A role for neuronal nicotinic acetylcholine receptors in ethanol-induced stimulation, but not cocaine- or methamphetamine-induced stimulation

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Psychopharmacology (Impact Factor: 3.88). 03/2008; 196(3):377-87. DOI: 10.1007/s00213-007-0969-7
Source: PubMed


Cocaine (COC), ethanol (EtOH), and methamphetamine (MA) are widely abused substances and share the ability to induce behavioral stimulation in mice and humans. Understanding the biological basis of behavioral stimulation to COC, EtOH, and MA may provide a greater understanding of drug and alcohol abuse.
In these studies we set out to determine if neuronal nicotinic acetylcholine receptors were involved in the acute locomotor responses to these drugs, our measure of behavioral stimulation.
A panel of acetylcholine receptor antagonists was used to determine if nicotinic receptors were involved in EtOH- and psychostimulant-induced stimulation. We tested the effect of these drugs in genotypes of mice (FAST and DBA/2J) that are extremely sensitive to this drug effect. To determine which acetylcholine receptor subunits may be involved in this response, relative expression of the alpha3, alpha6, beta2, and beta4 subunit genes was examined in mice selectively bred for high and low response to EtOH.
Mecamylamine, but not hexamethonium, attenuated the acute locomotor response to EtOH. The acetylcholine receptor antagonist dihydro-beta-erythroidine and methyllycaconitine had no effect on this response. The alpha6 and beta4, but not alpha3 or beta2, subunits of the acetylcholine receptor were differentially expressed between mice bred for extreme differences in EtOH stimulation. Mecamylamine had no effect on psychostimulant-induced locomotor activity.
Neuronal nicotinic receptors are involved in EtOH, but not psychostimulant, stimulation. These studies suggest a lack of involvement of some nicotinic receptor subtypes, but more work is needed to determine the specific receptor subtypes involved in this behavior.

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Available from: Helen Kamens, Aug 19, 2014
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    • "In addition, recent pharmacological studies have implicated a3b4 nAChR in ethanol consumption and seeking in rats (Chatterjee et al., 2011) as well as in alcohol and nicotine co-dependencies (Bito-Onon, Simms, Chatterjee, Holgate, & Bartlett, 2011). Also, the non-specific nAChR antagonist mecamylamine attenuates ethanol-induced stimulation in DBA/2J mice (Kamens & Phillips, 2008). Although mecamylamine is regarded as non-specific, low doses of this nAChR antagonist have been shown to be more specific for a3b4 nAChR (Papke, Sanberg, & Shytle, 2001). "
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    ABSTRACT: Abuse of alcohol and smoking are extensively co-morbid. Some studies suggest partial commonality of action of alcohol and nicotine mediated through nicotinic acetylcholine receptors (nAChRs). We tested mice with transgenic over expression of the alpha 5, alpha 3, beta 4 receptor subunit genes, which lie in a cluster on human chromosome 15, that were previously shown to have increased nicotine self-administration, for several responses to ethanol. Transgenic and wild-type mice did not differ in sensitivity to several acute behavioral responses to ethanol. However, transgenic mice drank less ethanol than wild-type in a two-bottle (ethanol vs. water) preference test. These results suggest a complex role for this receptor subunit gene cluster in the modulation of ethanol's as well as nicotine's effects.
    Alcohol (Fayetteville, N.Y.) 03/2012; 46(3):205-15. DOI:10.1016/j.alcohol.2011.11.005 · 2.01 Impact Factor
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    • "injections of mecamylamine a comparatively low dose of 3 ␮g was used since higher doses have been reported to have unspecific effects, for example on the N-methyl-D-aspartate (NMDA) receptor (O'Dell and Christensen, 1988; Papke et al., 2001). Hexamethonium (Sigma-Aldrich , Munich, Germany) was dissolved in normal saline and administered at 2 mg/kg i.p., in a volume of 1 ml/kg, a dose used previously in comparative studies with mecamylamine of central and peripheral effects of nAChR signaling (Tani et al., 1997; Kamens and Phillips, 2008). All central injections were performed using a microinfusion pump (CMA 400 syringe pump, Solna, Sweden). "
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    ABSTRACT: Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.
    Neuroscience 10/2010; 171(4):1180-6. DOI:10.1016/j.neuroscience.2010.10.005 · 3.36 Impact Factor
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    • "nicotine effects (Greenbaum et al. 2006; Kamens and Phillips 2008; Rigbi et al. 2008; Schlaepfer et al. 2008). Furthermore, it has been shown that ligands for α3, α6, β2, and β3 subunits influence alcohol-induced DA release in nucleus accumbens and reduce alcohol self-administration in rodents (Löf et al. 2007; Kuzmin et al. 2009). "
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    ABSTRACT: Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation. The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats. P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed. Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines. Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.
    Psychopharmacology 08/2010; 211(2):161-74. DOI:10.1007/s00213-010-1878-8 · 3.88 Impact Factor
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