Will I Get Addicted to Nicotine Again if I Stop Bupropion
Biochem Pharmacol. Author manuscript; available in PMC 2008 Oct xv.
Published in final edited course as:
PMCID: PMC2067251
NIHMSID: NIHMS32025
Bupropion inhibits the cellular effects of nicotine in the ventral tegmental surface area
Huibert D. Mansvelder
1 Department of Anesthesia & Critical Care, Academy of Chicago, 5841 Due south. Maryland Ave, MC 4028, Chicago, IL 60637, USA
Zara M. Fagen
2 Committee on Neurobiology, University of Chicago, 5841 S. Maryland Ave, MC 4028, Chicago, IL 60637, USA
Ben Chang
one Department of Anesthesia & Critical Intendance, University of Chicago, 5841 Southward. Maryland Ave, MC 4028, Chicago, IL 60637, USA
Robert Mitchum
two Commission on Neurobiology, University of Chicago, 5841 Southward. Maryland Ave, MC 4028, Chicago, IL 60637, USA
Daniel South. McGehee
1 Section of Anesthesia & Critical Intendance, University of Chicago, 5841 S. Maryland Ave, MC 4028, Chicago, IL 60637, United states
2 Commission on Neurobiology, Academy of Chicago, 5841 Southward. Maryland Ave, MC 4028, Chicago, IL 60637, U.s.
Abstract
Each year, tobacco use causes over 4 million deaths worldwide and billions of dollars are spent on handling for tobacco-related illness. Bupropion, an singular antidepressant, improves the rates of successful smoking abeyance, however, the mechanisms by which bupropion reduces cigarette smoking and depression are unknown. Here nosotros show that clinical concentrations of bupropion inhibit nicotine's stimulatory furnishings on brain reward areas. Many drugs of abuse, including nicotine, stimulate dopamine (DA) release in the mesoaccumbens advantage system. Nicotinic acetylcholine receptors in the ventral tegmental area (VTA) mediate nicotine's stimulation of DA release, as well as its rewarding effects. Nicotinic receptors are expressed by excitatory and inhibitory neurons that control DA neuron excitability, and by the DA neurons themselves. Bupropion is a broad-spectrum non-competitive nicotinic receptor antagonist. Here we report that pre-treatment of brain slices with a clinically relevant concentration of bupropion dramatically reduces the effects of nicotine on DA neuron excitability. Nicotinic receptors on VTA DA neurons and their synaptic inputs are inhibited past 75 – 95% later bupropion treatment. Nosotros likewise notice that bupropion alone reduces GABAergic transmission to DA neurons, thereby diminishing tonic inhibition of these neurons. This increases DA neuron excitability during bupropion handling in the absence of nicotine, and may contribute to bupropion's antidepressant actions.
Keywords: Acetylcholine, Dopamine, Glutamate, GABA, Synaptic Transmission, Nicotinic
Tobacco apply is the largest preventable crusade of death in developed countries, and despite significant public educational activity efforts the number of smokers continues to increase worldwide [i]. Over seventy% of adult smokers express a want to quit, but only a modest fraction succeed each year [two]. Nicotine replacement treatments for smoking cessation roughly doubles quit rate compared to placebo, merely a large percentage of that grouping relapses to smoking within 6 to 12 months [3, 4]. The atypical antidepressant, bupropion (Zyban™) significantly improves the quitting success charge per unit, fifty-fifty after one year [3], and until recently was the but approved smoking cessation aid other than nicotine replacement [5, 6]. Treatment for smoking cessation with bupropion lasts 7 to 12 weeks and starts while patients are withal smoking. Typically, the target date for quitting is in the 2d week of treatment when patients lose their appetite for smoking [3, 5]. Nicotine cocky-administration studies in rats demonstrate that repeated bupropion administration decreases responding for nicotine, similar to its effects on smoking cessation in humans [7].
Bupropion was introduced clinically equally the antidepressant Wellbutrin™ in the 1980s, merely its machinery of action is non completely understood [8-x]. Bupropion lacks interaction with almost major receptor classes [8], just it inhibits [3H]-dopamine uptake (IC50 = ii μM) and [3H]-norepinephrine uptake (IC50 = v μM) by rat brain synaptosomes [9]. In addition, bupropion is a broad-spectrum antagonist of nicotinic acetylcholine receptors (nAChRs) in heterologous expression studies [11], and in both in vitro and in vivo assays of native nAChR function [12-14]. Despite these of import advances, bupropion's mechanism of activity and the importance of its interaction with nicotinic receptors in smoking abeyance remains unclear.
Nicotine reinforces behavior by acting on nAChRs in the mesolimbic dopamine system [xv, 16]. Every bit with many drugs of abuse, nicotine increases dopamine release in the nucleus accumbens (NAcc) from midbrain dopamine neurons located in the ventral tegmental surface area (VTA) [17, 18]. A unmarried exposure to nicotine increases dopamine release in the NAcc for over an hour in vivo [18, nineteen]. The rewarding effects of nicotine, as assayed by self-assistants of the drug, along with nicotine-induced dopamine overflow in the NAcc are dependent upon activation of nAChRs within the VTA [15, 16]. It is important to note that although bupropion has been reported to cake native nAChRs [xiii, 14] these studies have not examined the furnishings of the drug within the VTA.
We have shown that nicotine modulates VTA synaptic transmission in a persistent manner, which likely contributes to the prolonged excitation of dopamine neurons [20, 21]. Investigating the effects on excitatory transmission, nicotine promoted long-term potentiation of inputs onto dopamine neurons [20]. In add-on, nicotine exposure caused a transient enhancement followed by a low of inhibitory GABAergic inputs to the dopamine neuron, and the latter consequence is due to desensitization of nAChRs that mediate tonic inhibitory drive to the dopamine neuron [22]. Here we investigate whether clinically relevant concentrations of bupropion affect cellular responses to nicotine inside the VTA. Nosotros study that bupropion dramatically reduces nicotine'due south effects on the mesolimbic dopamine system. In add-on, bupropion treatment alone decreases the inhibitory bulldoze to this system.
Materials and Methods
Horizontal brain slices were prepared from Sprague-Dawley rats (10–14 days of historic period). Following rapid decapitation, the brain was removed, the olfactory bulbs were cutting abroad, and the midbrain was cut at the level of the ivth ventricle. Then the brain was placed in water ice-cold artificial cerebrospinal fluid (aCSF) containing (in mM) NaCl 125, KCl ii.v, MgCl2 1, CaCltwo 2.v, Glucose xx, NaH2PO4 1, NaHCO3 25, ascorbic acrid ane; bubbled continuously with 95% O2/5% CO2, pH vii.3. From each brain, two or three slices (250–300 μm) were cut in cold aCSF and incubated for at least one 60 minutes (32–34°C). Slices were pretreated with bupropion at the examination concentration during this incubation. For recording, the slice was transferred to a sleeping room superfused (~two ml min−ane) with aCSF lacking ascorbic acrid at room temperature. Bupropion was included in all perfusion solutions at the exam concentration.
Neurons were visualized nether infrared illumination using an upright microscope (Axioskop, Zeiss). When recording GABAergic manual, electrodes (two.5–4 MΩ) contained (in mM): K-Gluconate 78, KCl 77, EGTA 1, HEPES 10, Glucose x, ATP 5, GTP 100 μM (pH 7.iv with KOH). When recording glutamatergic transmission, electrodes were filled with (in mM): Grand-Gluconate 154, KCl 1, EGTA 1, HEPES 10, Glucose ten, ATP v (pH 7.4 with KOH). Standard whole-prison cell voltage clamp recordings were fabricated using an Axopatch 200B amplifier, a Digidata 1320A interface, and pCLAMP viii software (Molecular Devices Corp. Sunnyvale, CA). In whole-cell recordings, DA neurons in the VTA can be distinguished from other cell types in the nucleus by activity potential firing rates, action potential duration, soma diameter and the presence of a prominent hyperpolarization activated current, Ih [23]. Recent findings propose that non-DA neurons in the VTA may likewise express Ih [24, 25]. Cell morphology has some predictive value for identifying dopaminergic cells, only it is not entirely reliable [24], but we contend that the combination of these parameters yields a population of neurons that is predominantly dopaminergic. Neurons were held at −60 mV to assess the presence of Ih, simply were held at −seventy mV throughout the residue of the voltage clamp experiments. All experiments described here were performed on cells that expressed Ih > 30 pA at −120 mV. Spontaneous transmission was filtered at ane kHz and digitized at 5 kHz. In experiments measuring membrane potential in current clamp recording fashion, we used perforated patch recording methods with amphotericin B (660 μg/ml final concentration, Sigma) dissolved in DMSO was added to the pipette solution. These experiments were started when the series resistance dropped below forty MΩ, merely was typically fifteen–thirty MΩ. In whole-prison cell recordings, series resistance values were four-6 MΩ. To isolate GABAergic manual, experiments were done in the presence of ten μM 6,7-Dinitroquinoxaline-2,3-dione (DNQX) to cake glutamate transmission [26]. Glutamatergic transmission was isolated past adding 20 μM bicuculline to the bath solution to block GABAergic synaptic inputs [27]. Nicotine tartrate, bicuculline methiodide, (both from Sigma, St Louis, MO), DNQX (Tocris, Ellisville, MO) and bupropion HCl (Sigma) were applied through bathroom perfusion during recording. Bicuculline and DNQX were present in the bath at to the lowest degree xv minutes before the effect of nicotine was assessed. A new slice was used for each experiment, so that neurons were exposed only in one case to nicotine.
Spontaneous IPSC and EPSC were recorded continuously at a property current of −70 mV and data analysis was carried out using MiniAnalysis software (Synaptosoft, Inc., Decatur, GA). Amplitude, rise-time and area thresholds were used to acquire events and the amplitude threshold was gear up to five times the RMS noise of each recording, as determined by the software. Each caused issue was visually inspected to protect against software errors. Graphical representations of the results were constructed with SigmaPlot seven.0 (SPSS, Inc.).
Later plotting synaptic activity frequency histograms determination of 'responsive' cells involved comparison, via Student'southward t-test, the baseline frequency for a ane min period immediately prior to nicotine application with a ane min period centered on the peak nicotine event. In the absenteeism of a clear nicotine-induced change in frequency, the frequency data were sampled from a 1 min window centered one min after the commencement of the nicotine application. This time point most ordinarily corresponds to the maximal effect of nicotine on synaptic manual [20, 21]. The magnitude of each alter in synaptic manual was defined as the difference betwixt the average frequency 1 min immediately prior to nicotine application and an average of 30 sec of frequency data sampled around the peak nicotine response. Once more, in the absence of a articulate effect of nicotine, the baseline frequency was compared with the frequency during a 30 sec window centered ane min after the kickoff of the nicotine application. In bupropion pretreated samples, the same methods were used for determining response prevalence and magnitude.
Action potential frequencies were also determined using MiniAnalysis software. For examining the furnishings of each drug handling on action potential activity, baseline firing charge per unit was sampled and averaged over 1 min immediately prior to drug awarding, for nicotine, the response magnitude was determined comparing the baseline frequency determination with the average frequency during a thirty sec window centered on the peak effect. In the absenteeism of an result on firing charge per unit, the baseline was compared with a 30 sec window centered thirty sec after the beginning of the nicotine application, which was by and large the superlative of the nicotine effect. Bupropion'due south effects on firing charge per unit were much slower to develop, equally such, we perfused bupropion for at least 20 min prior to sampling the frequency during a 30 sec window. Decision of pregnant differences in the modulation of activity potential frequency in Figure 1c, each treatment condition (nicotine, bupropion, and the combination of the two drugs) was compared to its own baseline control period (no drug for nicotine and bupropion, bupropion alone for the combination of nicotine and bupropion) using paired t-tests.
Bupropion inhibits nAChRs on VTA dopamine neurons. a) Bath application of 1 μM nicotine increases action potential frequency (n = 7). b) In slices pretreated with 1 μM bupropion nicotine does not alter activity potential frequency in dopamine neurons (n = 4). c) Summary of boilerplate activity potential firing rates in VTA dopamine neurons under different treatement paradigms. Acute application of nicotine (1μM) induced a significant increase in action potential activeness relative to pre-nicotine baseline activity (n = seven, * p<0.05 by paired t-test). In acute tests of bupropion'due south effects on activeness potential activeness, baseline firing rate was sampled and averaged over ii min immediately prior to i μM bupropion, which was perfused for at least 20 min prior to sampling the frequency for another 2 min. Nether these weather, bupropion besides a meaning increase in firing rate (due north=6, * p<0.05 by paired t-test), but the magnitude of the modify was smaller than nicotine. d) For assessing interaction of bupropion with nAChRs straight, responses to focal application of 1 mM ACh onto VTA dopamine neurons were used. In control cells without bupropion treatment, rapid inward currents were seen in the presence of inhibitors of synaptic manual. The lower trace illustrates the lack of response from a neuron post-obit pretreatment with 10 μM bupropion for > 2 hrs. e) To assess the sensitivity to bupropion, slices were pretreated with with diverse concentrations of the drug for > two hrs. Summary information of the inhibition of the ACh-induced in current by a range of bupropion concentrations. (Northward= 23, 22, 17, xiii for 0, 0.1, ane, and x μM, respectively, * p < 0.01). Note that bupropion also blocks the increase in racket induced by nicotine, every bit with other nAChR antagonists [20], further supporting the idea that bupropion straight inhibits nAChRs on the dopamine neurons. Recordings of membrane potential were made in amphotericin perforated-patch whole-cell current clamp style. Recordings of the current induced by nicotine were made in normal whole-cell voltage clamp.
Data are presented as hateful ± standard error. Statistical comparison of response magnitudes in the presence and absence of bupropion was evaluated using Student's t-examination. Multiple comparisons in Effigy 1d were done using Bonferroni protection, where the three comparisons required p < 0.16 by Student's t-exam.
Results
In brain slices containing the VTA, dopamine neurons that projection to the nucleus accumbens are depolarized by nicotine concentrations experienced by smokers, which leads to increases in action potential frequency [28-30]. Using perforated-patch recording from VTA DA neurons, we establish that bath awarding of 1 μM nicotine increased the activity potential firing frequency to 242 ± 87 % of command (Fig 1a, 1c; due north = 7; p<0.05 past paired t-test). Plasma levels of bupropion in humans treated with Zyban for as a smoking abeyance assist can rise to a top between 0.5 to one μM [31, 32]. It is reported that pre-application of bupropion reduces the apparent ICl on cloned nAChRs [12] and patients on Zyban treatment have elevated bupropion plasma levels for weeks. When we tested acute application of clinically relevant bupropion concentrations we saw a weak issue on firing charge per unit (Fig 1b, 1c; north=half dozen; p< 0.05 by paired t-test). Acute bupropion application as well inhibited currents induced by focal awarding of ACh, just both of these effects were wearisome to develop (~20 min for steady-country inhibition with 1 μM bupropion, information non shown), which complicated the information interpretation equally the ACh responses can testify varying degrees of run-downward in whole cell recordings over a similar fourth dimension scale. Therefore, nosotros assessed nAChR antagonism in VTA slices that were pre-exposed to bupropion for a minimum of two hours (average pretreatment time: 186 ± ten min, n = xl). As shown in Fig 1b, i μM bupropion pretreatment resulted in a small-scale increment in action potential firing over baseline (138 ± 17% of pre-drug baseline, n = half dozen, p < 0.05 past paired t-exam). In the presence of bupropion, nicotine did non alter the firing frequency of VTA dopamine neurons (northward = 4; p = 0.92 by paired t-test; Fig 1b, 1c). Note that the weak excitatory consequence of bupropion is not likely to occlude resolution of the strong effect of nicotine on firing rate. Bupropion pretreatment dose-dependently inhibited the depolarizing inward current induced by focal application of 100 μM acetylcholine (Fig 1d, 1e). Currents were normalized to prison cell capacitance and averaged from all recordings under each pretreatment condition. The bupropion concentration that caused 50% of the maximal inhibition (IC50) was 0.28 μM, with a Hill number of 0.99. Meaning inhibition of the ACh induced currents by one μM and 10 μM bupropion (p < 0.01) and nearly complete inhibition of the currents with ten μM bupropion. These data were averaged from both Ih-positive dopaminergic and Ih-negative non-dopaminergic neurons (n = 39 and 24, respectively). Plotting the data from Ih-positive neurons independently yielded an identical IC50.
Excitatory glutamatergic manual in the VTA regulates dopamine neuron excitability [33, 34] and it contributes to the nicotine-induced enhancement of excitation of these neurons both in vitro and in vivo [19, 20]. When recording from dopamine neurons in the presence of 20 μM bicuculline to block GABAergic transmission, the remaining fast synaptic transmission is glutamatergic and is blocked by 10 μM DNQX (non shown)[20]. Nicotine increased the frequency of spontaneous glutamatergic manual past about 400% relative to pre-drug baseline in 63% of the dopamine neurons (Fig 2). This higher frequency of sEPSC was non associated with a shift in the aamplitude of the events, supporting the idea that the nAChRs responsible are expressed on presynaptic terminals, as we have reported previously (information not shown) [20] Subsequently pretreatment of slices with 1 μM bupropion, nicotine however increased the spontaneous excitatory postsynaptic current (EPSC) frequency in 58% of the neurons, just the increase was reduced by 73% (Fig 2b,c). Thus, by inhibiting the nicotine-induced inward current in dopamine neurons and by reducing the nicotine-induced enhancement of excitatory transmission to these neurons, bupropion removes the excitatory effects of nicotine on the mesolimbic dopamine reward organization.
Enhancement of excitatory glutamatergic transmission by nicotine is inhibited by bupropion. a) Bath application of ane μM nicotine enhances the frequency of spontaneous EPSCs. In addition, nicotine also increases the noise in the recording, due to the activation of postsynaptic nAChRs, as in the traces of Effigy 1c. To reliably detect individual EPSCs, amplitude, surface expanse and rise fourth dimension thresholds were set with the aamplitude threshold at to the lowest degree 5 times the RMS noise measured in the presence of nicotine (meet Methods)[20]. b) Histograms of EPSC frequency with and without ane μM bupropion pretreatment. c) Summary graph illustrating the average % change in EPSC frequency following nicotine handling with and without 1 μM bupropion. These averages include data from only those cells with statistically significant difference in frequency following nicotine treatment. Nicotine but north = 13 of 21; bupropion + nicotine, n = vii of 12; * p < 0.05.
VTA dopamine neurons receive GABAergic inputs from local interneurons and projection fibers from the NAcc and the ventral pallidum [35]. In vivo biochemical data indicates that dopamine neurons are under tonic inhibitory command by GABA [36]. Recently, it was reported that non-dopamine neurons in the VTA limited nAChRs that excite these neurons upon activation by nicotine [37]. Fast GABAergic transmission can exist recorded selectively by bathing slices in ten μM DNQX. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was increased by the application of nicotine to 318 % on boilerplate relative to pre-drug baseline (Fig three). This increased frequency is associated with a shift to larger sIPSC amplitudes. Fifty-fifty though there is an effect on synaptic electric current magnitude, it is most likely mediated by nAChRs expressed presynaptically, as the consequence is TTX sensitive [21]. This suggests that the larger aamplitude events in the presence of nicotine are due to multi-vesicular, activity potential dependent release events. Pretreatment of slices with 1 μM bupropion inhibited the outcome of nicotine on IPSC frequency past 85% on average (Fig 3b,c). Thus, bupropion likewise inhibits the majority of nAChRs expressed by GABA neurons that projection to the VTA dopamine neurons.
Bupropion inhibits the enhancement of GABAergic transmission induced past nicotine. a) Nicotine (1 μM) increases the frequency of spontaneous IPSCs. b) Frequency histograms showing the increase by nicotine and the inhibition of nicotine's enhancement by 1 μM bupropion. c) Summary graph illustrating the boilerplate % alter in IPSC frequency following nicotine treatment with and without 1 μM bupropion. Averages are from all cells tested equally nicotine induced statistically pregnant increases in IPSC frequency in all of the recordings. Nicotine merely, n = 12; bupropion + nicotine, n = 12; * p < 0.001.
Interestingly, the baseline frequency of spontaneous IPSCs was significantly lower in slices that were pretreated with bupropion than in untreated command slices (Fig 4a,b). In dissimilarity, the baseline spontaneous EPSC frequency was unaltered past the pretreatment with bupropion (Fig 4c). Possibly, the GABA neurons receive a tonic excitatory drive from cholinergic inputs from the laterodorsal tegmental and the pedunculopontine nuclei. It has been shown that the GABA neurons in the VTA receive cholinergic projections from these nuclei to the VTA [38]. Thus, inhibiting nicotinic receptors with bupropion could remove the excitatory cholinergic bulldoze from GABA neurons, which would decrease inhibitory drive to VTA DA neurons. As a effect, long-term exposure to bupropion may increase the basal level of excitation of dopamine neurons through prolonged disinhibition. Consequently, dopamine levels in the mesolimbic reward system may be increased in patients that are treated with Zyban, which may contribute to the antidepressant furnishings of the drug.
Bupropion reduces the basal frequency of spontaneous IPSCs. a) Examples of spontaneous IPSCs in command slice without drug handling, and slice pretreated with i μM bupropion. b) Summary graph shows a significantly lower IPSC frequency in slices pretreated with ane μM bupropion (* p < 0.03; no drug northward = 12, bupropion, n = 12). c) EPSC frequency is unaffected by pretreatment with 1 μM bupropion (no drug north = 12 bupropion due north = 12
Using extracellular recording configuration we monitored the acute effects of ane μM bupropion handling on action potential activity in VTA neurons and found an boilerplate increase in firing rate to 135 ± 11 % of the pre-drug firing rate, measured in the aforementioned neurons (n = 4; Figure 5A–C). This effect was consistent with the disinhibition of the DA neurons illustrated in Figure 4. While DA reuptake is only weakly affected by this low bupropion concentration [39], a depression level of inhibition might alter local DA levels. Increases in extracellular DA within the VTA would be expected to activate D2 autoreceptors on the DA neurons, causing a subtract in firing frequency and an underestimation of the excitatory effects of bupropion. Nosotros tested the effects of nomifensine (10 μM), a selective DA transport inhibitor in the VTA slice and found no effect on DA neuron firing frequency, as shown in Effigy 5C. Therefore, it is unlikely that the weak inhibition of DA transport by bupropion contributes significantly to the observed changes in VTA action potential activeness.
Bupropion increases action potential firing in VTA DA neurons. a) Example traces of spontaneous activeness potential firing in control and post-obit treatment with bupropion (ane μM; left panels). The frequency histogram from some other neuron shows a articulate increment in firing rate post-obit bath perfusion with bupropion (1 μM; right panel). Information were nerveless using extracellular recording. Calibration bars 0.5 mV, 0.5 sec b) Interspike interval distributions before and 20 min after treatment with bupropion (1 μM). These information were collected from the same neuron shown in the histogram in (a). c) Summary data of the spike frequency effects of nomifensine (10 μM; n=3) and bupropion (1μM; n=4; * p < 0.05).
Give-and-take
Cigarette smoking is addictive, at least in part, through the effects of nicotine on midbrain dopamine reward centers [2, 40]. Nicotine acts directly on VTA dopamine neurons too as the synaptic inputs to these neurons [20, 21, 29]. In this study nosotros showed that bupropion exposure for more than i hr removes the excitatory deportment of nicotine on the dopamine reward system. It dramatically diminishes the excitatory effects of nicotine on VTA dopamine neurons and on the glutamatergic and GABAergic synaptic inputs to these neurons.
Compared with other normally used antidepressants, bupropion has relatively weak effects on dopamine re-uptake at clinical concentrations. Our findings advise that bupropion'south inhibition of nicotine-induced excitation of the mesolimbic reward organization may depend largely upon its inhibition of nAChRs within this circuitry. Although clinical tests of the non-competitive nicotinic antagonist mecamylamine has yielded negative results for smoking cessation [4]. Recently the fractional agonist of nAChRs, varenicline, has been approved for smoking cessation [41, 42]. Administering this drug induces weak activation of nAChRs, which may enhance dopamine release and limit abstinence-induced craving. Varenicline would also antagonize the effects of nicotine at the aforementioned receptors, interfering with its reinforcing effects. Thus, antagonism of nAChRs may exist a key element in the efficacy of bupropion in combatting nicotine addiction. In this context, the low affinity of bupropion may be an advantage relative to other more efficacious antagonists such as mecamylamine. We found that bupropion never inhibited nicotine'southward effects completely, simply a small response of ten to 25% remained, suggesting that reward was reduced simply not eliminated. In calorie-free of these observations, it would exist interesting to examination whether low concentrations of mecamylamine, mimicking the weaker antagonistic effects of bupropion, would be efficacious in the treatment of smoking cessation.
Bupropion alone reduced the inhibitory GABAergic input to dopamine neurons. We previously found that GABA neurons in the VTA feel a tonic excitatory drive past endogenous acetylcholine transmission [21], most likely originating from the cholinergic laterodorsal and the pedunculopontine tegmental nuclei. During smoking, desensitization of nAChRs on GABA neurons by nicotine removes this excitatory drive and reduces activity of GABA neurons, thereby diminishing inhibitory input to VTA dopamine neurons. Bupropion is an antagonist of nAChRs [11, 12] and inhibits the effects of nicotine on GABA neurons. This blockade of nAChRs will too remove the excitatory drive to GABA neurons by acetylcholine. As a result, GABAergic transmission to the VTA dopamine neurons is macerated and these neurons receive less inhibition. Thus, people treated with Zyban may feel elevated dopamine levels. This is consistent with the ascertainment that nicotine and bupropion share like discriminative effects in behavioral studies [43].
The reduction of GABAergic transmission in the VTA and the subsequent disinhibition of the dopamine organization may contribute to the effectiveness of bupropion in smoking abeyance. It is reported that monoamine oxidase (MAO) is chronically inhibited in the brains of smokers compared to non-smokers and former smokers [44], and MAO inhibitors help heavy smokers to successfully quit. Therefore, disinhibition of the dopamine system past bupropion may compensate for reduced dopamine levels when a person quits smoking. It is non known whether chronic MAO inhibition is office of smoking-related reward, only the disinhibition of the dopamine system past bupropion may reduce negative symptoms associated with abstinence from smoking. Abstinence symptoms are a major cause for relapse in unaided smokers. Indeed, it is reported that in addition to removing the appetite for smoking, bupropion also alleviates abstinence symptoms [45].
It should be emphasized that our investigation focused solely upon acute furnishings of bupropion in naïve animals that have not been previously exposed to nicotine or other addictive drugs. Thus, the effects of repeated, prolonged exposure to nicotine and bupropion may induce very different physiological furnishings in the VTA, as well equally other brain areas. To improve approximate the atmospheric condition of the human smoker, future studies will necessarily include investigating bupropion effects in animals that have been chronically exposed to nicotine. This is particularly important as upregulation of nAChR function is known to occur post-obit chronic nicotine exposure [46, 47]. In this regard, it will besides exist interesting to assess possible changes in nAChR role following chronic bupropion treatment in animals.
Bupropion was the first antidepressant that conspicuously improved smoking cessation [5]. Other antidepressants have been tested more recently, with some encouraging results with the tricyclic antidepressant, nortriptyline [47, 48]. Mood and affect are potent motivators for smoking. Symptoms of melancholia disorders are more abundant among smokers than amidst non-smokers. In addition, people are more than likely to fume when they have a negative affect and these individuals find quitting to be extremely difficult [49]. Bupropion finer reduces smoking in patients with a history of depression [50]. Disinhibition of the dopamine system by bupropion that we describe here, may also contribute to the antidepressant actions and its success in patients with a history of depression.
A contempo behavioral study of in rats suggests that inhibition of dopamine reuptake does contribute to bupropion-induced attenuation of anhedonic effects during nicotine withdrawal [52]. In that report, the furnishings of nicotine on extracellular dopamine levels were not significantly adulterate past bupropion administration, simply it is non clear the extent to which bupropion disinhibition of dopamine neurons might contribute to the observed effects, by the mechanisms explored in our experiments. It is possible that the efficacy of bupropion as a smoking cessation aid derives from the combined inhibition of nAChRs and dopamine reuptake.
In human being adolescents the initial symptoms of nicotine dependence can already be present later on smoking only a few cigarettes [53]. Recently, nosotros reported that pocket-size doses of nicotine, similar to that received from 1 cigarette, induce a long-term enhancement of dopamine neuron excitability through synaptic mechanisms [twenty, 21]. These persistent changes in excitability within the brain reward system may reflect the early steps of nicotine dependence. Equally shown in this written report, clinical concentrations of bupropion dramatically reduce the effects of nicotine on synaptic transmission in the VTA. Therefore, pretreatment with bupropion in an early stage of nicotine exposure may help protect individuals from addiction to tobacco.
Summary diagram of nAChR effects in VTA and their inhibition past bupropion. A. An illustration of the proposed pattern of nAChR expression on VTA dopamine neurons every bit well as the glutamatergic and GABAergic inputs to these cells. Presynaptic α7 nAChRs enhance glutamate inputs to VTA dopamine neurons. Non-α7 nAChRs on the cell torso of the dopamine neuron increase excitability of the dopamine neurons directly. Non-α7 nAChRs in the preterminal, somatic and dendritic regions of the GABA neurons assist set up the basal inhibitory tone to the dopamine neuron via cholinergic input from the pontomesencephalic tegmental nuclei (PMT). The receptor localization derives from this report and numerous previous investigations [xi, xv, 16, xix-22, 28-30, 36-forty].
B. In the presence of bupropion, the effects of nicotine on each of these receptor classes is inhibited. Blockade of the nAChRs on the GABA neurons past bupropion may be particularly of import every bit it disinhibits the dopamine neuron past limiting cholinergic excitatory drive to the GABA neurons [21, 22]. This effect may raise dopamine release and contribute to the antidepressant furnishings of the drug.
Acknowledgments
We thank Drs. J.R. Keath and J.R. Genzen for comments on before drafts of the manuscript. This work was funded by the National Science Foundation DGE0202337 to ZMF, the Netherlands System for Scientific Research NWO S93-334 to HDM, the National Institutes of Health DA07255 to BC, DA015918 and DA019695 to DSM, and by the Brain Research Foundation.
Footnotes
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2067251/#:~:text=Bupropion%20is%20an%20antagonist%20of,these%20neurons%20receive%20less%20inhibition.
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