|The mesolimbic reward pathway and the alteration of the dopamine neuromodulators. |
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. 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. Changes in the reward pathway also affects behavior; specifically in the nucleus accumbens that leads to craving and pleasure-seeking behavior through synaptic plasticity.
Table of Contents
1 Reward Pathway
|The Neurocircuitry of Addiction |
The mesolimbic dopaminergic (DA) pathway is largely associated as a reward pathway, consisting of the ventral tegmental area, nucleus accumbens, amygdala and hippocampus. 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.
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. The DA D2 autoreceptors are one of the dopamine neuron subtypes that has been associated in reinforcing signals in reward circuit. With disruption of this receptor, it would lead to drug abuse and addiction. 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. Furthermore, Volkow et al. showed that individuals with alcohol addiction have lower than average levels of D2 receptors and mesocorticolimbic metabolism.
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. 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. 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. 
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. 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.  At the same time, it also transiently inhibits DA activity by activating nAChRs on GABAergic neurons. Eventually with the nicotine exposure, these nAChRs start to desensitize, decreasing the GABA inhibitory control on the dopaminergic transmission. During desensitization, nicotine also binds to nAChRs on glutamatergic neurons, increasing glutamate transmission on to dopaminergic cell bodies through NMDA-type glutamate receptors. 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). 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. 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.
|Drugs and µ-Opioid receptors|
|Drugs activate µ-opioid receptors, lowering GABA release,
eventually decreasing inhibitory effect on dopamine release. 
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. Alcohol addiction is associated with the endogenous opioid system and with exposure, it alters the GABAergic neurons. 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. This showed that ethanol modulated GABAergic transmission; and with obstruction in the GABAergic innervation, it enhanced the activity of VTA dopaminergic neurons.
To further acknowledge the function of the GABA receptors and its effect on the dopaminergic neurons, electrophysiological recordings were performed using picrotoxin (GABAA antagonist) and muscimol (GABAA agonist). 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). 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.
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. With ethanol exposure, it activates MORs by enhanced ß-endorphin release, resulting in inhibition of GABAergic neurons and lowering inhibitory postsynaptic current (IPSC) frequencies. 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. 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. However with DAMGO, HFS failed to induce LTPGABA, suggest a strong suppression of IPSCs.
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.
|Drugs inducing LTP|
|Drugs induce LTP within the postsynapse and
inhibit GABAergic neuron functions. 
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. 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. When there is an overexpression of the GluR1 subunit, it is known to cause an increase in craving behavior for cocaine injections. 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.
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]. When the 5-HT system is activated by the 5-HT2A receptors, it mediates hyperactive behaviors that are evoked by cocaine usage.
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). 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. In addition, by using a 5-HT2A agonist alone in VTA, they showed that it was sufficient to obtain hyperactivity in rats.
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 
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. 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. In drug-naïve rats, almost all of the AMPA receptors contain GluA2 subunits. 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. This action increased NAc sensitivity and enhanced motivation, provoking strong cravings for cocaine. 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). 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. When it was treated with Naspm (CP-AMPA receptor antagonist), there was a remarkable decrease in cue-induced cocaine-seeking behavior.
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. 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. 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. 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.
Interestingly, the metabotropic glutamate receptor 1 (mGluR1) negatively modulates CP-AMPA receptors within the NAc. When mGluR1 is activated, it promotes CP-AMPA receptor removal from the synapses of MSNs and inserts CI-AMPA receptors in exchange. 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. 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.
3 See Also
- Receptors in Addiction
- Genetics of Addiction
- Addiction Comorbidity
- Sexual Addiction
- Video Game Addiction
- Heroin Addiction Crime
- Treatment of Addiction