Dual effects of nicotine on dopamine neurons mediated by different receptor subtypes

Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 04/2003; 6(1):1-11. DOI: 10.1017/S1461145702003188
Source: PubMed


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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Available from: Monica Mameli Engvall, Jan 30, 2015
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    • "α4-β2nAChRs are sufficient for these reinforcing effects (Besson et al., 2012), likely via direct effects on DA neurons (Wooltorton et al., 2003; Besson et al., 2012). However, stimulation of α7nAChRs activates DA neurons via glutamatergic inputs (Yoshida et al., 1992; Schilstrom et al., 2000, 2003; Garzon et al., 2013). Thus, α7nAChR activation ultimately increases DA, but this is largely mediated via glutamatergic effects. "
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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 06/2014; 5:553. DOI:10.3389/fpsyg.2014.00553 · 2.80 Impact Factor
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    • "Such features equip ␣7 nAChR for a role in synaptic plasticity (Mansvelder and McGehee, 2000; McKay et al., 2007). Glutamate release, and its enhancement via ␣7 nAChRs, has been implicated in the switch to burst firing in the VTA, mediated by NMDA receptors (Chergui et al., 1993; Overton and Clark, 1997; Schilström et al., 2003). "
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    ABSTRACT: Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the "gold standard" for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting α6β2* and α4β2* nAChR may prove useful in the management of Parkinson's disease.
    Pharmacological reviews 12/2011; 63(4):938-66. DOI:10.1124/pr.110.003269 · 17.10 Impact Factor
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    • "Stolerman et al performed similar studies [43] that confirmed that 0.5 mg/kg was an optimal and effective dose to study the influence of nicotine in the neural firings of DA neurons. Many others [31,44,45] also used 0.5 mg/kg dose of nicotine to study the behavior of DA neurons. Therefore, these studies encouraged us to focus on the single, optimal dose to investigate the influence of nicotine on the dynamics of neural firings of DA neurons. "
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    ABSTRACT: The dopaminergic (DA) neurons in the ventral tegmental area (VTA) are widely implicated in the addiction and natural reward circuitry of the brain. These neurons project to several areas of the brain, including prefrontal cortex (PFC), nucleus accubens (NAc) and amygdala. The functional coupling between PFC and VTA has been demonstrated, but little is known about how PFC mediates nicotinic modulation in VTA DA neurons. The objectives of this study were to investigate the effect of acute nicotine exposure on the VTA DA neuronal firing and to understand how the disruption of communication from PFC affects the firing patterns of VTA DA neurons. Extracellular single-unit recordings were performed on Sprague-Dawley rats and nicotine was administered after stable recording was established as baseline. In order to test how input from PFC affects the VTA DA neuronal firing, bilateral transections were made immediate caudal to PFC to mechanically delete the interaction between VTA and PFC. The complexity of the recorded neural firing was subsequently assessed using a method based on the Lempel-Ziv estimator. The results were compared with those obtained when computing the entropy of neural firing. Exposure to nicotine triggered a significant increase in VTA DA neurons firing complexity when communication between PFC and VTA was present, while transection obliterated the effect of nicotine. Similar results were obtained when entropy values were estimated. Our findings suggest that PFC plays a vital role in mediating VTA activity. We speculate that increased firing complexity with acute nicotine administration in PFC intact subjects is due to the close functional coupling between PFC and VTA. This hypothesis is supported by the fact that deletion of PFC results in minor alterations of VTA DA neural firing when nicotine is acutely administered.
    Journal of NeuroEngineering and Rehabilitation 02/2011; 8(1):13. DOI:10.1186/1743-0003-8-13 · 2.74 Impact Factor
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