Reward Pathway and Behavior in Addiction

20-26 minutes

The mesolimbic reward pathway and the alteration of the dopamine neuromodulators. [4]

Human survival mandates us to sustain our vital functions of our lives by nourishing ourselves
with food and water and engaging in sexual activity to avoid human extinction by reproducing.
All of these factors have an effect on the reward circuit, triggering pleasurable stimulations in
our brains. As humans, it is psychological for us to seek pleasurable stimulations while avoiding
pain as much as possible.[1] Therefore when the reward circuit is exploited by abusive behaviors
and addictive substances via substance, social and sexual addictions, the reward circuit is
dramatically affected and altered. The reward circuit is composed of 3 major dopaminergic
pathways of which one, the mesocorticolimbic, is largely associated with reward stimulation and
reward-seeking behaviors. With any addiction, it alters this pathway, affecting reward regulation,
motivation and behaviors. This happens by modifying the level of dopamine neuromodulators
and its receptors. One of the main sources of the dopaminergic neurons is located in the ventral
tegmental area (VTA). When an individual is exposed to addictive substance, the activity of the
VTA dopaminergic neurons are affected which contributes to the overall change in the level of
dopamine, modulated by the activity of GABAergic neurons.[2] Changes in the reward pathway
also affects behavior; specifically in the nucleus accumbens that leads to craving and pleasure-
seeking behavior through synaptic plasticity.[3]
The Neurocircuitry of Addiction [22]

The mesolimbic dopaminergic (DA) pathway is largely associated as a reward pathway,

consisting of the ventral tegmental area, nucleus accumbens, amygdala and hippocampus. [5] The
pathway implicates various rewards, motivated and addictive behaviors. With addiction, this
pathway is affected, dysregulating its function and neurochemistry which alters the individual’s
reward pathways and their behaviors.[6]
1.1 Dopamine

1.1a Dopamine D2 Receptors

Dopamine (DA) is a powerful neuromodulator within the mesolimbic reward pathway, playing
an important role in reinforcing effects of drugs and alcohol.[7] The DA D2 autoreceptors are one
of the dopamine neuron subtypes that has been associated in reinforcing signals in reward
circuit.[7] With disruption of this receptor, it would lead to drug abuse and addiction.[6] In
cocaine addicts, Volkow et al. have shown that there was a significant decrease in the D2
receptors, which lead to disruption in DA levels, leading to compulsive cocaine drug abuse.[7]
Furthermore, Volkow et al. showed that individuals with alcohol addiction have lower than
average levels of D2 receptors and mesocorticolimbic metabolism.[7]
The level of D2 receptor availability is also crucial in developing addiction and abuse. In a study
conducted by Volkow et al., they showed that when an individual with a history of alcoholic family
have a high levels of D2 receptor availability, it served as a protective function against developing
alcohol abuse.[7] Similar study conducted by Thanos et al., showed that with overexpression of DA
D2 receptor in the nucleus accumbens, it significantly reduced preference and intake of ethanol. [8]
Certainly the level of D2 receptor availability will also be affected by genetics.

Dopamine D2 Receptor
Drugs/Alcohol inhibit the function of D2 autoreceptors, increasing the level of dopamine
availability in the synaptic cleft. [23]

1.2 Ventral Tegmental Area

1.2a Nicotinic Acetyl Choline Receptors

Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels that are located
throughout the brain. The ones that are found in ventral tegmental area (VTA) play a critical role
in rewarding effects of drugs such as nicotine. The activation of nAChRs by either nicotine or
acetylcholine will lead to cation influx, modulating various neurons such as glutamatergic,
GABAergic and especially dopaminergic transmission within the mesolimbic pathway.[9] The
VTA is regulated by both excitatory glutamatergic neurons and inhibitory GABAergic
interneurons. When there is a presence of drugs and/or alcohol, it activates the nAChRs,
modulating VTA neuronal activity that stimulates accumbens dopamine release. [9] At the same
time, it also transiently inhibits DA activity by activating nAChRs on GABAergic neurons. [10]
Eventually with the nicotine exposure, these nAChRs start to desensitize, decreasing the GABA
inhibitory control on the dopaminergic transmission.[11] During desensitization, nicotine also
binds to nAChRs on glutamatergic neurons, increasing glutamate transmission on to
dopaminergic cell bodies through NMDA-type glutamate receptors.[10] As a result, there would
be an increase in the frequency of spontaneous excitatory postsynaptic current (sEPSC) inputs on
the dopaminergic neurons, triggering reward-related firings and increasing dopamine outputs.

In a study conducted by Pidoplichko et al., by using microdialysis they have shown that with self-
administration of drugs such as nicotine, amphetamine and cocaine, it dramatically increased
dopamine concentration and remained elevated for a period of time (over an hour). [11] In addition,
they have shown that there was a significant rapid nAChR desensitization on the GABAergic
neurons upon the DA neurons for a short period of time (few minutes). Even with a relatively low
concentration of nicotine administration, they observed that it caused a considerable amount of
nAChR desensitization because subsequent addition of a higher concentration had no effect.
Similarly, Mansvelder et al. injected small concentration of nicotine that caused a significant increase
in spontaneous inhibitory postsynaptic current (IPSC) frequency followed by a subsequent
decrease.[9] This implicated that desensitization occurred by the effects of nicotine. The increasing
effects of IPSC were explained by an increase in the GABAergic transmission through nAChR
activation by the presence of nicotine. In other words, with the increase in IPSC, there would be an
increased inhibition of dopamine release for a brief period in the initial presence of
nicotine. However since the nAChRs subsequently becomes desensitized, there would be less
IPSC and higher dopamine release, causing a higher activation of reward-related firings within
the mesolimbic pathway. Despite having nAChR becoming desensitized on the GABAergic
neuron, there is a recovery of the GABAergic neuron, enhancing inhibitory transmission back to
normal. This may have been suggested that the time it takes for inhibition to restore, it would
determine the timing of next cigarette intake.[9]

Drugs and µ-Opioid receptors

Drugs activate µ-opioid receptors, lowering GABA release, eventually decreasing inhibitory effect
on dopamine release. [24]

1.2b GABA Receptors and µ-Opioid Receptors

In the VTA, the dopaminergic neurons are regulated by the tonic innervations of the GABAergic
neurons. The inhibitory postsynaptic potential (IPSP) is known to be primarily mediated by the
GABAA receptors and some inhibition effect by the GABAB receptors.[2][12] Alcohol addiction
is associated with the endogenous opioid system and with exposure, it alters the GABAergic
neurons.[13] Upon exposure of alcohol, it inhibits synaptic transmission of GABAergic neurons
to dopaminergic neurons by presynaptic mechanisms. Theile et al. have shown that with acute
ethanol injections in the experimental rats and mice, there was an increase in dopaminergic
neuron firing rate in the VTA.[12] This showed that ethanol modulated GABAergic transmission;
and with obstruction in the GABAergic innervation, it enhanced the activity of VTA
dopaminergic neurons.[2]
To further acknowledge the function of the GABA receptors and its effect on the dopaminergic
neurons, electrophysiological recordings were performed using picrotoxin (GABA A antagonist)
and muscimol (GABAA agonist).[12] With picrotoxin, it showed a significant increase in the
firing rate of the dopaminergic neurons, displaying a disinhibitory effect. On the other hand,
muscimol considerably inhibited dopaminergic neuron firing rate. Additionally, they have also
examined the effect of GABAB receptor function on the dopaminergic neurons in the VTA by
using SCH0911 (GABAB antagonist).[12] Although SCH0911 did have an effect, it only moderately
increased the firing rate. It was concluded that by having both the antagonists picrotoxin and
SCH0911, it would have a complete restriction of GABA resulting in a transcendent increase in
dopamine firing rate.[12]
Since alcohol addiction is associated with the endogenous opioid system, it has an effect on its
receptor identified as µ-opioid receptors (MORs) in the VTA. It is mostly expressed in the
GABAergic neurons and with activation of this receptor, it causes hyperpolarization.[2] With
ethanol exposure, it activates MORs by enhanced ß-endorphin release, resulting in inhibition of
GABAergic neurons and lowering inhibitory postsynaptic current (IPSC) frequencies.[2] In Guan
and Ye., they investigated the effect of MORs activation contributing to the hindrance of GABA
long-term potentiation (LTPGABA) when it is exposed to ethanol.[13] By using high frequency
stimulation (HFS), naloxone (MORs competitive antagonist) and DAMGO (MORs agonist) were
applied and the electrophysiological recordings of LTPGABA were determined. With the presence
of ethanol, naloxone with HFS exhibited normal levels of LTPGABA.[13] However with DAMGO,
HFS failed to induce LTPGABA, suggest a strong suppression of IPSCs.[2]

As noted in Feduccia et al., addiction is known to be a type of learning, associating rewarding

effect of drugs to the environmental cues, leading to compulsive behaviors and a possible risk of
relapse.[10]

Drugs inducing LTP

Drugs induce LTP within the postsynapse and inhibit

GABAergic neuron functions. [25]

2.1 Ventral Tegmental Area

2.1a AMPA and NMDA Receptors

Since learning involves synaptic plasticity, AMPA receptors and NMDA receptors are affected
within the VTA. During self-administration of cocaine, there is a “dynamic regulation” of
AMPA receptors contributing towards addiction, facilitating future cocaine use.[14] With
presence of cocaine in the VTA, there is an up-regulation of GluR1 and GluR2 AMPA glutamate
receptor subunits. The increase in the GluR1 protein subunits is associated with the increase in
GluR1 mRNA.[14] When there is an overexpression of the GluR1 subunit, it is known to cause an
increase in craving behavior for cocaine injections.[14] In addition, acute cocaine intake activates
cAMP/PKA pathway mediated by the dopamine D5 receptor. This increases the function of
NMDA receptor by the NR1 and NR2B subunits insertion in the membrane. Higher insertion of
NMDA receptors will facilitates synaptic plasticity in the VTA neurons, potentially leading to
addiction development.[15]
2.1b 5-HT2A Receptors

Serotonin (5-HT) is an important neuromodulator that modulates the function of the

mesocorticolimbic circuit at 5-HT2A receptors that are localized to the VTA. The 5-HT2A
receptors are G-protein coupled receptors that are expressed throughout the mesocorticolimbic
circuit, making synaptic connections to dopaminergic and non-dopaminergic neurons [either
GABA or glutamate].[16] When the 5-HT system is activated by the 5-HT2A receptors, it
mediates hyperactive behaviors that are evoked by cocaine usage.[16]
In a recent study conducted by Herin et al., they have examined the importance of 5-HT2A
receptor on craving behavior induced by psychostimulants (mainly cocaine and
amphetamines).[16] By applying experimental rats with viral vectors of 5-HT2A receptors, they
have overexpressed the 5-HT2A proteins in VTA, which resulted in hyperactivity of behavior
elicited by cocaine administration. Furthermore, blockade of the 5-HT2A receptors by using an
antagonist, it significantly decreased psychostimulant-evoked hyperactivity/hypermotility and
associated dopamine release.[16] In addition, by using a 5-HT2A agonist alone in VTA, they
showed that it was sufficient to obtain hyperactivity in rats.[16]

Although this may be more strongly evident towards genetics factors (individual with having a
higher 5-HT2A receptor expression is more vulnerable to behavioral effects of psychostimulants),
the role of the 5-HT2A is still prominent for inducing hyperactivity of craving-behavior resulted
from the intake of psychostimulants.

2.2 Nucleus Accumbens

2.2a AMPA Receptors

Effect of Cocaine on MSNs in NAc

After cocaine administration, there is an up-regulation of

CP-AMPA receptors within the PSD [26]

The nucleus accumbens (NAc) is part of the mesocorticolimbic pathway, having critical role in
reward and motivated behaviors as seen in individuals with substance abuse. It is mostly composed
of GABAergic medium spiny neurons (MSNs), receiving glutamate transmission from cortical and
limbic areas of the brain that plays a key role in motivated behavioral regulation. [17][18] In drug
addition, the excitatory inputs to the MSNs are affected, distorting the process of reward information.
On the membrane of the MSNs, two subunits of AMPA receptors are present that mediates the
excitatory information. The AMPA receptor that is Ca2+-permeable (CP-AMPARs) contain GluA1
and lack a GluA2 subunit and the AMPA receptor that is Ca2+-impermeable (CI-AMPARs) contain
the GluA2 subunit.[17] In drug-naïve rats, almost all of the AMPA receptors contain GluA2
subunits.[17] However with cocaine injections, there is an up-regulation of CP-
AMPA receptors, creating a larger conductance of MSNs, which strengthens the synaptic
connections between the cortico-limbic excitatory inputs to the MSNs.[19][17] This action increased
NAc sensitivity and enhanced motivation, provoking strong cravings for cocaine.[17] During the up-
regulation of CP-AMPA receptors, it was observed that it also included ERK activation and
enhanced phosphorylation of GluA1 at protein kinase A (PKA).[17] In addition, after prolonged
cocaine withdrawal, CP-AMPA receptor accumulation in the NAc was observed from prolonged
cocaine self-administration. This observation lead to strengthened locomotor responses and
heightened motivation for cocaine.[17] When it was treated with Naspm (CP-AMPA receptor
antagonist), there was a remarkable decrease in cue-induced cocaine-seeking behavior.[17]

The mechanism of CP-AMPA receptor up-regulation plays a role in synaptic plasticity, sensitizing
the excitatory pathway to the MSNs in the NAc. This contributes to craving, reward-seeking
behavior and relapse. In Ferrario et al., they have examined some of these mechanisms that underlie
the accumulation of CP-AMPA receptors in NAc within the cocaine self-administration rats.[20]
AMPA receptor trafficking was shown to be maintained by the transmembrane AMPA receptor
regulatory proteins (TARPs) within the postsynaptic density (PSD). When the NAc was exposed
with cocaine, two types of TARPs (γ2 and γ4) level were affected. γ2 is expressed in both synaptic
and extrasynaptic membrane and γ4 is found mostly within the extrasynaptic membrane.
In biotinylation method conducted by Ferrario et al., it was observed that γ2 was associated with
GluA1 CP-AMPA receptors.[20] With an increase in the expression of CP-AMPA receptors it also
exhibited an increase in the γ2 TARP. In addition they have also observed that increased levels of
phosphorylation at serine 845 in GluA1 (pS845 GluA1), resulted in synaptic insertions of CP-
AMPA receptors that are associated with γ4 TARPs. It was also observed that it additionally
supplied the synapse with extrasynaptic AMPA receptors. This suggested that CP-AMPA
receptors were mainly synaptic insertions. Moreover, the maintenance of the AMPA receptors
was found to be mediated by the activation of CAMKII and extracellular signal-regulated kinase
2 (ERK2) proteins within the PSD.[20] With cocaine administration, there was an increase in
both of these proteins, promoting higher AMPA receptor synaptic insertions. Overall Ferrario et
al. have shown the effects of cocaine, leading to changes in the level of AMPA receptor
expression at the synapses, promoting craving behavior.[20]
Interestingly, the metabotropic glutamate receptor 1 (mGluR1) negatively modulates CP-AMPA
receptors within the NAc.[17] When mGluR1 is activated, it promotes CP-AMPA receptor removal
from the synapses of MSNs and inserts CI-AMPA receptors in exchange.[21] McCutcheon et al.
examined the function of mGluR1 more carefully by using a mGlu1 agonist, DHPG. Stimulation of
mGluR1 with DHPG removed CP-AMPA receptor transmission either by inhibiting its function or by
internalizing the receptor.[17] Additionally, protein kinase C (PKC) also played a key role in this
mechanism because by blocking PKC with a protein kinase C inhibitor (PKI), postsynaptic
transmission mechanism of DHPG was also blocked. This was an important finding for proposing a
strategy for drug relapse by reducing cue-induced cocaine craving and motivated behaviors.

 Receptors in Addiction
 Genetics of Addiction
 Tolerance
 Addiction Comorbidity
 Sexual Addiction
  Video Game Addiction
 Heroin Addiction Crime
 Treatment of Addiction

 Reward
 Reward Signalling
 Drugs and the Brain
 Drugs Alter the Brain's Reward Pathway

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