On Impulsivity: The Neuroscience of Behavior Associated with Addiction

by Diana Martinez, MD and Pierre Trifilieff, PhD | June 12, 2014

Impulsivity - or the inability to inhibit responses despite their negative consequences - may partly explain why some individuals are more prone to develop addiction when exposed to drugs of abuse. For clinicians, understanding the neuroscience underlying impulsive behavior is central to improving treatment outcomes for addiction.

Animal and human studies reveal that addiction results from a complex interaction between genetic, environmental, social and behavioral factors. Impulsivity is one behavioral feature closely associated with addiction. Furthermore, new evidence in animal models and humans shows that impulsivity predicts the escalation of drug intake, and increases the vulnerability to relapse after periods of abstinence. This suggests that there may be an underlying alteration in brain function that predisposes individuals to impulsive behavior and increases the risk of developing addiction (read ASAM's Definition of Addiction).

From a neurobiological point of view, impulsivity has been linked to a dysfunction of dopaminergic transmission within the mesolimbic pathway, a main system involved in the modulation of reward and motivation. In other words, a lack of effective regulation of dopamine signaling in the brain can skew behavior. This altered regulation can lead to impulsivity, which is characterized by a tendency to choose immediate rewards, as opposed to incentive motivation, which is the willingness to work for more effortful but higher-value outcomes over the immediate rewards of lower value (such as the now famous Stanford marshmallow experiment). Thus, incentive motivation could be thought of as the opposite of impulsivity, with the dysregulation of dopamine signaling translating into impaired motivation and excess impulsivity. Increased impulsivity and decreased motivation may render individuals more prone to developing addiction.

Here is an overview of the biology:

The cell bodies of dopamine neurons of the mesolimbic pathway originate from the ventral tegmental area of the midbrain and project to the ventral striatum. In the striatum, the medium spiny neurons express either one of the two main types of dopamine receptor families: D1 or D2. Neurons expressing the D1 receptors are referred to as the direct pathway, which promotes a behavioral approach ("Go" signal). The neurons of the D2 receptor-expressing pathway are referred to as the indirect pathway and tend to inhibit a behavior ("No-Go" signal). Therefore, low signaling at the D2 receptor is thought to result in a failure to inhibit behavioral responses and low signaling at the dopaminergic D2 receptor in the ventral striatum is accompanied by an increase in impulsive responses and reduced motivation.

How does this relate to addiction? Imaging studies consistently show that biomarkers of addiction are: 1) blunted dopamine transmission, and 2) decreased D2 receptor levels in the ventral striatum. These neurobiological changes indicate that reduced signaling at the D2 receptor could constitute neurobiological markers of impulsivity or impaired motivation embedded in a broader addiction-induced phenotype (e.g. the physical manifestations of addiction in the brain could originate from propensity to impulsivity).

Animal models help clarify the behavioral consequences of decreased D2 receptor signaling that are seen in addiction. The animal models look at the nucleus accumbens, which is the anatomical correlate of the ventral striatum in humans where some markers of impulsivity are found. In animal models, it has been demonstrated that decreased D2 receptor expression in the ventral striatum before any drug exposure, increases impulsivity and predicts escalation of drug self-administration. Furthermore, on the other end of the spectrum, when D2 receptor signaling is increased in the nucleus accumbens, animals show enhanced motivation and decreased drug self-administration. In animals, it seems then that impulsivity can be reduced and incentive motivation can be increased through D2 receptor signaling in the ventral striatum.

Comparable results have been found in two recent human imaging studies with cocaine and methamphetamine abusers.  Blunted D2 receptor expression and low dopamine release predicted likelihood of relapse, whereas higher D2 receptor signaling was associated with treatment response. The treatment in these studies consisted of presenting competing rewards to cocaine use, such as monetary rewards (contingency management) and positive reinforcement (community reinforcement approach). The subjects who responded to treatment by inhibiting their cocaine use in favor of non-drug outcomes displayed normal dopamine signaling. However, those who failed to respond to a behavioral treatment that focuses on enhancing motivation and reducing impulsive choices displayed low striatal dopamine signaling. Thus, clinicians should be aware of the possible differences in neurobiology that might underlie a patient's ability to respond to treatment that focuses on shifting reward driven behavior.

Animal models also show that drug self-administration itself can chronically impact both dopamine transmission and D2 receptor levels, suggesting that drug exposure could worsen the risk to develop addiction in vulnerable individuals. Importantly, the development and maturation of the mesolimbic system occurs during late adolescence, when individuals are more likely to experience drugs of abuse for the first time. This points out why prevention measures during adolescence are so important.

In terms of treatment, D2 receptor levels seem to impact both impulsivity and incentive motivation in opposite directions, such that increasing D2 receptor signaling in the ventral striatum would appear to be a reasonable treatment approach. However, a number of clinical trials have not shown definitively that dopamine agonists are successful in treating stimulant abuse. One reason for this may be that endogenous signaling of the dopamine neurons is fine-tuned and depends on the environmental context. Dopamine agonists cannot replace the fine-tuning of endogenous dopamine since they stimulate D2 receptors regardless of the environmental stimuli. However, recent clinical trials have shown some promise for this method of increasing dopamine signaling (for example, with levodopa-carbidopa) when it is combined with contingency management, which seeks to shift reward-driven behavior. Thus, combining medications that increase dopamine signaling with behavioral treatment could serve as a better treatment strategy.

Another approach would be to increase signaling at the D2 receptor itself, which in theory could be done with gene therapy (using a viral vector to increase D2 receptor levels) or with novel medications that increase the effect of endogenous dopamine at the D2 receptor. While both of these are not yet available for clinical use, they may eventually become future treatments for refractory addictive disorders.

Regardless, understanding impulsivity and the many other biological roots of addiction give treatment providers hope. Isolating the mechanisms that cause this brain disease allows researchers to develop new and novel treatment. To learn more about impulsivity and the research to-date, read the review on D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity.

Diana Martinez, MD

Dr. Martinez is an Associate Professor at Columbia University/New York State Psychiatric Institute. She is a psychiatrist and imaging researcher whose work has focused on using Positron Emission Tomography (PET) imaging in drug addiction. PET imaging allows the measurement of dopamine receptors and dopamine release in the human brain, and her work focuses on using this imaging technique, based on animal models of addiction, to better understand the neurochemistry of substance use disorders. Through these types of studies, her work is geared toward developing innovative treatments for addiction.

Pierre Trifilieff, PhD

Dr. Trifilieff is an Assistant Professor at INRA in the University of Bordeaux. His research focuses on the role of the mesolimbic dopaminergic transmission in physiologic and pathological conditions. Since the activity of the dopaminergic D2 receptor is altered in various psychiatric disorders that involve a dysregulation of the reward system, his work aims at unraveling the role of D2 receptor-dependent signaling in the modulation of reward processing and motivation. This includes studying the impact of D2 receptor manipulations on goal-directed behaviors as well as identifying environmental factors that impact D2-dependent signaling and related behaviors.


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  1. Michael HYTROS md Jul 20, 2014 - 05:41 PM

    Is Wellbutrin helpful here in any way ? 

  2. Pierre Trifilieff Jun 20, 2014 - 05:43 AM

    These are indeed important points. There are still a lot of unknowns about the exact consequences of altered D2 receptor density, but animal studies clearly show that manipulations of D2 receptor activity/expression lead to strong behavioral alterations that make this receptor a particularly relevant target for the development of new treatments. But of course, this is not the only factor responsible for impulsivity and/or addiction.
    In terms of neural circuits, the consequences of decreased striatal D2 receptor density on projection areas are poorly understood. Interestingly, one recent study from Dr. Kellendonk’s lab at Columbia University showed that manipulations of D2 receptor expression in the striatum, by impacting excitability of MSNs, leads to re-wiring of the direct pathway on projection areas, and behavioral alterations (Cazorla et al., 2014: It is then tempting to propose that similar mechanisms might also apply to impulsivity and addiction in which D2 receptor levels are decreased. Further studies should explore this possibility.
    An important aspect to take into account for interpretation of the findings is that, whereas the segregation of the direct and indirect pathways and their distinct projections are quite well characterized for the dorsal striatum, it is still not completely clear whether this model also applies to the ventral striatum, which seems particularly altered in addiction. Indeed, in the ventral striatum, some neurons co-express both D1 and D2 receptors, and it has been proposed that these neurons could constitute a “third” pathway of the basal ganglia. However, to date, the exact projections, properties and function of these atypical neurons is completely unknown as is their possible involvement in impulsivity and/or addiction.
    Additionally, the interpretation of the impact of decreased D2 receptor density is further complicated by the fact that the D2 receptors in the striatum do not only originate from MSNs of the indirect pathway. First, D2 receptors are also expressed by terminals of dopaminergic projections where they negatively regulate dopamine release. These receptors are as well expressed on the surface of cholinergic interneurons of the striatum, which are known to strongly modulate MSNs activity. It is then also possible that the decrease in D2 receptor density described in addiction originates, at least in part, from an alteration of those subpopulations of striatal receptors.
    Still a lot of work and brainstorming must be done to unravel the signification of the decrease in D2 receptor in addiction and impulsivity. As pointed out by Dr. Martinez, those could also be topics for the next installment of this column.

  3. Diana Martinez Jun 19, 2014 - 08:49 AM

    This is a great question, and could be the topic of the next installment of this column. The brief answer is that the medium spiny GABAergic neurons of the ventral striatum can be classified as either direct pathway (mostly D1 expressing) or indirect pathway (mostly D2). The indirect pathway projects  external segment of the globus pallidus. Dopamine at the D1 and D2 receptors is thought to modulate the corticostriatal loops that also circle through the striatum, and the interneurons of the striatum play a crucial role in this as well. 

    It is also correct that dopamine and D2 receptors are not necessarily the determinate factor in impulsive behavior. Most likely other neurotransmitter systems are involved as well. We often focus on dopamine though for the following reasons: 1) the imaging studies of humans imaging D2 receptors are very reproducible and consistent with animal studies; and 2) dopamine is largely modulatory. These make dopamine a good target for research and treatment development, since it implies that the changes in dopamine signaling are long standing and modulatory neurotransmitter systems are preferable for pharmacology - it's difficult to use treatments that target neurotransmitters (such as glutamate/gaba) since these often have widespread effects in the brain. Dr. Trifilieff may have more to add, and again this may serve as the starting point of another installment.

  4. John Hexem MD PhD Jun 16, 2014 - 04:26 PM

    I liked your article and considered it cogent. My question is "What happens downstream from the ventral striatum" How does function of the medium spiny neurons translate into observed behavior. To what structures do they project. In what fashion are any neural circuits receiving input from the MSN's altered. D2 receptor density or function may not be the determinant factor in impulsive behavior, just an important one.

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