A brief overview of our current understanding of the neurobiological processes that underlie addiction.
PDF Version Plus Figures
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?
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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 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.
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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).
Endogenous Opioids
Endogenous opioids are
a a class of peptide neurotransmitter. The m-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).
DFOSB
FOS is a protein
family of immediate early genes. In chronic substance use DFOSB, a stable variant of the FOS family,
accumulates in the Nacc and the dorsal striatum. This elevated level of DFOSB 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.
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 reward-motivated
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).
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, see PDF Version), 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.
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 m-opiate receptor binding potential has been seen in cocaine addicts and
levels of m-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 (see PDF Version) which shows the progression
of addiction from casual drug use to the fixed state of addiction.
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.