HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits
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cells
Review
HIV-Associated Apathy/Depression and Neurocognitive
Impairments Reflect Persistent Dopamine Deficits
Kristen A. McLaurin † , Michael Harris † , Victor Madormo † , Steven B. Harrod, Charles F. Mactutus
and Rosemarie M. Booze *
Department of Psychology, University of South Carolina, Columbia, SC 29208, USA;
mclaurik@email.sc.edu (K.A.M.); mwh2@email.sc.edu (M.H.); vmadormo@email.sc.edu (V.M.);
harrods@mailbox.sc.edu (S.B.H.); mactutus@mailbox.sc.edu (C.F.M.)
* Correspondence: booze@mailbox.sc.edu
† These authors contributed equally.
Abstract: Individuals living with human immunodeficiency virus type 1 (HIV-1) are often plagued
by debilitating neurocognitive impairments and affective alterations;the pathophysiology underlying
these deficits likely includes dopaminergic system dysfunction. The present review utilized four
interrelated aims to critically examine the evidence for dopaminergic alterations following HIV-1
viral protein exposure. First, basal dopamine (DA) values are dependent upon both brain region
andexperimental approach (i.e., high-performance liquid chromatography, microdialysis or fast-scan
cyclic voltammetry). Second, neurochemical measurements overwhelmingly support decreased
DA concentrations following chronic HIV-1 viral protein exposure. Neurocognitive impairments,
including alterations in pre-attentive processes and attention, as well as apathetic behaviors, provide
an additional line of evidence for dopaminergic deficits in HIV-1. Third, to date, there is no compelling
evidence that combination antiretroviral therapy (cART), the primary treatment regimen for HIV-1
Citation: McLaurin, K.A.; Harris, M.;
Madormo, V.; Harrod, S.B.; Mactutus,
seropositive individuals, has any direct pharmacological action on the dopaminergic system. Fourth,
C.F.; Booze, R.M. HIV-Associated the infection of microglia by HIV-1 viral proteins may mechanistically underlie the dopamine deficit
Apathy/Depression and observed following chronic HIV-1 viral protein exposure. An inclusive and critical evaluation of the
Neurocognitive Impairments Reflect literature, therefore, supports the fundamental conclusion that long-term HIV-1 viral protein exposure
Persistent Dopamine Deficits. Cells leads to a decreased dopaminergic state, which continues to persist despite the advent of cART. Thus,
2021, 10, 2158. https://doi.org/ effective treatment of HIV-1-associated apathy/depression and neurocognitive impairments must
10.3390/cells10082158 focus on strategies for rectifying decreases in dopamine function.
Academic Editor: Eliseo Eugenin Keywords: dopamine; HIV-1; combination antiretroviral therapy; pre-pulse inhibition; attention;
apathy; microglia; dendritic spines
Received: 6 July 2021
Accepted: 18 August 2021
Published: 21 August 2021
1. Introduction
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic,
published maps and institutional affil- neurocognitive impairments (NCI) and affective alterations have been associated with the
iations. disease [1,2]. Early in the AIDS epidemic, underlying focal processes and opportunistic
infections accounted for approximately 30% of the neurological complications in individu-
als with AIDS; a progressive dementia, however, was more commonly reported [3]. The
identification of human immunodeficiency virus type 1 (HIV-1) as the retroviral etiology
Copyright: © 2021 by the authors.
of AIDS [4,5] led to the hypothesis that NCI and affective alterations may result from
Licensee MDPI, Basel, Switzerland.
the direct effect of the virus on the brain. Indeed, HIV-1 penetrates the central nervous
This article is an open access article
system (CNS) early in the course of infection [6], evidenced by the presence of HIV-1 in
distributed under the terms and postmortem brain tissue [7–9], findings which led to the characterization of this progressive
conditions of the Creative Commons dementia, which became known as AIDS dementia complex (ADC, also recognized as
Attribution (CC BY) license (https:// HIV-associated dementia (HAD)).
creativecommons.org/licenses/by/ ADC, which afflicted approximately 66% of autopsy-verified AIDS patients early in
4.0/). the epidemic, was a neurological syndrome primarily occurring during the later phases of
Cells 2021, 10, 2158. https://doi.org/10.3390/cells10082158 https://www.mdpi.com/journal/cells
Cells 2021, 10, 2158 2 of 30
systemic AIDS [3]. Early clinical characteristics of ADC included NCI (e.g., forgetfulness,
loss of concentration), affective alterations (e.g., apathy) and motor system deficits [3,10,11].
Across time, most patients with ADC exhibited a steady decline in neurocognitive function,
leading to severe dementia, ataxia and motor weakness [10].
Pathologically, distinct abnormalities in the white matter and subcortical structures,
including the basal ganglia, were observed in the brains of individuals with ADC [12],
observations which led researchers to hypothesize dopaminergic system dysfunction as
a potential mechanism underlying the disease [13]. Cerebrospinal fluid (CSF) levels of
dopamine (DA [14,15]) and homovanillic acid (HVA [15–17]), the primary DA metabolite,
were significantly reduced in HIV-1/AIDS patients relative to seronegative controls. In
HIV-1-infected brains, significant reductions in tyrosine hydroxylase (TH), the rate-limiting
enzyme of DA synthesis, were also observed [18]. Most critically, the relationship between
CSF HVA levels and neuropsychological function in HIV-1-infected patients provided
compelling evidence for the role of dopaminergic system dysfunction in the pathogenesis
of ADC [17].
With the discovery and introduction of antiretroviral therapies, however, AIDS/HIV-1
became a chronic, manageable disease, albeit NCI and affective alterations persist. The
development of zidovudine (azidothymidine [19]), the first generation of antiretroviral
therapy, provided early evidence that effective inhibition of HIV-1 may have some effects
on cognitive function in AIDS patients [20–22]. Zidovudine monotherapy did not, however,
mitigate affective alterations [20]. The subsequent utilization of multiple antiretroviral
compounds to treat HIV-1 (i.e., combination antiretroviral therapy (cART)) led to a dra-
matic decrease in the severity of NCI and affective alterations associated with HIV-1 [23].
Specifically, in the post-cART era, ADC is rare, afflicting only 2–8% of cART-treated HIV-1
seropositive individuals [23]. However, milder forms of NCI and affective alterations
persist, afflicting between 30% and 70% of HIV-1 seropositive individuals [24–27].
Although the pathophysiology of HAND and affective alterations in the post-cART era
is likely multidimensional, dopaminergic system dysfunction persists [28–30]. Using four
interrelated aims, the present review will examine evidence for alterations in dopaminergic
levels in HIV-1 in the post-cART era. Given that approximately 73% of HIV-1 seropositive
individuals are currently accessing antiretroviral treatment [31], the present review focuses
on studies using biological systems (i.e., HIV-1 seropositive individuals, primates, rats,
mice) with viral suppression. First, we will report basal/tonic values of DA in the CNS,
including a discussion of the experimental approaches (e.g., high-performance liquid
chromatography (HPLC), microdialysis, fast-scan cyclic voltammetry (FSCV)) used to
measure DA. Second, the present review will examine the prominent evidence, including
both anatomical and clinical symptomology, for the persistent decreased dopamine in
HIV-1 seropositive individuals. Third, the potential effects of cART on the dopaminergic
system will be assessed. Finally, we will address the mechanistic implications for dopamine
decreases in HAND.
2. Basal Dopamine Concentrations in the Central Nervous System
The physiological significance of DA [32], and its presence in the brain [33–35], was
first established in the 1950s. Subsequent methodological advances, including the develop-
ment of microdialysis, HPLC and FSCV, afforded a critical opportunity to detect changes
in basal (or tonic) DA [36]. However, DAs precise influence on cognition and behavior
remains unclear, in large part due to inconsistencies in measured DA levels. Thus, one
of the primary goals was to illustrate the inconsistencies in values via examination of the
standard error of the mean and relative standard error.
DA concentration was estimated using the reported means, which were converted
into ng/g of tissue (Table 1). Reported estimates are collapsed across species and biological
sex under the assumption that the variability between brain regions and methodological
approach are greater than the variability between species and sex [37]. Each manuscript,
therefore, provided a single observation for each brain region that was reported. All
Cells 2021, 10, 2158 3 of 30
estimates, as well as information regarding species and biological sex, are reported in
Supplementary Table S1.
Critical evaluation of the literature revealed that basal DA values are dependent upon
not only brain region, but also methodological technique (between-subjects ANOVA with
log estimated DA concentration in ng/g of tissue as the dependent variable: brain region
by method interaction, F(5,104) = 7.05, p ≤ 0.001, ηp 2 = 0.253; Table 1; Figure 1). For
example, utilization of HPLC to measure DA in the nucleus accumbens (NAc) results in an
average estimated DA concentration over 40,000 times greater than the average estimated
DA concentration measured using microdialysis. This outcome might be anticipated due to
tissue homogenization prior to HPLC measurement; HPLC, therefore, measures total tissue
DA content, whereas microdialysis measures extracellular DA levels [38]. Additionally,
substantial variability in reported basal DA values within a single methodological approach
was observed. For example, the relative standard error for the NAc was 33.9%, 17.1% and
27.8% for HPLC, microdialysis and FSCV respectively, values which are even higher in
other brain regions (e.g., amygdala: 84.1% (HPLC) and 50% (microdialysis)). Given the
substantial variability within and between methodological techniques, a brief discussion
of some of the critical experimental considerations underlying these discrepancies is war-
ranted. In addition, the potential utility of the latest technology (i.e., G protein-coupled
receptor (GPCR) biosensors) for monitoring DA release is briefly reviewed.
Table 1. Estimated basal dopamine (DA) values. Abbreviations: High Performance Liquid Chromatogrphy (HPLC); Fast
Scan Cyclic Voltammetry (FSCV).
Estimated DA
Concentration in ng/g Relative Standard
Brain Region Methodology References
of Tissue Error
(X ± SEM)
HPLC 3683.85 ± 3097 84.1% [39–43]
Amygdala
Microdialysis 0.06 ± 0.03 50% [44–47]
HPLC 16,365.9 ± 12,341.04 75.4% [28,39,41,48–54]
Caudate
Microdialysis 0.88 ± 0.66 75% [44,55,56]
HPLC 200.73 ± 84.41 42.1% [28,39,42,52,54,57–62]
Frontal Cortex
Microdialysis 0.23 ± 0.10 43.5% [44,63–65]
HPLC 35,772.90 ± 12,020.28 33.6% [41–43,51,52,57,59,60,62,66–68]
Nucleus Accumbens Microdialysis 0.76 ± 0.13 17.1% [44,45,47,55,63–65,67–99]
FSCV 6.95 ± 1.93 27.8% [100–104]
HPLC 67,460.52 ± 29,013.28 43% [59,61,62,66,67,105–111]
Striatum
Microdialysis 1.42 ± 0.40 28.2% [64,73,74,76,79,82,85,112–114]
HPLC 9200 [66]
Ventral Tegmental Area
Microdialysis 0.25 ± 0.07 28% [75,83]
2.1. High-Performance Liquid Chromatography (HPLC)
Broadly, chromatography is a well-established separative and analytical technique
introduced by James and Martin [115]; the emergence of HPLC, however, is attributed to
Huber and Hulsman [116]. To conduct HPLC, a pressurized liquid solvent (i.e., mobile
phase) containing the sample is passed through a column filled with a solid adsorbent
material, and each compound elutes at a unique rate, resulting in the separation of compo-
nents as they flow through the column [117]. The isolated compounds are subsequently
identified and quantified using a detector (e.g., UV/Vis spectrometry). HPLC can be
further subdivided into multiple types dependent upon the type of column (e.g., liquid–
liquid, ion-exchange, size exclusion) and “mobile phase” (e.g., non-polar, polar), factors
which influence sensitivity, resolution and the method of brain tissue extraction. Critically,
Cells 2021, 10, 2158 4 of 30
Cells 2021, 10, x FOR PEER REVIEW 4 of 29 pH value,
differences in extraction methodology (e.g., time of initial extraction, aqueous
extraction solvents) result in drastic differences in percent recovery, an indirect measure of
basal DA concentration [118].
Figure 1. Graphical illustration of the profound differences in estimated dopamine (DA) concen-
tration (ng/g of tissue; X ± SEM) dependent upon methodology (i.e., (A) high-performance liquid
chromatography, (B) microdialysis, (C) fast-scan cyclic voltammetry) and brain region. Each dot
represents the estimated DA concentration from a study.Cells 2021, 10, 2158 5 of 30
Given HPLC’s wide use, sources of random and systematic error in HPLC have
been studied extensively [119]. The brief discussion in the present review will focus on
sources of error reported to affect the electrochemical detection of DA. First, the mobile
phase column composition (e.g., ion pairing agent type, organic modifier, pH) has a
pronounced effect on the capacity factor (k’), retention time, peak height units of DA and
peak symmetry [120–124]. Second, the flow gradient rate, similarly, has a prominent effect
on the resolution of the eluting compounds, k’ and background current [125]. Finally,
chromatographic instrumentation, including the column temperature, alters the retention
time of DA, whereby an increase in column temperature is associated with a decrease in
retention time [123]. Additionally, column age may influence the resolution between DA
and its metabolite (i.e., 3,4-Dihydroxyphenylacetic acid), whereby decreased resolution has
been observed after approximately 500 injections of the biological material directly onto
the column top [121].
2.2. Microdialysis
The utilization of microdialysis to quantify neurotransmitters in the brain was first
reported in the 1970s and 1980s [126–128], research which contributed significantly to
the widespread implementation of microdialysis methods. Microdialysis relies on the
principle of diffusion, whereby molecules move from an area of high concentration to
an area of low concentration. Methodologically, a microdialysis probe composed of a
semipermeable dialysis membrane is surgically implanted into the brain, and a perfusion
medium is infused slowly and continuously [129]. During perfusion, molecules in the
extracellular space diffuse through the semipermeable membrane, are transported into
outflow tubing and are collected for analyte quantification (e.g., HPLC [129]; Figure 2A).
Although microdialysis detects neurotransmitters at low- to sub-nanomolar levels (for
DA, see [113]), the technique has relatively low spatiotemporal resolution and is unable to
evaluate real-time changes in the neurochemical environment.
Despite being considered the “gold standard” for obtaining basal neurotransmitter
levels, methodological limitations may impede precise and/or consistent measurements.
The diameter of a typical microdialysis probe is approximately 300 µm, a size which is
substantially larger than neurons and glial cells (5–100 µm), as well as blood capillaries
(8–10 µm) and vessels (~1 mm) in the brain [130]. Implantation of microdialysis probes,
therefore, damages brain tissue, as evidenced by signs of ischemia [131,132] and a com-
promised blood–brain barrier [131,133]. Additionally, tissue damage resulting from the
microdialysis probe disrupts synapses and neurons [134]. Critically, dopaminergic activity
is disrupted by the implantation of microdialysis probes, as evidenced by both decreased
DA release over post-probe implantation time [135] and alterations in the amplitude of
evoked responses [136,137]. Recently developed novel approaches, including pharmaco-
logical agents [138,139] and a microfabricated probe [140], have the potential to mitigate
some of the concerns regarding tissue disruption.
Consistent measurement of basal DA levels is further dependent upon multiple
methodological details. Although HPLC is often used as a method to quantify the output
from microdialysis, the methodological details discussed within the present section are
conducted prior to the quantification of analytes. First, inappropriate concentrations of
specific ions (e.g., Ca2+ , NA+ , K+ ) in the perfusate medium disrupt the homeostatic balance
of the extracellular environment, altering the basal DA concentration. For example, in-
creases in basal DA concentration are observed when the perfusate medium contains higher
(e.g., 3.4 mM) levels of Ca2+ [63,141] or K+ [128]. In sharp contrast, utilization of a perfusion
solution with too little Ca2+ [128,142] or too little K+ [142] results in decreased extracellular
DA levels. It is vital, therefore, that the composition of perfusion solutions mimic the brain
extracellular fluid; additional parameters, including pH and temperature, are also critical
considerations [143]. Second, substantial increases in the concentrations of extracellular
DA occur immediately following death [144–146]. Basal DA levels subsequently decrease
as the postmortem interval increases [144–146]; albeit, basal DA concentration remainsCells 2021, 10, 2158 6 of 30
elevated, relative to pre-death levels, for at least an hour postmortem [144,145]. Third, in
neutral and basic aqueous solutions, DA degrades rapidly [147], including in many com-
mon (e.g., aCSF, brain dialysate) perfusion solutions [148]. Several approaches, including
temporal proximity (i.e., minimization of the time between sample collection and analy-
sis [149]), addition of stabilizing agents to either the collection bins [65] or microdialysis
media [150] and a microdialysis/LCMS system [148], have been implemented to mitigate
21, 10, x FOR PEER REVIEW 6 of 29
the DA instability problem. Despite the validity of these approaches, inter-laboratory
differences may preclude determining an estimate of the “true” basal DA concentration.
Figure 2. Technical illustration of three of the prominent methods utilized to detect dopamine (DA) levels in the CNS.
Figure 2. Technicalliquid
Given that high-performance illustration of three of the
chromatography prominent
(HPLC) is more methods utilized
classically usedtofor
detect dopamine
analyte (DA) on brain
quantification
levels in the CNS. Given that high-performance liquid chromatography (HPLC) is more classically
tissue homogenates or following microdialysis, the method is not illustrated. (A) During microdialysis, a probe composed
used for analyte quantification on brain tissue homogenates or following microdialysis, the method
of a semipermeable dialysis membrane is surgically implanted into the brain, and a perfusion medium (white arrows) is
is not illustrated. (A) During microdialysis, a probe composed of a semipermeable dialysis mem-
infused slowly
braneandiscontinuously. During perfusion,
surgically implanted molecules
into the brain, andina the extracellular
perfusion medium space diffuse
(white through
arrows) is the semipermeable
infused
membrane,slowly
and areandtransported
continuously.into outflow tubing andmolecules
During perfusion, collected in forthe
analyte quantification
extracellular (e.g., HPLC).
space diffuse through(B) theIn fast-scan
cyclic voltammetry, a small membrane,
semipermeable carbon-fiberand microelectrode is surgically
are transported into outflowimplanted
tubing into
and the brain. for
collected Theanalyte
voltagequan-
potential at the
carbon-fibertification
microelectrode is rapidly
(e.g., HPLC). increased
(B) In fast-scan and decreased,
cyclic resulting
voltammetry, in thecarbon-fiber
a small oxidation and reduction of is
microelectrode DA. During
surgically
the oxidation implanted
and reduction into thethe
processes, brain. The voltage
transfer potential
of electrons at the carbon-fiber
is measured in current at microelectrode
the surface ofisthe rap-
carbon-fiber
idly increased
microelectrode, and decreased,
and the amount of currentresulting in the oxidation
can be subsequently and reduction
converted into theof DA. During of
concentration theDA.
oxidation
Additionally, the
and reduction processes, the transfer of electrons is measured in current at the surface
voltammogram is used for analyte identification, whereby DA exhibits one oxidation and one reduction peak. (C) More of the carbon-
fiber microelectrode, and the amount of current can be subsequently converted into the concentra-
recently, G-protein coupled receptor (GPCR) biosensors for DA have been developed, affording an opportunity to track the
tion of DA. Additionally, the voltammogram is used for analyte identification, whereby DA exhibits
release dynamics of DA. DA biosensors have a circularly permuted fluorescent protein (e.g., Green: cpGFP, Red: cpmApple)
one oxidation and one reduction peak. (C) More recently, G-protein coupled receptor (GPCR) bio-
inserted into the third
sensors forintracellular
DA have been loop of the DAaffording
developed, receptor.anWhen DA binds
opportunity toto the the
track endogenous ligand, the
release dynamics GPCR exhibits
of DA.
a conformational change, resulting in an increased fluorescent intensity. Our laboratory
DA biosensors have a circularly permuted fluorescent protein (e.g., Green: cpGFP, Red: cpmApple) has recently transfected cells
with GRAB-DA2m, a DAthe
inserted into receptor 2 subtype biosensor,
third intracellular loop of thein vitro. Upon stimulation
DA receptor. When DA with binds100 nm endogenous
to the DA, an increase in the
fluorescenceligand,
intensity
theof cpGFP
GPCR is observed.
exhibits a conformational change, resulting in an increased fluorescent intensity.
Our laboratory has recently transfected cells with GRAB-DA2m, a DA receptor 2 subtype biosensor,
2.3. Fast-Scan
in vitro. Upon stimulation withCyclic
100 nm Voltammetry (FSCV)
DA, an increase in the fluorescence intensity of cpGFP is
observed. FSCV, an electroanalytical technique developed in the early 1980s [151,152], affords
a method to detect rapid neurotransmitter dynamics in the brain [153]. From a theoreti-
Despite being considered FSCV
cal perspective, the “gold standard”
relies for obtaining
upon chemical sensingbasal neurotransmitterat carbon-fiber
of neurotransmitters
levels, methodological limitations
microelectrodes. may impede
Specifically, theprecise
voltageand/or consistent
potential measurements.
at the carbon-fiber microelectrode is
The diameter of a typical
rapidly microdialysis
increased probe isresulting
and decreased, approximately 300 μm, and
in the oxidation a size which isof electroactive
reduction
substantially larger than neurons
substances and glial cells
[154]. Examination (5–100
of the μm),
cyclic as well as blood
voltammogram, whichcapillaries
presents data as time
(8–10 μm) and(x-axis)
vesselsby (~1voltage
mm) in(y-axis),
the brain [130].
allows forImplantation of microdialysis
compound identification probes,
[155,156]. The strengths of
therefore, damages
FSCVbrain tissue,
include as evidenced
its high by signs of acuity,
spatial (micrometer) ischemia
high[131,132]
temporaland a com-
(sub-second) resolution
promised blood–brain barrier [131,133]. Additionally, tissue damage resulting from the
microdialysis probe disrupts synapses and neurons [134]. Critically, dopaminergic activ-
ity is disrupted by the implantation of microdialysis probes, as evidenced by both de-
creased DA release over post-probe implantation time [135] and alterations in the ampli-
tude of evoked responses [136,137]. Recently developed novel approaches, includingCells 2021, 10, 2158 7 of 30
and high chemical (nanomolar range) sensitivity. However, FSCV is limited by the need
for digital background subtraction [157], which restricts measurements to relative neuro-
transmitter changes, a factor which precludes the measurement of basal concentrations of
electroactive species [154]. Therefore, FSCV has typically been utilized to measure phasic,
rather than tonic, DA release. Recent novel modifications have afforded an opportunity
to investigate tonic DA concentrations using FSCV [103,104,158,159]. While an in-depth
discussion of these modifications is beyond the scope of this review, it is an emerging
area of research that has the potential to transform our ability to accurately measure basal
DA levels.
2.4. G Protein-Coupled Receptor (GPCR) Biosensors
GPCR biosensors for DA (or DA biosensors), the most recent method developed for
monitoring DA dynamics, were first reported in 2018 [160,161], and contemporary versions
have expanded upon these initial reports [162,163]. Theoretically, fluorescent DA biosensors
rely upon the interaction between DA and D1 - and D2 -like GPCRs. DA biosensors were
developed by inserting a genetically encoded, circularly permuted fluorescent protein
(e.g., Green: cpGFP, Red: cpmApple) into the third intracellular loop of the naturally
occurring human DA receptor. When DA is released, it binds to the endogenous ligand,
causing a rapid conformational change in the GPCR, a conformational change that induces a
profound increase in fluorescence intensity (i.e., 90–900%, for a review, see [164]; Figure 2C).
DA biosensors exhibit high selectivity, molecular specificity, affinity (sub-micromolar) and
resolution (sub-second [160–163,165]), making them ideally suited for tracking DA release.
However, DA biosensors may be limited by low basal fluorescence levels, which precludes
the detection of basal DA levels. A more comprehensive discussion of GPCR biosensors
for DA is provided by Labouesse et al. [164].
2.5. General Experimental Considerations
Ideally, an estimate of basal DA values would be highly replicable when measurements
are obtained in the same brain region, using the same methodological technique and
in nearly genetically identical animals. However, basal DA concentrations are altered
by natural biological variation within and between subjects. Independent of species,
there is natural biological variation in basal DA concentrations resulting from within and
between subject’s factors. For example, basal extracellular DA levels change across the
functional lifespan, with significantly decreased DA observed in aged, relative to young,
animals [166]. Furthermore, basal DA levels in the NAc [167,168], striatum [149,169]
and medial prefrontal cortex (mPFC [170]) fluctuate in a circadian rhythm. Additionally,
hormones have a profound impact on basal DA levels, as evidenced by changes across the
estrous cycle [171,172] and resulting from gonadectomy [173].
To date, the substantial variability between studies, even within a single methodologi-
cal approach, has obfuscated our ability to experimentally determine the “true” basal DA
concentration. When appropriate experimental controls are implemented, the impact of
a treatment (e.g., HIV-1, substance use) on basal DA concentration can be reliably deter-
mined; comparing between studies, however, remains challenging. Stringent and detailed
reporting of methodological procedures may aid in determining which studies can be most
accurately compared. From a practical perspective, however, the information compiled
in Table 1 (expanded in Supplementary Table S1) provides a summary of the techniques
currently in use.
In sum, HPLC of tissue homogenates may reveal total DA tissue content, while
microdialysis enables sampling of the extracellular basal DA levels, but lacks temporal
resolution (minutes) and spatial resolution. FSCV is currently used for relative changes in
DA signals, and not for assessing basal DA levels. Although GPCR biosensors for DA may
not clarify basal DA levels in the brain, their ability to rapidly detect DA function has the
potential to transform our understanding of neural circuits. Critically, each neurochemicalCells 2021, 10, 2158 8 of 30
method for assessing DA levels has benefits and limitations that must be weighed when
designing an experiment.
Cells 2021, 10, x FOR PEER REVIEW
3. Chronic HIV-1 Results in Decreased Dopamine
Inconsistencies in the estimated basal DA values does not preclude the utilization or
importance of these methodological techniques for evaluating 1 infectiongroupindifferences. As demon-little clin
humans, suggesting
strated in Table 2, HPLC, microdialysis and FSCV havedopamine. been fundamental in elucidating
how HIV-1 viral protein exposure alters basal DA concentration Another relative
notable to seronegative
inference that can be
individuals or controls. Results (Table 2) overwhelmingly support decreased
cART on DA function DA inconcentra-
HIV-1 seropositiv
tions following chronic HIV-1 viral protein exposure inzidovudine either HIV-1(azidothymidine),
seropositive humans was first im
or biological systems utilized to model HIV-1. Critically, the strong support for decreased
0, x FOR PEER REVIEW Despite the overwhelming support for a hypodopaminergic both the pre- 9state
ofand29 inpost-cART
HIV-1 (i.e.,era.
lowA more co
levels of DA), there are a few outliers. Three studies [174–176] have reported
of cART in dopaminergic10system transitory
Cells 2021, 10, x FOR PEER REVIEW 29 dysfuncti
increases in DA concentration in the CSF, caudate putamenUndoubtedly, and prefrontal cortexof(PFC),
long-term HIV-1 viral p
0, x FOR PEER REVIEW 9 of 29
respectively. The subjects (i.e., humans, mice) evaluated in these studies share a key
independent
1 infection in humans, suggesting little clinical relevance for assessing acute increasesofintreatment with cART. It is p
commonality: early or acute HIV-1. Specifically, the clinical in DAsampleimmediately included individuals
following HIV-1 infectio
dopamine.
0, x FOR PEER REVIEW in clinical stage 1 [174], which is characterized by
Caudateasymptomatic
Nu- infection
9 of 29 and persistent
Another notable inference that can be drawn from Table 2 regards the influence of 1 seropositive individuals [179,180], howe
1 infection in humans, suggesting
generalized little clinical relevance
lymphadenopathy for assessing
[177]. Preclinical acute increases
measurements
cleus were in conducted either
cART on DA function in HIV-1 seropositive individuals. While monotherapy, the currentincludingclinical syndrome.
dopamine. one [176] or three [175] days after the completion of Tat
Globus protein induction by a doxycycline
Palli-
zidovudine (azidothymidine), was first implemented in 1985 [19], cART began in 1996.
Another notable regimen.
Kumar inference Critically,
et al., 2011 that canthese be drawn increases
from in DA 2either
Table regards
dusfailed
the to
Table persist
influence
2. Influence for longer viral
of intervals
Critically,
1 infectionthe strong support
in humans, for decreased
suggesting little dopaminergic
clinical relevance HIVfunction
for assessing spansacuteacross studies
Human
increases in of HIV-1HPLC protein exposu
cART on DA function after[29]
inTat protein
HIV-1 induction
seropositive (i.e.,
individuals.10 Days:
While [178], 40 Days:
monotherapy, trols. [175])
including
Asterisks or(*)were brain
indicate region- that me
manuscripts
both the
dopamine. pre- and post-cART era. A more comprehensive discussion for
Putamen the potential role
specific [176].was
zidovudine (azidothymidine), Moreover, there is no evidence
first implemented for a cART
in 1985 [19], hyperdopaminergic
began in 1996. state during chronic
of cART in dopaminergic
Another notable systemthat
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References Relative to Con- Viru
thecART
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system
the dysfunction
strong support isfor
presented
decreased in Section
dopaminergic5.
NAc function spans across studies in
in DA immediately following
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10 of 29 expectancy for HIV- trols
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and viral
the [179,180],
[175] pre- proteinera.
post-cART exposure
A more leads to persistentdiscussion
comprehensive DA deficits, for the potential role
1Table
seropositive
2. Influenceindividuals
of HIV-1 viral protein however,
exposure onthe acute
dopamine phase
(DA) fails to Puta-
Caudate
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toal.,con-
1991
independent of treatment
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in cART.
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system that there
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Section 5. HIV
the current
trols. clinical syndrome. men [16]
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immediately manuscripts
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( ) indicates(*)noindicate manuscripts
statistically significantthatdifferences
measured in DADA metabolites (e.g., between
concentration
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Puta- HIV et
Sardar acid).
andal.,con-
1996
seropositive Globus Palli-
individuals [179,180], however, the acute HIV
trols. men phase fails [15] to accurately reflect the
Kumar et al., 2011 Table 2. Influence of HIV-1
current viral protein
dus exposure on dopamine (DA) concentration relative to con-
Symbols: DA concentration HIV isclinical
decreased syndrome.
( ) orHuman
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)HPLC
relative to controls. The equal sign
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[29] trols.
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statistically
Kesby thatdifferences
significant
al., 2016 measured in DADA metabolites (e.g., between
concentration homovanillic
Di Rocco,
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2000 [17]
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Putamen Protein Mouse HPLC
trols. References Relative
Table 2. Influence of HIV-1 viral [178] to Con- Virus Brain Region
protein exposure on dopamine (DA) concentration relative Species Method
to controls. Asterisks (*) indicate
Symbols: DA concentration is decreased ( ) or increased ( PFC
) relative to controls. The equal sign
trols Substantia
(Larsson ) indicates DA Concentration
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et al., 1991 Nigra differences in DA concentration between HIV and con-
manuscripts that measured DA
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Relative to Con-(e.g., Virus
homovanillic
HIV acid).
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statistically
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Kesby et al., 2016 et al., 1996
Javadi-Paydar trolset al.,
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Berger [15]
et al., 1994 HIV HumanNAc HPLCRat
[175] Larsson et al., 1991 2017 [187] HIV cleus
teins
CSF Human Koutsilieri,
HPLC 2002 ammetry
[14] DA ConcentrationCaudate Puta-HIV CSF Pro- Human HPLC* HIV
[16] Denton et al., 2019 HIV-1 [182]
References
Di Rocco,
Sardar et 2000 [17] Relative to men
al., 1996 HIV Virus Caudate CSF Nu-BrainHuman
Region
NAc Species
HPLC*
Rat Method
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[30]
et al., 1994Tat Protein
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teins HPLC et al., 2004
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[14] Saloner et al., 2020 [183]
HIV CSF Human HPLC
Larsson etDi Rocco,
al., 1991 2000
[16]
Sardar et al., 1996 [17] [188] HIV HIV CSF
Hippocampus
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CSF Scheller
HPLC*et al., 2005
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Czub et al., 2001
[15] cleus [184]
men SIV PFC
[181] Strauss et al., 2020 Acute Tat Primate HPLC
Berger et Di
al.,Rocco,
1994 [14]2000 [17]Acute[176]Tat HippocampusHIVHIV Hippocampus CSF Human Mouse
HPLC* HPLC
Kesby et al., 2016 Protein CSF
PFC Human HPLC
Czub et al., 2001 Protein Mouse HPLC Striatum
[178] PFC SIV Putamen Primate HPLC
[181] Denton et al., 2021 HIV-1 Pro- Kumar et al., 2009
Koutsilieri,
Sardar et al., 1996 [15] 2002 HIV Hippocampus
PFC Caudate NucleusNAc Human
Rat HPLC
FSCV HIV
[189] HIV Striatum
teins Primate HPLC[28]
Czub [182]
et al., 2001 OFC
SIV Putamen Primate HPLC
Jenuwein et al., 2004
[181]
Koutsilieri, SIV NAc Primate HPLC
Horn et al., 2017 [183] 2002 4. HIV-1
HIV ClinicalCSF Symptoms HIVHumanReflect aPFC
Hypodopaminergic
Striatum HPLC Primate State
HPLC
[186] [182]
Scheller et al., 2005 In 2007, the nosology for neurological Putamen complications in HIV-1 seropositive individu-
avadi-Paydar et al., Jenuwein et al., 2004
HIV-1 Pro- SIV Putamen
Ex vivo slicePrimate
volt- HPLC
Ferris et al., 2009
[184]
Koutsilieri, 2002als was updated NAc
to reflectSIV
the Rat
milder NAc
phenotype Primate
of NCI and HPLC alterations, collec-
affective Tat Pro
2017 [187] [183] teins HIV StriatumammetryPrimate [185]
HPLC
[182] tively Caudate Nu-
Denton et al., 2019 Scheller et al., 2005 HIV-1termed
Pro- HIV-1-associated neurocognitive disorders (HAND), Scheller et observed
al., 2010 in the post-cART
trols.
1Table on DA function
seropositive individualsin HIV-1 seropositive
[179,180], however, individuals. While fails
monotherapy, including
both
Symbols:
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dopamine.
independent
zidovudine
pre- and
2. Influence of
DA concentrationofpost-cART
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treatment
(azidothymidine), viral
with
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from in
Table Section
2 regards5. the influence of of
29
(trols.
in Asterisks
)
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1 infectionindicates
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between HIV
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acid).
and con-
for HIV-
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increases in
cART
trols. Undoubtedly,
on DA function
References long-term
in HIV-1
Relative HIV-1
to Con- viral
seropositive protein exposure
Virus individuals.
Brain leads to
WhileSpecies
Region persistent
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including
Method
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both seropositive
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[19], cART began into91996.
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The equal sign
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29
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Cells 2021, 10, (Critically,
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seropositive
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29
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[181]
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References
[181]
[28]
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[184]
[16]
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2000 2002
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Table Rocco,
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[28]
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[15]
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References
[181]
[28]et al., 2004 Relative to Con- SIV
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Table Rocco,[184]
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[174]
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1991 DA Concentration HIV
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References
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[28]et al., 2004 Relative to Con- SIV
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Virus Putamen
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Region Human
Species HPLC
HPLC*
Method
[184]
[16]
Koutsilieri, Acute
SIV Tat Nigra
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Scheller et Di al.,Rocco,
2010
Sardar
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et
et
[183] al.,2002
2000
al., [17]
1996
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[15] al., 2009
et al., 2005
1991 HIV
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[14]
[185] Substantia
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Jenuwein [28]etal.,
al.,2016
2004 SIV
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Di Rocco, et
[184]
[16]
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[17] SIV
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et al., 2010 Globus
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et
et
[174]
al.,
al.,
etal.,
[15] al., 1994
2009
al.,2001
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2005 HIV
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[14]
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Jenuwein [181]
[28]et al., 2004 SIV Putamen
men Primate HPLC
Di Rocco,[184] Tat Protein
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et
[183] al., [17]
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[174]
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[29]al.,2001
al., 2009
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[185]
[181]
[28] SIV Putamen Primate HPLC
Di Rocco,[184]
Koutsilieri, 2000 2002
[17] HIV Caudate
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[174] 2009
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[181]et al., 2004 Acute Tat Hippocampus cleus
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[30] HIV
teins Substantia
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[28] SIV Putamen Primate HPLC
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HIV CSF Nu- Human
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HPLCYou can also read
