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Heroin Addiction: How the Body Learns Through the Ventral Tegmental Area (VTA)
John Rencher
Behavioral Sciences Department, Liberty University
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Heroin Addiction: How the Body Learns Through the Ventral Tegmental Area (VTA)
The purpose of this work is to highlight the problematic behavior of Heroin Substance
Use Disorder (H-SUD). According to the National Institutes of Health (2021), in 2019 over
50,000 people died in the United States from opioids. This number included exogenous opioids
such as hydrocodone/acetaminophen pain medication, fentanyl, and heroin. This presents a social
problem among many family households, given the inability of a person affected by H-SUD to
perform the daily tasks associated with providing care and provisions for both themselves and
their children. The catalyst which led to the increase started in the early ’90s when medical
providers were assured that addictive behaviors would not manifest if there were an increase in
prescriptions (National Institutes of Health, 2021). By 2017, the numbers had increased
exponentially with more than (1.7Million) people affected by SUD and 47,000 overdoses. This
work will examine research related to how the body learns to become addicted, providing
explication for this process which occurs within the mesolimbic area of the brain. Accordingly,
this work will explore the varying methods of treating H-SUD, the learning principle exclusive
to opioids, and provide a discussion with future insights to future research on this topic. Millions
of people and their families are being affected by exogenous opioids, which are leading to
overdoses, divorce, homelessness, and should be an overall major concern of academia and the
general public.
Addiction is a learned behavior between the body and the brain through a process that
occurs in the mesolimbic area of the brain with three key components the ventral tegmental area
(VTA), nucleus accumbens, and the prefrontal cortex (Vargas-Perez et al., 2009). This signaling
pathway is known as the reward pathway and responds to the area of the brain that controls
behavior and memory (Vargas-Perez et al., 2009). The pathways in the VTA are dopaminergic
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pathways, where the dopamine neurons release dopamine that provides the euphoria which is
essentially the reinforcement for the problematic behavior to occur (Pidoplichko et al., 2004).
Dopamine is a learning neurotransmitter, that allows the body to establish the connection
between the use of the drug and pleasure (euphoria), and this ensures the behavior will be
repeated. This principle is best understood from a behavioral psychological perspective using a
four-term contingency- Motivation Operation (MO)
+Antecedent+Behavior+Consequenc[ CITATION Coo \l 1033 ]. Motivation Operation (MO) is
the internal processes or desires of an individual that change or improve the value of a certain
stimulus. The initial catalyst is the individual taking the drug for the first time and experiencing
“dopamine overload.” The establishing operation (EO) is under the umbrella of (MO), which is
facilitated by the concept of deprivation. Withholding increases, or motivates, or establishes the
desire to achieve, attain, or seek what is being withheld (Cooper, Heron, & Howard, 2020). The
desire to avoid aversive stimuli creates negative reinforcement for the problem behavior to occur.
For example, a person that is affected by SUD will use their drug of choice (problem behavior)
to avoid the aversiveness of the withdrawal symptoms (aversive stimulus). These concepts can
be applied across all behaviors; however, specifically with Heroin, these concepts are especially
relevant. The major component of the addiction process is the dopamine reinforcement schedule
occurring in the mesolimbic region of the brain.
Ventral Tegmental Area (VTA) Reward Activation
There is a dramatic conversion from a dopamine-independent to a dopamine-dependent
reward system involving an interchange between γ-aminobutyric acid type A [GABAA] receptors
of VTA GABAergic neurons resulting in excitatory signaling (Vargas-Perez et al., 2009).
Research conducted by Vargas-Perez et al. (2009), demonstrated that rats chronically exposed to
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drugs found an increase in the brain-derived neurotrophic factors (BDNF) levels in the VTA
neurons. To demonstrate this, researchers designed between-subjects designs using two groups of
rats. One group was used as a control [nondependent] n=14; whereas the other group [morphine
dependent] n=12 (Vargas-Perez et al., 2009). The results were presented with significance-
(P>0.05), with a CI of .95 %, demonstrated that in those rats that were opiate-dependent 44% of
GABAergic neurons interchanged to excitatory [GABAA] (Vargas-Perez et al., 2009). These
findings provide empirical support that the transition from non-user to the user can be studied by
measuring BDNF infusion and measuring the presence of the [GABAA].
Essentially, the VTA is the locus point that controls the interchange and is mediated by a
dopamine-independent neural system ( e.g., brainstem pedunculopontine tegmental-[PPTg]
nucleus) (Vargas-Perez et al., 2009). The functionality of the structure PPTg is related to
locomotion, posture, and gaze affecting motor control[ CITATION Kol15 \l 1033 ]. The PPTg
also affects the cognitive processes of attention, memory, and learning. The interconnection
between the PPTg and the Basil Ganglia assists in the excitatory activation much like a
“highway” for dopamine (Vargas-Perez et al., 2009). Relative to the four-term-contingency, these
neurological structures assist in the formation of the establishing operation (EO). Establishing
Operation (EO) by definition, alters the reinforcing effectiveness of a stimulus. The stimulus
being dopamine is altered during the later stages of the addiction as a result of the disruption of
homeostasis due to the overproduction of dopaminergic neurons. To better explicate, and
conceptualize this point, consideration must be given to the biochemical processes that affect
signaling frequency and latency (Bosch et al., 2015).
Biochemical Pathways Related to Addiction
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The mesolimbic region undergoes alterations to the mRNA expression which affect
addictive behavior due to the changes in RNA that occur in the Ventral Tegmental Area (VTA)
(Bosch et al., 2015). Research revealed 150 mRNA and 78 miRNA transcriptions which were
differentially expressed. These are single strands of messenger and micro ribonucleic acids
[mRNA/miRNA] (Bosch et al., 2015). A full transcription is the addition of DNA strands which
would imply genetic factors of addiction rather than RNA expression correlative to addiction.
The single-strand mRNA consists of codons (e.g. UUU, UAG, AUG) with bases Uracil,
Guanine, and Cytosine. Bosch et al. (2015), studied addiction from a biochemical perspective
using methamphetamine as the independent variable (IV) and rats as the dependent variable.
RNA expression was also an (IV), where the rate and volume of expression were measured to
establish if there was a relationship between the introduction of methamphetamine to the trained
rats (Bosch et al., 2015). The results of the research revealed amelioration for the metabolic
process of dopamine during a metabolic analysis. Furthermore, the research results of those rats
that were trained to self-administer methamphetamines to replicate a long-time user, confirmed
varying gene expression patterns (Bosch et al., 2015). This section of the research implies
additional risk factors for the use of methamphetamine related to the genetic predisposition for
schizophrenia (Bosch et al., 2015). Accordingly, it also supports the learning principle through
the metabolic process of dopamine up-regulation and down-regulation. This is a key concept for
understanding how the body builds tolerance by seeking to regulate intake [drug administration]
and output [dopamine release] (Bosch et al., 2015).
Conditioned Place Preference (CPP)
Motivational effects can be measured using the Pavlovian conditioning-CPP where a
person prefers a specific place over another due to reward pairing (Zhu et al., 2019). Individuals
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affected by SUD will often loiter in places where they can receive rewards that indirectly serve
as positive reinforcement. For example, a majority of female heroin users engage in sexual acts
for the exchange of drugs or money. Therefore, they frequent those areas where they are likely to
find someone that is seeking sexual trade (e.g., gas stations, a certain street, motels, and
websites). The reward of cash allows them to gain access to the drug and both behaviors are
likely to be repeated. If user (A) stands at the XYZ quick mart, she finds three persons seeking
sexual trade. XYZ quick mart is now paired with the reward of money. The user (A), has a dealer
that lives within walking distance from XYZ quick mart. This further reinforces the likelihood of
the user (A) to remain in the area, specifically XYZ quick mart, the (CPP). Accordingly, the user
(A) is primarily motivated to remain to gain access to heroin. Access is considered direct (e.g.,
the dealer and other users), and indirect (e.g., sexual trade prospects) which leads to direct
access. Research conducted by Zhu et al. (2019) demonstrated this concept in their research
using rats in a between-subject design using paired t-tests to report all mean values and one-way
analysis of variance [ANOVA] with post hoc analysis. The investigators found that rats that had
not been subjected to heroin would engage in exploratory behavior of their environment. Over a
period of 7-days rats were subjected to heroin (n=10) (F3,36 = 28.814.; P < 0.01 by ANOVA).
(Zhu et al., 2019). Baselines were established between two different conditions, group (a) saline
treatment [control group] and group (b), pre-exposure conditions [experimental group] (Zhu et
al., 2019). A Fisher's least significant difference (LSD) test for pair-wise comparisons post hoc
revealed that there was no significant difference between the two groups: (109.52 ± 6.73 vs.
106.95 ± 8.80 s for the control and the experimental groups; P > 0.05) and no difference between
before and after saline treatment in the control group (109.52 ± 6.73 vs. 105.22 ± 6.62 s; P >
0.05) (Zhu et al., 2019). The light chamber was representative of the aforementioned “quick
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mart” in the previous example. The saline treatment is comprised of 0.9% NaCl and .91% of
H2O. Therefore, dopamine activation will not occur to allow for paring a reward. (Zhu et al.,
2019). This is why in the pre-treatment condition and the treatment condition [saline] there were
no significant differences in the comparisons. However, after the introduction of heroin in the
light chamber (XYZ quick mart) over a duration where Duration time=7days, there was a dramatic
increase in the behavior of loitering in the light chamber (Zhu et al., 2019). Baseline
measurement (106.95 ± 8.80 s
baseline
Vs.; 211.75 ± 14.59
Heroin
P < 0.05) and compared to controls
following saline treatment (105.22 ± 6.62s Saline vs.; 211.75 ± 14.59Heroin P < 0.01) (Zhu et al.,
2019). Inferences can be made that reward paring occurred resulting in the experimental group
remaining in the area at an increased rate of 50% compared to baseline and pre-exposure. Aside
from the reward pairing, the research results allow for inferences to be made that learning
occurred through the VTA. Once heroin was introduced, this led to dopaminergic surges within
the prelimbic (PL) and infralimbic (IL) cortices (Zhu et al., 2019). Once this occurs the signaling
pathway within the reward system underwent redirection from dopamine-independent to
dopamine-dependent(Vargas-Perez et al., 2009). This was demonstrated by a distinct behavioral
change from exploratory behavior Δ to loitering to receive the reward of [euphoria], from the
release of dopamine after receiving heroin. This behavior is consistent with all relevant behaviors
associated with heroin substance use disorder [H-SUD] in human subjects. The VTA basal
ganglia signals between the ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala,
and medial prefrontal cortex (mPFC) (Zhu et al., 2019). The structural function of the mPFC is
related to memory, retrieval, and consolidation(Zhu et al., 2019). The prelimbic cortices are
greatly affected by the dopaminergic surge and strongly affect drug-seeking behavior which was
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also observed in the research by the 50% increase in duration waiting for heroin, same as seeking
heroin in the CPP (light-chamber) (Zhu et al., 2019).
Tolerance Causes Extinction Resistance
Extinction of behavior occurs when reinforcement is introduced in the absence of the
problem behavior leading to a lower frequency of occurrence, and eventually ending (Hagopian
et al., 2000). Theoretically, the body is trying to bring the behavior of heroin use under extinction
by withholding dopamine release [euphoria] due to learned tolerance. However, the result is an
extinction burst; the behavior increases in frequency and intensity. (Hagopian et al., 2000).
Repeated binding and dopamine release results in the body needing a larger dose before
dopamine will be released even though binding is occurring (Kobrin et al., 2017). This is the
body’s response to create homeostasis, but it has now learned to need the drug. Therefore, other
body functions no longer function properly (e.g., cognitive functions, histamines, sleep-wake-
cycle) creating automatic reinforcement (Miltenberger, 2005) Automatic reinforcement is non-
related to the social environment, this is an internal process[ CITATION Mil05 \l 1033 ]. From a
clinical perspective, it is advised that behaviors that are under the control of automatic
reinforcement should be withheld by blocking the observable behavior from
emittance[ CITATION Coo \l 1033 ]. As this relates to heroin, this process is not advised as
extinction burst is likely to occur to avoid the aversive stimuli of withdrawal symptoms, thus
negatively reinforcing the behavior[ CITATION Mil05 \l 1033 ].
Pharmacological Treatment
The preferred method of bringing heroin substance use disorder under extinction is
pharmacological treatment[ CITATION Bel14 \l 1033 ]. Methadone (opioid agonist) Removes
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the aversive stimuli (withdrawals), the agonist binds to the Mu, Kappa, and Delta receptors
preventing heroin from binding, thus there is no euphoric event[ CITATION Bel14 \l 1033 ].
Discussion
The presented research has presented results that make strong empirical support for the
learning principles surrounding the behaviors that are associated with heroin substance use
disorder [H-SUD]. The examined research has discussed the concept of learning through the
ventral tegmental area [VTA], in that the introduction of heroin elicits the production of the
learning neurotransmitter dopamine in the learning pathway. The majority of the research uses
rodents as subjects which presents some limitations according to Kobrin et al. (2017). The main
argument presented was the duration of addiction 6-14 days inferring this is unrealistic to human
addiction over years. However, some considerations provide a viable rebuttal to this limitation.
Heroin produces such a large dopaminergic surge during the onset of use, which affects the
prelimbic cortices. According to Zhu et al. (2019), the effect of this dopaminergic introduction on
this structure greatly facilitates drug-seeking behavior. Therefore, humans will respond similarly
to rodents and within the same timeframe. The CPP research provided a clear representation of
the similarities to how humans respond once addicted. Typically, illicit drugs such as cocaine,
heroin, methamphetamines don’t require years for the affected individual to become addicted
(Bosch et al., 2015).
Suggestions for Future Research
Bosch et al. (2015), was successful at teaching rodents to self-administer the drug
methamphetamines, which would be essential for creating a naturalistic observational design
using cameras given the research subject type. The design should be a between-subjects design
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across conditions. The purpose of the research should last one year to improve reliability, and the
videos should be analyzed by third-party trained observers to further improve reliability/validity
through inter-rater agreement [IOA]. Baselines should be measured under two conditions C1-
non-treatment separate enclosure. C2- Saline treatment separate enclosure for the control group.
The experimental group should be exposed to the same conditions; however, the third condition
will introduce the rodents to the enclosure where heroin will be available to measure the
differences in behavior. After six months of living in the heroin enclosure, remove the rodents
from the enclosure and separate them into two groups. Group (a)- will have access to return to
the heroine enclosure or remain in the current. Researchers can place food in the current
enclosure, and count the days that the rodent chooses heroin over food, latency, frequency of use,
time until addicted. Group (b), these rodents should be removed from the heroin enclosure
without having access to the heroin enclosure except the investigator. This will allow the
investigator to measure the latency onset of withdrawals and how the rodent responds when
allowed to return to the heroin enclosure. For the remaining 6 months, the researchers can
introduce saline to the heroin enclosure and observe differences in behavior once the rodents
realize the treatment is not heroin. All rodents should be released to a larger enclosure where
heroin is present; however, it cannot be accessed. Means should be compared by paired t-test or
one-way analysis of variance (ANOVA) with post hoc Fisher's least significant difference (LSD)
test for pair-wise comparisons. A P-value < 0.05, instead of <0.01 should be considered
significant for all tests when reporting. A robust understanding of how heroin alters cognitive
processes can be learned. Accordingly, the design is representative, from a social psychological
perspective, of a family moving into a drug area where drugs are accessible; allowing the
researcher to measure decline. If the rodent chooses heroin over food, inferences can be made
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that the drug, through the pleasure center is stronger than multiple physiological needs. It is
common for human addicts to not eat for several days. Inferences can also be made that there is
an association between not eating and a human not working, having a lowered self-image, self-
esteem, and comorbid depression. This suggested design can also observe these behaviors
depending on how the (IV) is manipulated. The research is of social significance, to better
understand the various ways heroin affects humans. This could provide breadth to the current
research, and also a broader understanding to better assist affected families.
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