Stellenbosch University

Shaun Shelly|076-511-0863 shaun.shelly@yahoo.com

The neurobiological underpinnings of addiction.

Shaun Shelly
It is only recently that the idea that addiction is a brain disease has begun to be accepted by the general population. The disease model was at the centre of the AA/NA message long before it became accepted by even the medical field. As we make advances in neuroscience we are finding that many of the conclusions drawn from anecdotal evidence have, in fact, a sound neurobiological basis. There is indeed a strong neurological underpinning for addiction, and in this essay I will summarise the current understanding of this. What should we focus on? If we are looking for the neurobiological underpinnings of addiction rather than the neurobiology of individual substances, we need to focus on the commonalities of all drugs of abuse (and, I would argue, behavioural addictions). This would immediately exclude certain aspects of substance use that have been of great emphasis in the past. (physical withdrawal being one since many of the most addicting drugs do not produce severe symptoms of physical withdrawal (Leshner, 1997)). All substances of abuse seem to have a final reward pathway, but the hijacking of this would seem to be insufficient to explain the complex bio-psycho-social aspects of the disease. All addicts, no matter what their drug of choice, appear to have the same issues: an unbearable wanting for their drug which manifests itself in an increased drive, a lack of control or inability to make reasoned decisions around their drug use, an increased sensitivity to stress and drug related cues and the risk of relapse even when abstinent for an extended period of time. This would seem to indicate a dysfunction in the circuits that are involved with memory, reward, drive and control (Volkow, Baler, & Goldstein, 2011).

Box 1: What is Addiction? The American Psychiatric Association defines addiction as a "chronically relapsing disorder that is characterized by three major elements: (a) compulsion to seek and take the drug, (b) loss of control in limiting intake, and (c) emergence of a negative emotional state when access to the drug is prevented". The American Society of Addiction Medicine have much more extensive short and long definitions of addiction which encompass these three concepts. This moves us away from the DSM-IV concept of abuse and dependence, which focus on issues of tolerance and withdrawal. It has been demonstrated that dependence can develop without the criteria for addiction being met, for example in the case of Beta-blockers. Addiction is not simply substance use or abuse. It is, in my opinion, a Page 1 of 9

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pathological relationship with the substance or activity at the expense of more appropriate or beneficial relationships. It is this state of addiction, after chronic drug use that results in changes in the brain and manifests in the behavioural patterns described in the definition, above that is covered in this essay.

The components
Before attempting to put it all into context, I will describe the major individual components that are responsible for the neuroplasticity that occurs during the transition from user to addict. The Chemicals Dopamine (DA) We know that dopamine is vital in the acute reinforcement of drug taking it is the neurotransmitter that lies at the heart of the reward system. Through numerous studies (pharmacological, lesion, transgenic and microdialysis) it has been established that substances of abuse all increase dopamine in the synapses made by the VTA neurons on the NAcc. Paradoxically we also know that addiction to both substances and addictive behaviours has been shown to result in DA hypo-activity and decreased D2 and limbic activation during cue induced craving after chronic use (Dackis & O'Brien, 2005). It further appears that once the state of addiction has been reached there is lower dopamine activation in frontal hypometabolism (Roberts & Koob, 1997). It is interesting to note that once an individual has become addicted, DA release into the NAcc is not critical for craving or wanting the drug of choice (Kalivas & Volkow, 2005). This immediately makes it clear that although dopamine is essential for the reinforcement of drug taking, it is not the only cause of addiction, or, in fact, a critical component for late stage addiction that involves compulsive drug seeking. Serotonin (5-HT) Like DA, 5-HT is a monoamine neurotransmitter. The role of 5-HT is to regulate bodily rhythms, appetite, sexual behaviour and emotional states. It has been linked to the effects of LSD, MDMA, amphetamines, cocaine, nicotine and alcohol. It has also been extensively linked to behavioural addictions and depression. Recent research involving cocaine addicted rats showed marked reductions in forebrain serotonin utilisation and by increasing these levels, compulsive drug seeking behaviour was curtailed (Pelloux, Dilleen, & et al, 2012). This is reinforced by the decreased levels of oxidase B (a possible peripheral marker of 5-HT function) in those with substance use disorders (Grant, Brewer, & Potenza, 2006).

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Endogenous Opioids Endogenous opioids are a a class of peptide neurotransmitter. The opioid system processes reward, pleasure and pain and thereby playing a possible role in reward processing regulation. Its also thought that individuals with altered opioidergic system may experience drug related euphoria in a more intense way, thereby increasing the probability of repeating the behaviour (Grant, Brewer, & Potenza, 2006). Glutamate Glutamate is an amino acid transmitter found throughout the brain and is important in learning and plays an essential role in the hippocampus. It has been proposed in very recent studies that it is in fact glutamate, and not dopamine, that plays the primary role in late stage addiction (Berridge & Kringelbach, 2011). It appears that the glutamatergic pathway is the final common pathway responsible for the reinstatement of drug use (see sensitisation). The move from drug use to drug addiction may be a move from dopamine based behaviour to glutamate based behaviour. cAMP Cyclic AMP is an intracellular second messenger. It can initiate a number of changes in the postsynaptic cell. The upregulation of the cAMP pathway has been opserved in the chronic use of many substances of abuse. The upregulation of cAMP leads to the decreased acute effect of the drug, which is experienced as tolerance. CREB Cyclic AMP Response Element Binding protein is a transcription factor and is stimulated by cAMP. Transcription factors bind to proteins to increase or decrease their expression. CREB has been shown to have a significant role in several forms of long-term memory (Yin & Tully, 1996) (Silva, Kogan, Frankland, & Kida, 1998).

FOSB
FOS is a protein family of immediate early genes. In chronic substance use FOSB, a stable variant of the FOS family, accumulates in the Nacc and the dorsal striatum. This elevated level of FOSB has a long lasting effect on neural functions across broad areas of the brain. These elevated levels have been linked to an increase in the number of dendritic branches and spines on neurons in the NAcc and PFC. It is this molecular mechanism that could lead to sustained changes in gene expression long after drug ceases (Nestler, Barrot, & Self, 2001).

GABA GABA is the primary brake of the brain. It achieves this status through the hyperpolarisation of neurons which inhibits them from firing. Drugs of abuse tend to reduce the release of GABA. This in turn allows for increased DA levels in the reward system. By reducing GABA there is a decreased level of anxiety, disinhibition, sedation and euphoria.

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The Structures (Many of the brain structures are discussed in my previous essay and are not repeated here unless I wish to highlight a different aspect of the area.) Cellular Structure and plasticity Plasticity is the ability of the brain to change under certain cues or circumstances. This includes the formation/elimination and changes to synapses as well as the remodelling of axons and dendrites (Chklovski, Mel, & Svoboda, 2004). It has been observed that with chronic cocaine use there is a notable increase in number of dendritic spines in the neurons of the NAcc and prefrontal cortex (Robinson & Berridge, 2000). The Prefrontal Cortex The prefrontal cortex is vital in the establishment and upgrading of goal-directed behaviours. As such it is not so much involved in determining whether a stimulus is positive or negative, but rather it regulates the motivational importance or salience of the stimulus and then mediates the intensity of the response (Jentsch & Taylor, 1999). More recently, studies in the level of connectivity between the PFC and other brain regions have been found in people addicted to many substances of abuse, and the level of abuse seems to be directly related to the degree of addiction (Goldstein, 2002). Amygdala(e) The amygdalae are 2 small groups of nuclei situated deep within the medial temporal lobes. The amygdala has been linked to emotional learning related to both appetitive and negative stimuli. The Amygdala is to fear-motivated behaviours what the NAcc is to rewardmotivated behaviours (Kalivas & Volkow, 2005). A functional integration with the PFC has been demonstrated when individuals are exposed to stimuli associated with motivationally relevant events. Hippocampus The hippocampus forms part of the limbic system and records memories and experiences, including where, when and with whom significant events occurred. Some Concepts Gene Expression Due to the long term effects of addiction long after substance use has been terminated it is thought that long term brain changes may be due to changes in gene expression. It is proposed that through chronic drug use transcription factors may be altered due to continued disturbances and variations in the synapses that are sensitive to the drug (Nestler, Barrot, & Self, 2001). Currently there is research being conducted into chromatin remodelling as the molecular basis for possibly life-long alterations in gene expression in the reward regions of the brain (Tsankova, Renthal, & Nestler, 2007).

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Sensitisation Once an individual is addicted they become sensitised to various stimuli. These stimuli fall into three categories: Cue Primed It has been shown in various experiments by Berridge and Robinson that rats become sensitised to an environment, and that environment can reinstate voluntary drug administration. This has been shown to be true in humans and is expressed in the AA/NA mantra of people, places, things. Stress Primed In the same set of experiments when previously addicted rats were exposed to stress (electric shocks), even after protracted abstinence, they would soon start self administering cocaine at previous levels. Drug Primed Similarly, even small amounts of cocaine will immediately reinstate compulsive drug use. This has been observed in human addicts and statements such as Alcohol is a very patient drug. It will wait for the alcoholic to pick it up one more time (Mercedes McCambridge) and the NA slogan of one is too many and a thousand never enough tell of the anecdotal evidence that confirms this.

Putting it all Together

Considering all the above and understanding that the definition of addiction lies not in tolerance and withdrawal, but rather in the pathological behaviours that result from the overpowering motivational strength to use drugs and the decreased ability to control the desire to obtain drugs, we see that addiction cannot simply be linked to the reward system and be motivated by the desire for hedonistic pleasure. Rather it involves a multitude of systems and areas of the brain (figure 1, below and attached), and while the initial journey toward addiction starts with the dopaminergic reward system, once the metaphorical switch of addiction is flipped, there are other pathways that sustain this addictive state, even after the individual is no longer administering substances of abuse. One of the newer and more useful hypotheses is proposed by Goldstein, Volkow et al termed iRISA impaired Response Inhibition and Salience Attribution (Goldstein, 2002). Basically this says that addiction can be considered an impairment in inhibition and/or an over exaggerated drive or motivation. During drug use there is a repetitive cycle of drug taking, craving, bingeing and withdrawal (included in Figure 2, attached). Each of these phases involves different brain regions and neurotransmitters and neuropeptides, but what is obvious both neurologically and behaviourally is the repetitive self-reinforcing behaviours that cumulatively lead to the development of late stage addiction. These can be seen in figures 1 & 2.

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It is further proposed in Goldstein and Volkows much cited paper Dysfunction of the prefrontal cortex: neuroimaging findings and clinical implications, that the normal executive functions of the Dorsal PFC are eclipsed by drug related functions due to enhanced input from the ventral PFC, and so the higher order PFC areas that normally are able to control impulsive behaviours are usurped, leading to repeated drug administration even if there is no high-level cognitive desire to do so. While this model may effectively explain active addiction, it does little to explain the longterm sensitisation to drug related cues and the propensity for relapse among addicts, even years after last drug exposure. One of the more researched areas that could lead to an explanation of this prolonged sensitivity, or even help explain the predisposition to addiction, is the decreased striatal dopamine D2 receptor availability in not only substance using addicts, but also in those suffering from behavioural addictions and eating disorders. Endogenous opioids are also involved in the mediation of responses in many drugs of choice. Higher opiate receptor binding potential has been seen in cocaine addicts and levels of opiate receptor binding in areas of the PFC and ACC have been suggested as a possible indicator for treatment success in cocaine addicted individuals (Ghitza, Preston, Epstein, & et al, 2010). Similarly reduced 5-HT transporter availability has been observed in abstinent abusers of many types of drugs and, although not yet observed in humans, there have been many animal studies that demonstrate adaptions of the glutamate and endogenous cannabinoid systems regulating activity in the PFC. As previously discussed, drug abstinence is accompanied by a hypoactive state in many of the systems described in this essay. For example, the natural reward system does not operate to the same potential when exposed to natural rewards. We also see this hypo activity in regard to negative stimuli or events, such as the loss of money. This may explain why addicted individuals do not react to the downward spiral of their life. At the same time, we see hyper activity regarding negative emotional responses and stress. Addicted subjects have been shown to be more sensitive and hostile regarding interpersonal relationships (Payer et al, 2008). This hyper/hypo active mix could create a perfect storm for relapse. The addicted individual is depressed, bored, frustrated, angry, fearful and volatile for long periods after drug taking has stopped. Added to this are the exaggerated positive memories of hedonic states of drug taking and the reduced control of executive function in the PFC. Perhaps the real question is not why do addicts relapse, but why do some manage to maintain sustained recovery? So as to attempt to gain an integrated understanding of all the neurobiological underpinnings of addiction I have put together figure 2 (attached) which shows the progression of addiction from casual drug use to the fixed state of addiction.

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Conclusion
It is obvious that the neurobiological underpinnings of addiction are diverse, complex and as yet are not nearly comprehensively understood. Recent developments in PET scanning, radiotracers and pre-clinical trials as well as increasing evidence gained from human studies will reveal more of the neurobiology of addiction and provide a better understanding of the complex social and behavioural pathologies that are symptoms of the disease. While I personally feel that finding a silver bullet to cure addiction is probably impossible, a better understanding of the neurobiological underpinnings of addiction will help tailor interventions as well as improve outcomes via medically assisted treatment programs.

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Figure 2: A diagram representing the progressive state of addiction and the underlying neurobiology of the changes that are thought to take place. Impaired Response Inhibition and Salience Attribution Syndrome Cycle Recreational Use Drug Use/Intoxication Craving Bingeing Withdrawal Abstinence Relapse Use and Abuse - In many people who use and even abuse substances there may be no long-term neuroplasticity, and as such these individuals may never become addicted. Salience Attribution: - Through activation of the reward pathway the drug acquires salience. - Acute reinforcing takes place - DA levels in limbic brain regions particularly NAcc, - evidence of DA levels in frontal regions. Drug Expectation: Strong desire to use the drug which increases over time. Impaired Inhibition: Binging stage where drug use is compulsive even if no longer enjoyed or rewarding. Depression: State of anhedonia, dysphoria and irritability.

- Likely involvement of Amygdala, PFC and Hippocampus. - Activation of Thalamoorbitofrontal circuit and anterior cinculate.

- Loss of top down control - DA, 5-HT & Glutamate play active role

- Disruption of frontal cortical circuits. - DA - 5-HT

PATH TO ADDICTION Initial casual drug use & abuse is a fairly fluid state that is not characterised by pathological drug seeking behaviour

- cAMP decreases acute effect leading to tolerance & need.

- sustained activation of CREB enhancing expression of target genes.

- of brain reward circuitry - glutamate response & strengthened memories

- gradual FOSB in NAcc creating hypersensitivity

- Prolonged State of - Permanent anhedonia, dysphoria sensitisation to and irritability. stress, low drug - Often crossdoses, drug cues & sensitised to other possibly other drugs or behaviours. substances. - Striatal DA levels 4 - Sensitisation, months after last use salience to drug, in Cocaine addicts natural rewards, - Metabolism in PFC, stress, coping leading to possible mechanisms lead to impaired inhibition. life-long risk of - DA in response to relapse. natural reward behaviours STATIC STATE OF ADDICTION - Enduring cellular End stage addiction changes such as is a static state that increased dendritic leaves the individual spines at long-term risk of - possible other relapse. changes in gene expression

A representation of the change in gene expression over 3 phases of addiction: ACUTE drug effects; TRANSITION from recreational to patterns of use characterised by addiction Change in Gene and END STAGE addiction which is characterised by Expression deminished ability to control drug use and reduced pleasure from natural rewards (Goldstein & Volkow, 2005).

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