







































Interplay of Nicotine and Social 
Stress Mediate Dopaminergic Neuron 
Firing in the Ventral Tegmental Area 

—Nucleus Accumbens Pathway, 
Contributing to Stress and Depressive 

Mood Disorders
Danya Adams, Nicholas Kaliss, Alexander Missner, Mary Meg 

Valentine 

Volume One 
Edition One 
February 2021 

 
GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

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https://doi.org/10.48091/SUVN5250 

The Interplay of Nicotine and Social Stress Mediate 
Dopaminergic Neuron Firing in the Ventral Tegmental Area 
- Nucleus Accumbens Pathway, Contributing to Stress and
Depressive Mood Disorders.

Danya Adams*, Nicholas Kaliss*, Alexander Missner*, Mary Meg Valentine*

1 Department of Biology, Georgetown University, Washington, DC, USA 
* Indicates equal contribution

E-mail: daa112@georgetown.edu, ndk14@georgetown.edu, am3212@georgetown.edu,
mmv57@georgetown.edu

Abstract 
Nicotine use and social stress have a complex interplay, which has been shown to be mediated by 
cholinergic neurons in the ventral tegmental area (VTA). Social stress is often comorbid with nicotine 
consumption, and the presence of either stress or nicotine use significantly increases the risk of developing 
the other. In fact, it has been shown in mice that nicotine injection is sufficient to increase susceptibility to 
social defeat, a reliable model for stress and anxiety-like behavior. Stressful events can molecularly remodel 
cholinergic synapses, inducing the production of more cholinergic transporters and increasing the number 
of nicotinic receptor binding sites. One way stress and nicotine remodel cholinergic synapses are through 
long-term potentiation (LTP) in cholinergic pathways in the VTA, enhancing the experience of stress 
and the effects of addiction. Despite both primarily acting on the 𝛼𝛼7 subtype nicotine receptor, nicotine
and stress induce LTP in vastly different ways: nicotine acts quickly via ligand-gated ion channels while 
stress activates a slower hormonal-induced G-protein coupled receptor pathway. These findings suggest 
that dopaminergic VTA neurons may be a useful therapeutic target for depression, anxiety, and other 
stress-related disorders. Deep brain stimulation has preliminarily shown to be a potential therapeutic 
treatment for untreatable depression, especially when it targets the medial forebrain bundle within the 
VTA-NAc pathway. Sleep patterns are also partially regulated by dopaminergic VTA neurons, and sleep 
deficits may contribute to social stress and other depressive symptoms. The role of nicotine dependence 
in stress-related mental illnesses is especially important to consider given the recent increase in adolescent 
nicotine use with the advent of vaping. Adolescents already have an increased risk for developing mental 
illnesses, and it is important that young people are made aware of the potential psychological harms of 
nicotine use. 

Keywords: 𝛼𝛼7 subtype nicotine receptor, cholinergic synapses, long-term potentiation, nicotine, stress,
nucleus accumbens, and ventral tegmental area

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1. Introduction
According to the National Institute on Drug

Abuse, nicotine is classified as a highly addictive 
substance, ranking among other drugs of abuse 
such as cocaine, amphetamines, and heroin.1 The 
US Department of Health and Human Services 
estimates some 20% of all Americans are addicted 
to nicotine, whether by smoking cigarettes, 
chewing tobacco, or vaping.2  While many—up to 
seventy percent each year—will try to quit, only 
around three percent will succeed.3  The smoking 
rate is doubled in individuals who have mood or 
stress disorders, like clinical depression, and 
although these individuals will attempt to quit at 
the same rates, their chances of success are even 
lower than their neurotypical counterparts.4   Each 
condition heightens the risk of developing the 
other: depressed individuals are more likely to 
begin smoking and experience more potent 
withdrawal symptoms when they try to stop, and 
smokers have a higher chance of becoming 
depressed at some point in their lifetimes than 
non-smokers.5 This pattern seems to follow for 
other drugs of abuse as well, as it has been reported 
in both human and animal studies that stress is 
sufficient enough to significantly increase the 
likelihood of drug self-administration and/or 
relapse following a period of abstinence from the 
drug.6  The difficulty that many face in trying to 
quit using tobacco products and the comorbidity 
between stress disorders and nicotine dependence 
can be explained in part by the biological effects 
nicotine and stress have on certain areas of the 
brain, particularly in the reward pathway.  
 The brain’s reward pathway - the 
dopaminergic mesolimbic system - typically 
functions to reinforce survival-promoting 
behaviors, such as eating, or positive social 
interactions, producing positive feelings, and 
serving to motivate such behavior.7  Drugs of 
addiction, however, act on the same pathways to 

produce their characteristic “high” and reinforce 
drug seeking-behaviors and dependence.7  
Nicotine, for example, is an agonist of the 
endogenous neuronal nicotinic acetylcholine 
receptor (nAChR), an ionotropic receptor type 
found widely dispersed throughout the CNS. 
nAChRs have been found to be critical in the 
modulation of dopaminergic activity throughout 
the mesolimbic system.8  
Several brain regions have been linked to the 
encoding of reward-related behaviors, including 
the nucleus accumbens (NAc), ventral tegmental 
area (VTA), amygdala, and hypothalamus, with a 
particular emphasis on the dopaminergic 
projections from the VTA to NAc. The VTA and 
NAc are strongly implicated in both nicotine 
addiction and many stress and mood disorders.5, 9  
The variety of inputs that both the VTA and NAc 
receive - glutamatergic, cholinergic, peptidergic, 
and serotonergic - function to modulate 
dopaminergic neuron firing between the VTA and 
NAc (Figure 1).10  At the core of encoding reward-
related behaviors in these two regions are the 
distinct modes of the firing of the VTA 
dopaminergic neurons innervating the NAc: tonic 
and phasic. Tonic firing is low-frequency and 
regular, whereas the phasic mode is characterized 
by high-frequency bursts of firing. Cholinergic 
signaling - especially as mediated by nAChRs - is 
critical in facilitating the switch between VTA 
neurons’ tonic and phasic modes and, therefore, in 
encoding reward-related information and 
behaviors.10  Further, both stress and drug 
addiction have been reliably shown to be key in 
determining the basal firing rate for dopaminergic 
neurons.10  Combined, this evidence points toward 
an important connection between stress, addiction, 
and cholinergic signaling in the dopaminergic 
mesolimbic system.  

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Figure 1 . A variety of complex neural inputs 
modulate dopaminergic signaling from the ventral 
tegmental area (VTA) to the nucleus accumbens 
(NAc). The illustration above shows a simplified 
summary of several well-established circuits that 
influence mood and have been implicated in the 
dysregulation of mood. Glutamatergic areas 
include the prefrontal cortex (PFC), hippocampus 
(HP), and amygdala (Amy), where the dorsal 
raphe/locus coeruleus (DR/LC) mainly transmit 
serotonin and norepinephrine (5HT, NE). The 
hypothalamus (Hypo) also influences the VTA 
and NAc with peptidergic inputs. (Figure taken 
from Nestler and Carlezon, 2006). 
 Like all complex neural systems, the ability of 
the mesolimbic system to encode nuanced 
information relies on the amount and type of 
afferent input it receives. nAChR subtypes are 
differentially expressed on different types of 
neurons throughout the VTA and NAc; 
depending on the subunit composition of the 
receptor, its affinity for endogenous or 
pharmacological agonists varies. These receptors’ 
unique expression patterns lend each region the 
ability to integrate a variety of signals and encode 
complex behaviors and are differentially implicated 
in the pathology of both nicotine dependence and 
stress. This paper explores these cholinergic 
influences in the mesolimbic system and the 
convergence and divergence of the pathologies of 
nicotine and stress, implicating mechanisms of 
long-term potentiation (LTP) and exploring 
potential therapeutic targets.  

2. Nicotinic Receptors and Social Stress’ Role on
the VTA
 Interestingly, mood disorders and social stress 
have also been shown to affect dopaminergic 
signaling in the same pathways.9  Several studies 
have found that the effects of nicotine use and 
stress can exacerbate each other, independent of 
the withdrawal effects common in nicotine 
addiction.12  Morel et al., 2018 found that this 
bidirectional relationship between nicotine and 
stress is likely mediated by dopaminergic (DA) 
VTA neurons.5  Because the etiologies of stress-
related and depressive symptoms are often quite 
varied and complex, studying these in animal 
models can pose a difficult challenge.  
 Both nicotine exposure and social stress have 
been shown to increase the frequency and bursting 
activity of VTA DA neuron firing.12  Interestingly, 
this study found that the effects of stress seem to 
depend upon the same nAChRs that nicotine acts 
on. Specifically, both nicotine and stress interact 
with the 𝛼𝛼7 homomeric and 2-containing
heteromeric nAChRs, the two primary nAChRs 
in the brain. 𝛼𝛼7/ 2 double knockout mice who
experienced the social defeat (SD) paradigm did 
not show the same increased VTA DA neuron 
firing as wild type mice who experienced SD.  

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Figure 2. Knockout of nAChRs eliminates 
the effects of social stress on VTA DA neurons 
and social behavior. The 7/� 2 knockout is 
a� knockout for both of the primary nAChR 
subtypes in the brain. For graph a, less time 
spent in the interacting zone is taken to mean 
higher effects of social stress on the mouse. 
The frequency and burst activity�
measurements seen in graphs b and c are 
measurements from VTA DA neurons. Graph b 
shows VTA DA neuron frequency and bursting 
activity in mice without the nAChR knockout, 
while graph c shows VTA DA neuronal activity 
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� Additionally, knockout mice did not exhibit 
social aversion, contrasting the typical results of 
SD on wild type mice (Figure 2). Corroborating 
this information suggests that nAChRs in the 
brain are key to both the cellular and the behavioral 
effects of stress. Unsurprisingly, nicotine injection 
also failed to induce increased VTA DA neuron 
firing in knockout mice, confirming that stress and 
nicotine interact with the same nAChRs.  
 Furthermore, mice given acute nicotine along 
with subthreshold SD (SubSD) exhibited much 
higher VTA DA neuron excitability compared to 
control mice who experienced SubSD with no 
nicotine administration. This demonstrated a clear 
remodeling of nicotinic synapses on the VTA. 
Mice who underwent SD also had a greater 
number of cholinergic transporters and nAChR-
binding sites, indicating a comprehensive effect of 
stress on nicotinic pathways in the VTA.  

Morel et al., 2018 employed PNU, an 𝛼𝛼7�
nAChR positive allosteric modulator, to explore 
subtype-specific effects. PNU-treated mice who 
experienced SubSD exhibited DA VTA firing 
increases equivalent to that found in mice 
experiencing the full SD paradigm. Additionally, 
these mice exhibited social aversion quite similar to 
those undergoing the full SD paradigm. Mice who 
underwent SubSD and were pre-treated with 
NS9238, a 2 nAChR positive allosteric�modulator, exhibited DA VTA firing and 
behavioral changes similar to WT mice who 
underwent SubSD. Thus, it seems that activation 
of the heteromeric 2 nAChR does not�
significantly modulate the effects of stress. Both 
PNU and nicotine administered via a cannula led 
to increased social aversion when paired with 
SubSD, confirming that this stress-nicotinic 
relationship was occurring specifically in the VTA.  

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These results implicate 𝛼𝛼7 nAChRs as the primary
receptor upon which stress has its synaptic effects 
in the cholinergic VTA system. 𝛼𝛼7 nAChRs can
therefore be considered as possible therapeutic 
targets for stress and mood disorders going 
forward.  
 Interestingly, stress and nicotine both seem to 
have a significant effect on long-term potentiation 
(LTP) of synapses on DA VTA neurons. Mice 
who underwent SD were found to have an 
increased AMPAR/NMDAR ratio for their DA 
VTA neurons, signifying LTP occurring at these 
synapses. AMPAR/NMDAR ratio serves as a 
marker of LTP, as the insertion of AMPARs, and 
thus an increase in AMPAR/NMDAR ratio, is 
the primary biomarker of LTP.  LTP at these 
synapses helps to complete the picture of the 
cholinergic-stress-VTA pathway as it likely 
contributes to greater firing rates and bursting 
activity in DA VTA neurons for mice under stress. 
Mice treated with PNU also experienced increased 
LTP on DA VTA neurons (Figure 3).  

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� Changes in LTP may be the main way in 
which stress and nicotine remodel VTA DA 
synapses. They both initiate molecular changes 
which result in AMPAR insertion into VTA DA 
neurons, leading to an increase in the firing rate of 
their neurons and likely mediate the behavioral 
changes associated with stress. Being that these 
neurons are highly implicated in addiction, LTP 
at these neurons may also increase the 
susceptibility of an individual to addiction, 
nicotine or otherwise. This implicates stress as a 
risk factor for addiction and also implicates 
nicotine use as a risk factor for increases in 
stress response and potentially mood 
dysregulation.  
3.� Synaptic Mechanisms: Role of LTP in the�
Reward Pathway
 Morel et al., 2018 found that dopamine firing 
is likely modulated through LTP as a response to 
nicotine and/or stress. Here, the mechanisms of 
modulated dopamine firing through LTP are 
examined. Through this mechanism, LTP 
amplifies the reward associated with dopamine 
release in the mesolimbic pathway. Both stress and 
nicotine affect the signaling strength of excitatory 
and inhibitory synapses on dopamine neurons in 
the VTA through NMDAR-dependent LTP and 
GABAAR-dependent LTP, respectively.12, 13  The 
mechanisms by which stress and nicotine alter 
these pathways are very different, but these same 
pathways play a large role in addiction and reward 
association.  
 NMDAR-dependent LTP is crucial for 
increasing the strength of excitatory synapses. 
Glutamate signaling on dopaminergic neurons in 
the VTA drives this process through the 
reinforcement of excitatory synapses via insertion 

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of AMPARs postsynaptically.14 This LTP 
pathway involves both AMPAR subtype GluR1 
and NMDARs (Figure 4). When glutamate is 
released from the presynaptic terminal, it binds to 
GluR1 receptors on the postsynaptic terminal. The 
binding of glutamate onto GluR1 allows the influx 
of sodium (Na+) and potassium (K+), which 
depolarizes the postsynaptic cell. Once the 
membrane is depolarized, the magnesium (Mg2+) 
voltage-dependent block on NMDA receptors is 
released and glutamate binds to these receptors 
with the help of a glycine or serine cofactor. Once 
glutamate binds to NMDA, there is an 
intracellular influx of calcium (Ca2+), which 
activates Ca2+/calmodulin-dependent protein 
kinase (CaMKII) through Ca2+-dependent 
autophosphorylation. Following this, CaMKII 
phosphorylates GluR1 to increase conductance 
and targets stargazin-like transmembrane 
AMPAR regulatory protein in order for AMPA 
localization and clustering to occur, leading to an 
increase in AMPARs.  

Figure 4. NMDAR-mediated LTP pathway.15, 16 

(Adapted from Dr. Mann.) 
 The way nicotine and stress contribute to this 
LTP pathway differs. In the VTA, some nAChRs 
are located on the presynaptic terminals of 
glutamatergic neurons.17 Once nicotine binds to 
nAChRs on the presynaptic terminal, it allows for 
the influx of Na+ and Ca2+, which depolarizes the 
presynaptic neuron. Depolarization causes further 

Ca2+ influx, which mediates the docking and 
release of glutamate. Following its release, 
glutamate binds to AMPARs on the postsynaptic 
membrane of dopaminergic neurons, leading to 
NMDAR-mediated LTP as described 
previously.18  
�����For stress-induced NMDAR-mediated LTP, 
G-protein coupled (GPCRs) glucocorticoid 
receptor (GR) signaling is crucial.19 Exposure to 
acute stress leads to a sympathetic nervous system 
response in which adrenaline is released from 
the adrenal medulla.20 Following this, there is 
an increase in noradrenaline (NA) in the CNS. 
With the increase of NA in the brain, 
corticotropin-releasing factor (CRF) neurons 
in the hypothalamus are stimulated, which 
stimulates the anterior pituitary, and 
adrenocorticotropin is released. This activity in 
the hypothalamic-pituitary-adrenal (HPA) axis 
elicits the release of corticosteroids from the 
adrenal cortex into the bloodstream. These 
corticosteroids can pass through the blood-brain 
barrier, and once in the brain, they bind to GRs. 
GRs in dopaminoceptive neurons of the nucleus 
accumbens (NAc) communicate with 
dopaminergic neurons in the VTA through 
glutamatergic interneurons.21 When the corticoids 
bind to these GRs on dopaminoceptive neurons, 
glutamate release through this positive feedback 
pathway excites the dopaminergic neurons in the 
VTA, which when stimulated leads to LTP. 
While nicotine and stress both increase DA VTA 
firing, nicotine acts quickly through an ionotropic 
receptor while stress acts slower on a metabotropic 
receptor that requires many different 
neuroendocrine pathways.  
 Conversely, both nicotine and stress inhibit 
GABAAR-mediated LTP, which leads to 
decreased inhibition of dopaminergic neurons in 
the VTA (Figure 5). This form of LTP is 
characterized by an enhancement of inhibitory 
postsynaptic potentials (IPSP) via increased 

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GABA release.22 When GABAergic neurons 
release GABA from their presynaptic terminals, 
GABA binds to GABAARs on the postsynaptic 
terminals of dopaminergic neurons in the VTA, 
hyperpolarizing these neurons via an influx of 
intracellular chloride (Cl-). Following numerous 
IPSPs, there is a rebound depolarization of the 
membrane, and, subsequently, voltage-gated Ca2+  
channels (VGCC) on the dendrite are activated. 
With the activation of VGCCs, there is an influx 
of Ca2+ . Furthermore, when glutamate activates 
NMDARs, GABAARs in neighboring synapses 
may be potentiated. The influx of Ca2+  is crucial 
for the mechanism of LTP. It is suspected that this 
increase of intracellular Ca2+  leads to the release of 
nitric oxide (NO), a retrograde messenger. NO 
activates presynaptic soluble guanylate cyclase, 
which produces cyclic guanosine monophosphate 
(cGMP). cGMP activates the cGMP-dependent 
protein kinase, which increases GABA release 
from the presynaptic neuron. When this type of 
LTP is inhibited, GABA release decreases, 
resulting in less inhibition on DA neurons in the 
VTA. Research shows that there is an impairment 
of this form of LTP following the injection of 
nicotine and acute stress. 

Figure 5. GABAAR-mediated LTP pathway.23 

(Adapted from Govindpani et al.) 
 The mechanism by which nicotine and stress 
lead to inhibition of GABAAR-mediated LTP is 

not completely known. α7-containing nAChRs
are localized on the presynaptic terminals of 
GABAergic neurons in the VTA.13 When nicotine 
binds to these nAChRs, the GABAergic 
presynaptic terminals desensitize quickly. This 
leads to less release of GABA, which inhibits the 
LTP pathway on postsynaptic terminals of DA 
neurons in the VTA. For acute stress, the 
glucocorticoid pathway described in NMDAR-
mediated LTP contributes to reduced GABA 
firing.24 The initial response to this acute stress is 
an increase in GABA firing mediated through the 
NO-cGMP-PKG pathway, but the long-term 
effect of this acute stress is an inhibition in this 
form of LTP. After sustained hyperpolarization, 
there is a shift in Cl- reversal potential, making 
GABA become excitatory rather than inhibitory. 
Although more research needs to be performed to 
elucidate the specific pathway, both nicotine and 
stress affect this LTP pathway. 
 These two LTP neural mechanisms play a key 
role in how nicotine and stress increase DA VTA 
release on a synaptic level. By increasing excitatory 
input on dopaminergic neurons via NMDA-
receptor mediated LTP and decreasing inhibitory 
input on dopaminergic neurons via GABA-
mediated LTP, there is an increase in excitatory 
postsynaptic potentials (EPSP) on the 
dopaminergic neurons, leading to enhanced 
dopamine firing. With greater DA firing, the 
reward association increases as the mesolimbic 
pathway of reward is more active. Since nicotine 
and stress have similar results on DA VTA firing 
via different pathways involving nAChRs and 
GRs, respectively, showing that nicotine and stress 
exacerbate each other. With nicotine and stress’s 
underlying LTP mechanisms, which modulate the 
firing rates of DA VTA neurons, long-term 
nicotine use and stress can both have detrimental 
effects on the excitation of DA neurons and 
transmitter release; in this way, increased 

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dopamine signaling underlies the neural 
mechanism for addiction. Furthermore, with LTP 
changing neural connections, this can lead to 
effects such as depression during withdrawal of 
nicotine due to not enough stimulation of 
dopamine pathways in the brain. 
4. Future Directions: Decreasing Dopamine
Firing as a Potential Therapy
 Morel et al. 2018 demonstrate that social 
defeat triggers increases in VTA DA neuron 
spontaneous activity. This is exacerbated by 
nicotinic binding to the 𝛼𝛼7 nAChR in the VTA.
Both the frequency and burst activity increases 
significantly in mice exposed to SD and nicotine. 
This novel finding demonstrates that local VTA 
exposure to nicotine and SubSD is sufficient to 
trigger social aversion. Given that activation of 
nAChRs has an effect on DA VTA signaling, DA 
signaling is implicated. Altogether, this data 
suggests that dopamine signaling is necessary for 
the behavioral manifestations of social stress. 
Preventing this increased dopamine firing could, 
therefore, be a potential therapy for social aversion, 
which has been established to be a symptom in 
depression.  
 To test how dopamine modulation directly 
impacts the VTA, Chaudhury, et al. 2013 
selectively altered levels of dopamine in the VTA 
using optogenetics to test social avoidance in order 
to evaluate depression-like symptoms in mice.25 
While Morel et al. found that nicotinic binding 
leads to alterations in DA signaling, it did not 
directly establish that modifying DA signaling 
changes social aversion-like symptoms. This is 
why optogenetic inhibition of dopamine in the 
VTA is a powerful tool to investigate the potential 
therapeutic opportunities for altering dopamine 
signaling.  
 Induction of phasic firing in VTA neurons in 
the VTA-NAc pathway in mice that were 

undergoing SD induced a susceptible depressive 
phenotype with increased social avoidance. Mice 
that were resistant to social avoidance, after being 
exposed to SD, became depressed when DA phasic 
firing was optogenetically induced. Stimulation of 
phasic dopamine firing corresponded to a rapid 
onset of the susceptible phenotype after stress 
exposure. The fact that social stress was a precursor 
to dopamine alteration in rendering a depressed 
phenotype shows the context-dependent 
alterations that occur. This finding emphasizes 
that dopamine is being directly acted on, which 
confirms that VTA DA neurons serve in stress-
response modulation, contributing to a depressive-
like phenotype.  
 Deep brain stimulation (DBS) therapies to the 
VTA could be an effective way to reduce dopamine 
firing and mediate anti-depressive effects. The 
circuit and context-specific nature of this pathway 
make it a prime therapeutic target. If dopamine 
activity is restored to tonic firing following stress, 
social defeat scores decrease.25 In DBS surgery, an 
electrode is stereotactically implanted into specific 
neuroanatomical regions, and electrical 
stimulation is provided via a pacemaker-like 
stimulator.26 DBS is used in movement disorders 
such as Parkinson’s disease. Recently, DBS has 
been studied for neuropsychiatric disorders. 
 Open-label studies have convincing data that 
suggest that DBS is effective in mediating 
antidepressant effects in individuals who do not 
respond to conventional treatments for 
depression.26 Data from clinical studies of the 
neurophysiological effects of DBS suggest that 
electrical stimulation leads to both short-term and 
long-term effects on firing rates and patterns. 
Although the direct mechanism of action by which 
DBS works is unknown, it has been proposed that 
DBS inhibits neurons being stimulated, 
potentially by modulating the electrical activity of 
potassium and sodium channels. Another 

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proposed mechanism of DBS is that it disrupts 
neuronal signals and activity from being 
propagated in neural pathways.  
 Recently, a review was published that 
investigated DBS for treatment-resistant 
depression.27 The review highlights clinical trials 
where DBS was used to treat depression in 
different brain regions. The results from this 
review emphasize the importance of the medial 
forebrain bundle (MFB)—a pathway between the 
VTA and lateral hypothalamus—as a potential 
therapeutic target for DBS in the VTA-NAc 
pathway (Figure 6). 

Figure 6. The medial forebrain bundle 
(MFB) connects the VTA and lateral 
hypothalamus. The VTA is connected to 
subcortical and cortical prefrontal regions. 
The mesolimbic reward pathway is contained 
within the MFB, composed of dopaminergic 
axons that project from the VTA to NAc.28 
(Figure taken from McGill University) 
 
�����The nerve fibers of the reward circuit are 
located in this pathway, which is composed 
of dopaminergic neuron axon projections that 
go from the VTA to the NAc. Even though 
this pathway involves brain regions beyond the 

75"���NAc connection that Morel et al. focus 
on, it is useful to evaluate DBS as a potential 
therapy.  
 Despite being limited to 11 patients, findings 
indicate that DBS of the MFB could induce 
antidepressant effects. Short-term bilateral 
stimulation of the MFB led to a rapid reduction of 
depressive symptoms in 6 out of 7 patients in one 
study. In other studies, the antidepressant effects 
were also consistent, with no evidence of cognitive 
impairment following months of stimulation. 5IF�
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� � � � �DBS is a promising future direction given 
that phasic dopamine firing in the VTA – 
NAc pathway leads to depressive features in mice, 
which optogenetic alterations reduce. The study 
cited makes evident that DBS is surgically viable 
and potentially modulates the VTA – NAc 
projection. If DBS can alter dopamine in the 
VTA, as proposed, then this therapy is especially 
promising. 
5.�Sleep Disorders: Contribution of Dopamine in�
the VTA - NAc Pathway
 It has been shown that nicotine users 
experience decreased sleep quality.29 Since Morel et 
al. focus on how nAChRs mediate the combined 
effect of stress and nicotine by altering the activity of 
DA neurons in the VTA, this activity may also 
affect sleep disorders. In addition to the stress and 
depression effects of altered DA signaling in the 

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VTA, DA regulates motivational processes via 
this pathway. DA neurons project from the 
VTA to many brain regions (Figure 6). To 
study how the VTA—NAc pathway 
specifically alters sleep, researchers used 
chemogenetic and optogenetic manipulations 
with polysomnographic recordings.30 These 
recordings are a diagnostic test used in sleep 
medicine to comprehensively record physiological 
changes during sleep. Chemogenetics is 
similar to optogenetics but uses chemically 
engineered molecules and ligands instead of 
light and light-sensitive channels (opsins). 
These methods provide incredible 
techniques to study the relationship 
between neuronal activity and behavior.  
 VTA dopamine neurons have been found 
to undergo changes in firing in rapid eye 
movement (REM) sleep and non-REM 
(NREM) sleep, making them interesting 
candidates to further examine. Through 
complex analysis of DA neuron activity in VTA 
projections, researchers found that these neurons 
are altered by different arousal states: in 
NREM sleep their activity is reduced, and 
when active they maintain long-term 
wakefulness.  Overall, dopamine neurons 
that project from VTA – NAc promote 
wakefulness and suppress sleep. Selectively 
optogenetically activating the neurons maintained 
wakefulness and suppressed nest-building 
behavior, which is where mice sleep. Inhibiting 
the activity of these neurons promotes sleep-
related nesting behavior. Even though this 
study examined the VTA projections to the 
NAc, prefrontal cortex, amygdala, and 
dorsolateral striatum, the NAc was the 
only projection that stimulated arousal. The 
NAc increased wakefulness and decreased 
NREM and REM sleep. While other pathways 
such as the prefrontal cortex have a larger 
effect on REM duration, NAc was still �
TJHOJGJDBOU�JO�NPEVMBUJOH�BSPVTBM����
�

� � 5IFTF� GJOEJOHT� BSF� JNQPSUBOU� CFDBVTF�
UIFZimplicate VTA dopamine in mediating stress 
and sleep-like behaviors. Nicotine, as 
established by Morel et al., increases the 
activity of these DA neurons, which induces 
stress-like behavior as a symptom of depression. 
It is also possible that the same mechanism leads 
to heightened arousal-like states, hurting the 
ability to sleep. A recent survey-based study 
found that college students who use electronic 
cigarettes report significantly higher difficulty 
sleeping compared to non-users.29 
Interestingly, electronic cigarette users also report 
more difficulty sleeping compared to traditional 
cigarette users, suggesting that electronic cigarettes 
may be more potent for nicotine than traditional 
cigarettes and thus may pose an increased risk for 
the side effects of nicotine. Taken together, 
nicotine’s effect on DA firing has extensive 
implications, which likely contribute to sleep 
difficulty.  
Conclusion 
 The combination of social stress and nicotine 
binding to acetylcholine receptors in the VTA 
modulates DA firing through various synaptic 
mechanisms. Modulations in DA firing in the 
VTA have broad implications related to several 
mood and sleep disorders. This social stress-
nicotine bidirectional interplay supports and 
partially explains the strong association between 
behavioral disorders and nicotine addiction. The 
data presented in this paper thus demonstrate a 
comorbidity between social stress and nicotine 
dependence: a pattern wherein both pathologies 
enhance the other. Elucidating the synaptic link 
between the disorders has therapeutic 
implications as well, where modulation of 
dopamine activity via DBS or antagonistic 
binding to acetylcholine receptors may reduce 
the stress and depressive symptoms that these 
mechanisms are sufficient to induce. The 
complexity of these mood-responses 

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https://doi.org/10.48091/SUVN5250 

are mediated by diverse neural, endocrine, and 
physiological pathways, which leaves a lot of 
mechanisms and connections unknown. Further 
investigating the connections between drugs and 
the environment, and the effects they have on 
synapses, will uncover more of the mechanisms by 
which a broad range of mood disorders arise.   
 The importance of understanding these neural 
processes is especially important today, as nicotine 
vaping rates have been rapidly increasing in the 
United States. In 2018, a steep increase in vaping 
was observed, with 37% of high school seniors 
reported vaping activity.31 In 2019, 10.5% of 
middle schoolers and 27.5% of high school 
students reported vaping, an alarming increase 
from past years.32 In many cases, these students do 
not know that nicotine is contained in their 
electronic cigarettes, or do not think that nicotine 
alone is harmful. Discovering these synaptic 
mechanisms will demonstrate to uninformed teens 
how nicotine is detrimental and can be a risk factor 
for mood and sleep disorders, especially when 
stressors are involved. It is imperative that 
information on these dangers of nicotine becomes 
more widespread so that society will have a 
comprehensive understanding of how consuming 
nicotine can put people at risk for adverse 
behavioral disorders, independent from addiction.  
Acknowledgments 
We would like to acknowledge Dr. Kathleen 
Maguire-Zeiss for her guidance and expertise. 
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