate that in freely-moving rats, nicotine can reduce or stimulate cerebral glucose utilization, depending on the brain area.

Chlorisondamine inhibits the nicotine-induced stimulation of c-fos in the pigeon brain for up to 2 weeks

“…The central blockade by chlorisondamine has a longer duration of action in the rat than was observed for pigeons (Clarke, 1984;Decker et al, 1994;el-Bizri & Clarke, 1994;Marenco et al, 2000;Reuben et al, 1998). The difference in duration of chlorisondamine's blockade between the rat and pigeon may be related to many factors including route of chlorisondamine administration (intramuscularly vs. icv) and species differences, such as overall metabolic rate, metabolism of nicotine, and the subtypes of central nicotinic receptors.…”

“…Another method of tracing alterations of functional activity in the brain is the measurement of local metabolic rates using local cerebral glucose utilization (LCGU). Using this method, Marenco et al (2000) mapped central nicotinic effects in the rat and the ability of chlorisondamine to block the central effects of nicotine. Marenco et al (2000) observed that chlorisondamine, administered intracerebroventricularly (icv) 4 weeks prior to nicotine, attenuated the nicotine-induced decrease in LCGU in several brain loci in the rat, including the nucleus accumbens, hippocampus, and intermediate habenula.…”

“…Using this method, Marenco et al (2000) mapped central nicotinic effects in the rat and the ability of chlorisondamine to block the central effects of nicotine. Marenco et al (2000) observed that chlorisondamine, administered intracerebroventricularly (icv) 4 weeks prior to nicotine, attenuated the nicotine-induced decrease in LCGU in several brain loci in the rat, including the nucleus accumbens, hippocampus, and intermediate habenula. The blockade of central nicotinic effects by chlorisondamine was found in similar regions of the pigeon brain.…”

“…Ex vivo, chlorisondamine blocks the nicotine-induced release of [ 3 H]-dopamine and [ 3 H]-norepinephrine from synaptosomes for 3-12 weeks (el-Bizri & Clarke, 1994;Reuben, Louis, & Clarke, 1998). Chlorisondamine also attenuates the nicotine-induced decreases in local cerebral glucose utilization in rats at 28 days (Marenco, Bernstein, Cumming, & Clarke, 2000). Thus chlorisondamine can antagonize the central and peripheral effects of nicotine depending on the dose.…”

Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

“…A bolus of nicotine given in the general circulation produces both localized dopaminergic activation (e.g., Champtiaux et al 2003;Marubio et al 2003;Maskos et al 2005;Mameli-Engvall et al 2006) and distributed effects such as the release of other neurotransmitters, the synthesis of transcription factors (Hiremagalur and Sabban 1995;Fu et al 2003;Rossi et al 2005), the consumption of glucose (London et al 1988;Marenco et al 2000) showing a nicotine-evoked stimulation of neural activation, and brain metabolism. However, the nicotine-stimulating effect is exerted both by β2*nAChRs and α7 subtypes expressed on GABAergic neurons and glutamatergic nerve endings, but also and mostly at nonsynaptic compartments, and can increase the influx of both Na+ and Ca2+ (Pakkanen et al 2005).…”