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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 longbefore 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 severesymptoms 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 moreextensive 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
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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 componentsBefore 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). Thisimmediately 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 forebrainserotonin 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 µ−opioid system
processes reward, pleasure and pain and thereby playing a possible role in reward
processing regulation. It’s 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. Thisincludes 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 stimulusand 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 reward-
motivated behaviours (Kalivas & Volkow, 2005). A functional integration with the PFC hasbeen 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 TogetherConsidering 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 thedesire 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 Volkow’s 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 long-
term 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 µ−opiate receptor binding potential has been seen in cocaine addicts and
levels of µ−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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ConclusionIt 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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