Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes.
ABSTRACT Burst firing of dopaminergic neurons has been found to represent a particularly effective means of increasing dopamine release in terminal areas as well as activating immediate early genes in dopaminoceptive cells. Spontaneous burst firing is largely controlled by the level of activation of NMDA receptors in the ventral tegmental area (VTA) as a consequence of glutamate released from afferents arising mainly in the prefrontal cortex. Nicotine has been found to effectively increase burst firing of dopaminergic cells. This effect of nicotine may be due to an alpha 7 nicotinic receptor-mediated presynaptic facilitation of glutamate release in the VTA. By the use of in-vivo single-cell recordings and immunohistochemistry we here evaluated the role of alpha 7 nicotinic receptors in nicotine-induced burst firing of dopamine cells in the VTA and the subsequent activation of immediate early genes in dopaminoceptive target areas. Nicotine (0.5 mg/kg s.c.) was found to increase firing rate and burst firing of dopaminergic neurons. In the presence of methyllycaconitine (MLA, 6.0 mg/kg i.p.) nicotine only increased firing rate. Moreover, in the presence of dihydro-beta-erythroidine (DH beta E, 1.0 mg/kg i.p.), an antagonist at non-alpha 7 nicotinic receptors, nicotine produced an increase in burst firing without increasing the firing rate. Nicotine also increased Fos-like immunoreactivity in dopamine target areas, an effect that was antagonized with MLA but not with DH beta E. Our data suggest that nicotine's augmenting effect on burst firing is, indeed, due to stimulation of alpha 7 nicotinic receptors whereas other nicotinic receptors seem to induce an increase in firing frequency.
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ABSTRACT: Nicotine is the principal addictive component that drives continued tobacco use despite users' knowledge of the harmful consequences. The initiation of addiction involves the mesocorticolimbic dopamine system, which contributes to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors. Acting mainly through nicotinic receptors containing the α4 and β2 subunits, often in combination with the α6 subunit, nicotine increases the firing rate and the phasic bursts by midbrain dopamine neurons. Neuroadaptations arise during chronic exposure to nicotine, producing an altered brain condition that requires the continued presence of nicotine to be maintained. When nicotine is removed, a withdrawal syndrome develops. The expression of somatic withdrawal symptoms depends mainly on the α5, α2, and β4 (and likely α3) nicotinic subunits involving the epithalamic habenular complex and its targets. Thus, nicotine taps into diverse neural systems and an array of nicotinic acetylcholine receptor (nAChR) subtypes to influence reward, addiction, and withdrawal.Annual Review of Neuroscience 07/2010; 34:105-30. · 20.61 Impact Factor
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ABSTRACT: Epidemiological studies consistently find correlations between nicotine and alcohol use, yet the neural mechanisms underlying their interaction remain largely unknown. Nicotine and alcohol (i.e., ethanol) share many common molecular and cellular targets that provide potential substrates for nicotine-alcohol interactions. These targets for interaction often converge upon the mesocorticolimbic dopamine system, where the link to drug self-administration and reinforcement is well documented. Both nicotine and alcohol activate the mesocorticolimbic dopamine system, producing downstream dopamine signals that promote the drug reinforcement process. While nicotine primarily acts via nicotinic acetylcholine receptors, alcohol acts upon a wider range of receptors and molecular substrates. The complex pharmacological profile of these two drugs generates overlapping responses that ultimately intersect within the mesocorticolimbic dopamine system to promote drug use. Here we will examine overlapping targets between nicotine and alcohol and provide evidence for their interaction. Based on the existing literature, we will also propose some potential targets that have yet to be directly tested. Mechanistic studies that examine nicotine-alcohol interactions would ultimately improve our understanding of the factors that contribute to the associations between nicotine and alcohol use.Biochemical pharmacology 07/2013; · 4.25 Impact Factor
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ABSTRACT: Nicotine alters appetite and energy expenditure, leading to changes in body weight. While the exact mechanisms underlying these effects are not fully established, both central and peripheral involvement of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) has been suggested. Centrally, the α7nAChR modulates activity of hypothalamic neurons involved in food intake regulation, including proopiomelanocortin and neuropeptide Y. α7nAChRs also modulate glutamatergic and dopaminergic systems controlling reward processes that affect food intake. Additionally, α7nAChRs are important peripheral mediators of chronic inflammation, a key contributor to health problems in obesity. This review focuses on nicotinic cholinergic effects on eating behaviors, specifically those involving the α7nAChR, with the hypothesis that α7nAChR agonism leads to appetite suppression. Recent studies are highlighted that identify links between α7nAChR expression and obesity, insulin resistance, and diabetes and describe early findings showing an α7nAChR agonist to be associated with reduced weight gain in a mouse model of diabetes. Given these effects, the α7nAChR may be a useful therapeutic target for strategies to treat and manage obesity.Frontiers in Psychology 01/2014; 5:553. · 2.80 Impact Factor