Drugs of abuse and their associated addictions are a prevalent issue in today’s world. Addiction, being defined as a chronic condition that involves inherently more than just social and environmental factors, suffers from a vague understanding of its biological and psychological basis (American Psychological Association). Being the world’s third leading health problem (Kaplan and Sadock 1991, Ornberg 1996), the need for understanding the neurochemical, neuroanatomical and neural basis of alcoholism is at its highest. With the Diagnostic and Statistical Manual of Mental Disorders (DSM) being updated every few years, the criteria for dependence and substance abuse is always changing (American Psychological Association).
As noted by Wise and Koob, addiction is not mentioned in the newest version of the DSM (V) because of the indistinct nature that it assumes (2013). To fixate on a particular aspect of addiction, the Mesolimbic Pathway, often referred to as the reward pathway, and the Ventral Tegmental Area (VTA) are of interest. Dopamine released into nucleus accumbens originates in the VTA (Ikemoto and Panksepp 1999). To delve into the importance of substance abuse and its everlasting effects of the brain, provided will be extensive focus on alcohol (ethanol), its neurochemical, neuroanatomical and neural basis for addiction, as well as the importance of techniques to counteract the effects that alcohol can produce either short term or long term.
The nucleus accumbens (NAc), known for its major role in the reward pathway (Russo et al. 2010), has been studied extensively in the way it contributes to addiction and reward seeking and motivating behavior. For example, dopamine (DA), a neurotransmitter primarily important in the Mesolimbic Dopamine Reward Pathway, shows a considerable amount in the nucleus accumbens when drugs of abuse are introduced into the body (Di Chiara 2002). With an increase in dopamine release, there is a simultaneous increase in the way reward is signaled and understood in the brain. To be specific, the Ventral Tegmental Area (VTA), a major site of DA neurons in the brain, has two pathways; the direct and indirect pathways that each have distinct functions when it comes to reward.
For the purpose of understanding the NAc and its responsibility in reward, the focus remains on the direct pathway which acts as a moderator for reward while the indirect plays a larger role in forming memories to avoid negative stimuli (Takatoshi et al. 2015, Volkow & Morales 2015). To determine the involvement of drugs of abuse and dopamine on reward, it has been found that psychostimulants, classified by alcohol, opiates, and others, cause a significant increase in DA by blocking reuptake into the presynaptic cell by the dopamine transporter (DAT) or by causing an increase of dopamine release from the presynaptic terminals (Di Chiara 2002). When blockers for DA receptors are given, a decrease in reinforcement in those subjects who were classically conditioned using a conditioned placement was found (Di Chiara 2002). This leaves a large amount of dopamine in the synapse and causes an increase in reward due to the abundance of dopamine available.
In attempts to distinguish between neuroanatomical regions and dopamine involved in the wanting and liking pathways, studies were conducted using appetitive and/or consummatory stimuli. A study in rats using a common bar press paradigm showed that the lever accompanied by sucrose was pressed more than the control lever after a dopamine agonist, amphetamine, was introduced into the nucleus accumbens. Alternatively, in the presence of a cue, a light stimulus, the sucrose lever was pressed even more than in the absence of a cue. Moreover, the “liking” aspect of this study consisted of a taste test. This revealed that pleasant reactions were slightly decreased in the presence of amphetamine and unfavorable reactions were increased. To clarify, the presence of a dopamine agonist injected directly into the shell of nucleus accumbens shows an increase in activity in the “wanting” of a drug, but not necessarily the “liking” of that same drug (Wyvell 2008).
Similarly, after finding activation in the nucleus accumbens when primates anticipate making a response for a reward (Mirenowicz & Schultz 1996), a study with humans was conducted in hopes of detecting nucleus accumbens activation by anticipation of responding for a reward than in anticipation for responding for no reward. It was also hypothesized that the ventromedial frontal cortex and orbital frontal cortex would be activated by presentation of reward outcomes than non-reward outcomes. Using a monetary incentive delay task and watching the corresponding neuroanatomical regions, it was found that the NAc is activated by anticipation of reward, lessened when reward received, and suppressed when rewards were not obtained. Also, it was found that there is a difference in central and forebrain sites for reward anticipation versus outcome in humans. With this, it can be concluded that the NAc is functioning similarly, to anticipation of a reward, in humans and in rats (Knutson 2001).
Dopamine is widely discussed in the reward mechanisms of drug dependency. Alternatively, the brains most excitatory neurotransmitter, glutamate, has been studied more recently in regard to dependency, tolerance and even withdrawal from alcohol. Glutamate binds to AMPA receptors and NMDA receptors. It has been found that glutamate is an essential neurotransmitter in alcohol related dependence, as it is partly responsible for the euphoric effects. Plasticity of the glutamatergic have been hypothesized to contribute to the dependency and tolerance of alcoholism (Krystal et al. 2003). The NMDA receptor has one of the highest associations for ethanol in the brain, because of this is has been seen that ethanol affects the excitability and transport of glutamate in the nucleus accumbens (Siggins et al. 2006, Sari 2014). With enhanced NMDA receptor sensitivity, glutamate levels show higher in the NAc when exposed to alcohol for 5 days (Sari 2014). Aside from glutamate, GABA the brains most inhibitory neurotransmitter has also taken a large role in alcohol moderation studies. Male mice were trained in the classic model of bar pressing for ethanol diluted in water. To test the hypothesis that GABA receptors were important modulators in alcohol consumption, a GABAB agonist, baclofen, was given.
The results observed indicated that GABAB agonists reduced the reinforcing effects present in alcohol exposure (Besheer et al. 2004). To combine the evidence from GABA and Glutamate, Besheer and Hodge tested the glutamate receptor subtype 5 (mGluR5), its effects on GABAA receptors and how this interaction plays a part in the discriminative effects of alcohol. Rats trained to differentiate ethanol from water were given a mGluR5 antagonist, causing its inhibition, and suffered a decrease in correct distinction between alcohol and water. To determine the relationship between mGluR5 and GABAA, pentobarbital and diazepam were substituted for ethanol because they substitute fully for effects of ethanol (Besheer et al 2003). It was found that pentobarbital caused no significant effects, while diazepam was affected by the introduction of the antagonist. Since there was a relationship between ethanol and diazepam discrimination after the mGluR5 antagonist, it prompted researchers to look for co-expression. Using fluorescent immune-staining, co-expression of the mGluR5 and GABAA receptors was found, signifying the relationship between both glutamate and GABA in the effects of alcohol. (2005).
To narrow down drugs of abuse to one of great importance, the nucleus accumbens has been said to be involved in the neurobiological aspect of reward in relation to addiction (Ganaraja et al. 2012). To be less broad, many studies have suggested a role in alcoholism and its link to the Mesolimbic Dopamine Reward Pathway, and nucleus accumbens distinctively. Although behavioral addictions are different than substance addictions, they hold a large consistency: the inability to resist temptation (Grant et al. 2010). According to the American Psychiatric Association, addiction, or substance dependence, is diagnosed as a negative method of use of addictive drugs that results in impairment or distress. To determine how alcoholism affects the neurochemical and neuroanatomical aspects of the brain, both human and animal studies have been completed to further the neuroscience field of understanding when it comes to substance abuse problems.
To illustrate the animal studies conducted to further research on the idea of alcohol and its effect on the nucleus accumbens, a study conducted using rats tested the hypothesis that neurotransmission of dopamine would be related to reinforcing effects of alcohol. After being anesthetized with a cannula inserted into the nucleus accumbens, dopamine activity was found to be directly related to excitatory action of alcohol on the transmission of dopamine (Di Chiara & Imperato 1985). Given that this acquisition was early, it has given rise to a multitude of studies curious about the same idea. Many studies, using electrophysiology, have shown that addictive drugs cause an increase in the ventral tegmental area activity, because of this idea it has been found that alcohol specifically increases the neuronal firing in this particular brain area (Gessa et al. 1985).
In an in vitro study of Sprague-Dawley rats, a coronal section of the brain containing the VTA was placed in the recording apparatus. From here, ethanol was infused through a tube directly into the artificial extracellular fluid the brain slice was in. Results showed that with alcohol administration, there were concurrent increases in dopamine reward neuron firing in the nucleus accumbens (Brodie et al 1990, Brodie et al 2006). Consistent with the findings of increased activation in the reward neurons in the nucleus accumbens, it has also been found that chronic alcohol exposure affects the transport of dopamine as opposed to only causing an increase of release (Di Chiara 2002, Carroll et al. 2006). To specify, the dopamine transporter (DAT) was expressed more on the cell surface when exposed to alcohol, by about 40-50%, subsequently causing an amplification in dopamine reuptake (Riherd et al. 2008). Interestingly, dopamine (D2) receptors are significantly decreased in the nucleus accumbens as well as other structures associated with the VTA in alcohol preferring rats (McBride et al. 2003, Martinez et al. 2005).
Aside from animal studies, there has also been substantial studies conducted concerning human subjects. Furthering the information found regarding dopamine release in the presence of alcohol in animal models, similar findings in humans mimic the mechanism related to DA release (Boileau et al. 2003). After oral administration of alcohol mixed with orange juice, subjects were given a tracer injection and the placed into a PET scan machine. Findings paralleled those in rat studies; when alcohol is existent, DA release in the nucleus accumbens increases (Boileau et al. 2003,). To concur with the reduction in D2 receptors in rats, it has been shown that dependency on alcohol leads to a decrease in D2 receptors in the nucleus accumbens in humans (Tupala 2003, Martinez et al. 2005).
On a separate note, alcoholics have been categorized into two subtypes: type 1 alcoholics and type 2 alcoholics. Type 1 is classified as having both genetic and environmental contributions, usually occurs later in life after years of heavy alcohol use and can occur in both men and women. Type 2 alcoholics primarily consist of the male offspring of male alcoholics with its only contributing factor being the environment. Type 2 usually occurs during teenage years or early adulthood and is commonly associated with criminality (Cloninger et al. 1996). In previous rat studies, dopamine D1 and D2 receptors both played a critical role in alcohol administration (McBride et al. 2003) With this in mind, a study comparing type 1 and type 2 alcoholics in humans showed similar results.
After obtaining postmortem brains from nine type 1 alcoholics, eight type 2 alcoholics and 10 controls, researchers used autoradiography to determine receptor participation. It showed that type 1 alcoholics suffer from lesser DAT in the nucleus accumbens and lower D2 receptors, while receptor density and DAT was the same for type 2 alcoholics and controls. These results bring great importance to the individualized differences that alcohol can have on neurochemical transmission and regulation.
In an experiment containing 3 separate tasks, researchers searched for a dissociation between the neurobiological systems underlying the “wanting” and “liking” of drugs of abuse. To begin participants tasted Evian water, apple juice, an ethanol infused solution and recorded their level of enjoyment. In an attempt to manipulate wanting, participants drank vodka with grape juice as a primer, or received only the placebo, grape juice. Then they completed a liking test involving two beers and two juices, presented at random, and rated their level of liking. In attempts to manipulate liking, participants were given Heineken beer or pineapple juice and asked to rate their liking on a variety of aspects. Across all experiments, there was little to no association found between the wanting a liking of alcohol. This data can be used to further the Incentive Sensitization Theory (IST) as proposed by Robinson and Berridge in 2001. (Hobbs et al. 2001).
As discussed earlier, with alcohol present in the body of human or animal models, there is a significant increase in dopamine release and activation in the mesolimbic dopamine reward system, or more discretely, the nucleus accumbens. Like any brain system, over exposure can lead to neuroplasticity. With this increase in dopamine there is simultaneous escalation of self-administering, or “wanting” With any drugs of abuse chronic use can lead to sensitization of corresponding pathways, leading to the “wanting” aspect of drug addiction. (Robinson & Berridge 2001, Miller & Goldsmith 2008). Since alcohol interacts with many neurotransmitter receptor sites (dopamine, GABA and glutamate as well as others not discussed here), it is understood that each system plays a role in the compulsivity of alcoholism (Miller & Goldsmith 2008). Concurrently, it has been said that the sensitivity to the drug of abuse may cause the unconscious “wanting” or craving of that particular substance but is outside the realm of “liking” (Miller & Goldsmith 2008).
With a basic understanding of the neural circuitry, neurochemical, and neuroanatomical regions of alcohol dependence in animal and human models, it is also important to note how any inconsistencies or disruptions may interfere with the neural mechanisms. In male Wistar rats, electrical lesions to the nucleus accumbens showed a non-significant increase in preference of 10% alcohol when only given the option of alcohol. When presented with the option of water or alcohol, the preference of the lesion group swayed towards water. With this, it can be said that the nucleus accumbens portion of the reward pathway may only play a part in addiction (Ganaraja et al. 2012). In addition to electrically induced lesions to test alcohol consumption, deep brain stimulation (DBS) can be used in the same respect.
Deep brain stimulation is done by implanting electrodes that can effectively deliver low intensity electrical stimulation to desired brain areas. Previous studies have shown that deep brain stimulation to the NAc reduced the levels of cocaine intake (Vassoler et al. 2008, Knapp et al. 2009). Based on the findings provided in the Vassoler et al. experiment, a similar study was conducted to test the same idea but with an alternative to cocaine. In the first deep brain stimulation study lesioning both the shell and core of the NAc did not reduce water intake in rats but did reduce alcohol intake (Knapp et al. 2009).
Due to the success of deep brain stimulation on alcohol consumption, more experiments were conducted in hopes of finding successful treatments for alcoholism. In order to do so, rodents were subject to chronic alcohol (ethanol) exposure. In a two-part experiment, the rats in the chronically drinking group were first given injects of a GABA agonist into shell of the NAc. Alternatively, in the second part of the experiment, the same chronically drinking rats had electrodes surgically placed into the shell of their NAc to monitor ethanol intake. Results showed that in rats with chronic alcohol exposure, a GABA agonist reduced ethanol intake by 55%. Similarly, stimulation of the NAc shell in the same rats reduced intake by 47% (Wilden et al. 2014). With success accompanying GABA agonists and more widely studied DBS, there is ample evidence that either and/or both could be effective treatments for alcoholism in humans.
Given the substantial amount of evidence surrounding the broad topic of alcohol and its copious effects on the brain, there are still questions awaiting an answer. Like most research, animal testing provides an appreciable foundation to understanding complex systems like the brain. As the psychological and neuroscience fields grow and attain more knowledge with each study conducted, the questions underlying addiction, alcohol, and the short- or long-term effects it may cause on our brain systems will likely be answered. Most of the research conducted has suggested many of the same findings and the same underlying brain mechanisms. As detailed here, a vast amount of research has already been completed in hopes of understanding the neurochemical, neuroanatomical and neural basis for addiction, as well as the importance of techniques to counteract the effects that alcohol can produce.
As the field continues, there is great hope that full understanding of the neurochemical components of addiction will be accompanied by treatments for neurochemical inhibitors and/or transporters that will provide relief from substance abuse. Furthermore, as knowledge is gained concerning drug addiction as a whole, neuroanatomical regions will become more understood in the particular roles they play in the reinforcing effects that come with drugs of abuse. Finally, as these aspects are discovered and widely understood, alcoholism, and drug addiction as a whole, will optimistically result in vast treatment and lead to less prevalence in our world.
