The Role of Impulsivity in Drug Addiction

Addiction is a multifaceted disorder involving a range of vulnerability factors including genetics, environment and exposure to drugs (Kreek, 2004). The role of impulsivity has recently become a focus of addiction research, and is thought to be a major factor in determining an individual's likelihood of developing a compulsive drug-taking behaviour – even being dubbed an “endophenotype for drug addiction” (Adinoff, 2011).While ‘compulsive’ drug-taking refers to an established habitual behaviour of drug self-administration, often in spite of lack of a pleasurable response and/or the emergence of adverse physiological reactions, impulsivity refers to the inherent or learned personality trait which results in an individual acting “on impulse”, i.e. without cognitively evaluating the outcomes of an action/behaviour before executing it – which may result in the individual's increased likelihood of engagement in risky behaviours, such as drug-taking. Impulsivity is often considered both a contributing factor and a consequence of compulsive drug abuse (Jentsch, 2014) – whereas compulsive drug use itself is considered a result of the drug's neurochemical interaction with natural reward/saliency pathways of the brain (Volkow, 2004).

Perry & Carroll (2008) describe three hypotheses regarding the role of impulsivity in addiction: that increased levels of trait impulsivity could be a risk factor for drug addiction (H1); that addictive drugs may lead to increased impulsivity (H2); and that impulsivity and drug addiction are associated by some third factor(s) (H3). H1 may be most relevant to the acquisition and escalation phases of addiction, while H2 may be more relevant in maintenance and relapse, as well as escalation; H3 proposes that various factors such as sex and reactivity to natural rewards may also interact with H1 and H2, further contributing to the role of impulsivity in drug addiction (Perry & Carroll, 2008).

It is important to note that the term 'addiction' encompasses a range of psychological and physiological aspects, including craving and dependency; each of which are characterised by distinct neural mechanisms. As such, impulsivity is regulated by a distinct set of circuits, separate from – but perhaps associated with – those involved in other factors of addiction. A common experimental measure of impulsivity is the 5-Choice Serial Reaction Time Task (5-CSRTT). This involves measuring premature responses by rats to a test in which they must correctly identify one of five holes in order to receive a sugar reward. Belin (2008) found a positive correlation between impulsivity scores (as determined by the 5-CSRTT) and the proportion of rats who transitioned to compulsive cocaine self-administration. This indicates a shift from impulsivity to compulsivity as a key feature of addiction – one which has recently been at the forefront of addiction research.

However, different experimental measures – such as the 5-CSRTT, reward discounting or the Stop Signal Reaction Time (SSRT) – appear to measure different types of impulsivity. Robinson (2009) showed that highly impulsive rats as determined by two tests (continuous performance and reward discounting) did not score high in impulsivity in a SSRT test, thus distinguishing “waiting impulsivity” and “stopping impulsivity” as two distinct aspects of impulsivity mediated by separate neural mechanisms. Dalley (2011) outlines much of the circuitry known to be involved in impulsivity, confirming the presence of two distinct neural networks. “Waiting impulsivity” involves pre-frontal cortical interactions with the amygdala, hippocampus and ventral striatum (including both the nucleus accumbens (NAcc) core and shell), as well as topographically organised inputs from the anterior cingulate cortex (ACC), pre-limbic and infra-limbic (IL) cortices. “Stopping impulsivity”, however, involves cortical motor areas (such as the primary motor cortex, supplementary motor area (SMA) and dorsal pre-motor area), the right inferior frontal gyrus (RIFG), the ACC, the orbitofrontal cortex (OFC) as well as interactions with the dorsal striatum (including the caudate/putamen) and other structures of the basal ganglia (including the globus pallidus and subthalamic nucleus), which in turn project to the pre-frontal cortex (PFC) via the thalamus.

Both of these networks are modulated by midbrain dopaminergic neurons in the substantia nigra and ventral tegmental area (VTA). This dopaminergic modulation – specifically the mechanism by which addictive drugs interact with dopaminergic innervations of the NAcc to directly modulate their reinforcing properties, leading to addiction – the mesolimbic dopamine hypothesis – has been the focus of much of addiction research over the past few decades.

Figure 1: Neural circuitry of "waiting impulsivity" and "stopping impulsivity". From Dalley et al. (2011).

Figure 2: Frontal cortical – ventral striatal circuitry modulating 

impulsivity in rodents. Descending pathways from the ACC (Cg1), 

OFC and IL project to the NAcc core and shell as well as the VTA 

and LC (the main nuclei of origin of the brain dopaminergic and 

noradrenergic systems, respectively). From Dalley et al. (2008).

However, these circuits are also modulated by serotonergic neurons in the Raphe nuclei (Kirby, 2011), as well as noradrenergic neurons in the locus coeruleus (LC) (Dalley et al., 2008). This suggests that the prevailing “mesolimbic dopamine hypothesis” of addiction is only part of the neural circuitry mediating drug's addictive properties, i.e. the transition from impulsivity to compulsivity. It has been proposed that addictive drugs may act to alter the balanced neurochemical connectivity within these circuits, thus altering normal learning, memory and behavioural inhibition and resulting in increased impulsivity, ultimately leading to the increased capacity for the drug/drug-related stimuli to “control” behaviour – i.e. hypothesis 2 (Jentsch, 1999). To further highlight the importance of impulsivity in drug addiction, and illustrate the dissociable effects of dopaminergic, noradrenergic and serotonergic modulation in the relevant neural circuits, Bari et al. (2009) measured the SSRTs of rats in a stop-signal task after selectively administering the monoamine transporter inhibitors citalopram, atomoxetine and GBR-12909 (which selectively block serotonin, noradrenaline and dopamine transporters, respectively). The researchers found that atomoxetine administration resulted in the greatest reduction in SSRT; however, GBR-12909 significantly reduced the 'go reaction time' (GoRT). This demonstrates that the two processes ('stop' and 'go') – two separate measures of impulsivity – are modulated by distinct neural networks. More importantly, the results show that pharmacological modulation of these networks by monoamine transporter inhibitors (addictive drugs such as amphetamine exert their effects via interactions with both dopamine transporters (Jones, 1998) and noradrenaline transporters (Xu, 2000)) directly correlates with measures of impulsivity. Additional research supports this – Eagle (2007) showed that cis-flupenthixol (a dopamine receptor antagonist) increased GoRT and methylphenidate reversed this effect, but modafinil did not; further supporting the hypothesis of multiple distinct neural substrates of impulsivity.

Indeed, there is evidence that many addictive drugs directly increase impulsivity (supporting H2). Voon (2014) found that alcohol and methamphetamine dependent subjects rated higher in impulsivity in a 5-CSRTT than healthy controls and subjects with binge eating disorder. Kirby (1999) found that heroin addicts' delay-discounting rates (another measure of impulsivity in which subjects are asked to choose between an immediate small reward or a larger, but delayed reward) were double those of matched controls, indicating higher impulsivity. Baker (2003) reported similar findings in cigarette smokers. However, a common issue encountered in such studies is the difficulty in determining whether high impulsivity is a risk factor for addiction (i.e. people who rate high in impulsivity are more likely to become drug addicts, H1) or if chronic use of addictive drugs increases impulsivity, which in turn increases the likelihood of addiction (H2) – there is evidence to support both hypotheses.

For example, Ersche et al. (2012) used diffusion tensor imaging to compare the brain structure of 50 stimulant-dependent individuals and their biological siblings who have no history of drug use, and found abnormalities in fronto-striatal systems implicated in impulsivity in both siblings from each pair, thus supporting H1. In contrast, research published by Albein-Urios et al. in the same year (2012) provides evidence in support of H2 – that the neural networks regulating impulsivity are directly affected by chronic exposure to addictive drugs; specifically that chronic use of drugs such as methamphetamine, cocaine or heroin causes 'neurotoxic' effects on top-down behavioural inhibition mechanisms, in addition to their established interactions with dopaminergic reward pathways (Albein-Urios et al., 2012). Thus, Goldstein & Volkow (2002) proposed the I-RISA (impaired response inhibition and salience attribution) model of addiction. This posits that drug addiction is “a syndrome of impaired response inhibition (i.e. increased impulsivity) and salience attribution (the mesolimbic dopamine hypothesis), resulting primarily from impaired functioning of PFC circuits and subcortical reward pathways. This corroborates with the work of Jentsch (1999), who proposed that chronic exposure to addictive drugs alters cortical and subcortical function, leading to a simultaneous reduction of response inhibition (due to impaired PFC function) and increased capacity for the drug to “control” behaviour (due to potentiated dopaminergic reward system function) – both factors highly relevant in impulsivity. Thus, Jentsch proposed that the shift from impulsivity to compulsive drug taking is a “functional synergism between augmented conditioned reward and deficits in the ability to modulate reward-related behaviors at a cognitive level” – resulting in the increased capacity for compulsive drug taking.

Figure 3: Increased conditioned stimulus-reward learning – due to augmented dopaminergic reward system function (bold, dashed arrows) – results in an enhanced motivation to seek the drug. Additionally, the response inhibition function of fronto-striatal circuitry (which regulates impulsivity) is impaired by chronic drug use, due to neurochemical alteration of cortical dopaminergic circuitry (grey, dashed arrows) and the subsequent impaired modulation of subcortical circuitry by descending corticostriatal projections (grey, solid arrows). From Jentsch (1999).

Furthermore, fMRI scans show decreased grey matter concentration in the OFC and ACC of cocaine-dependent subjects compared to non-users (Franklin, 2002), as well as lower overall volume of the PFC (Xiang, 1998), supporting the hypothesis of impaired PFC function leading to increased impulsivity and contributing to addiction (H2). However, again it is unclear whether the differences observed are a result of chronic drug use (H2), or an inherent trait which led these subjects develop drug addictions (H1). Volkow (2004) provides evidence to further suggest H2, showing that while acute administration of drugs such as cocaine/amphetamine markedly increases dopaminergic activity, chronic exposure results in decreased activity in the same circuits, perhaps due to receptor down-regulation. This results in dysregulation of the OFC, as well as the cingulate cortex. Inputs from the ACC are a crucial part of the circuitry regulating impulsivity (Figure 1 & 2). Reductions in cingulate activity, as well as in pre-SMA activity (involved in waiting impulsivity) were observed in fMRI scans of cocaine-dependent subjects when compared to controls (Kaufman, 2003), with the authors postulating that addiction may therefore be a consequence of a disruption of top-down cognitive behavioural control – further supporting Jentsch and Volkow's hypotheses. These studies strongly indicate the importance of impulsivity in the escalation/dysregulation phase of addiction.

Everitt et al. (2008) review a host of empirical evidence regarding impulsivity and addiction in both humans and rats, such as Dalley et al.’s (2007) finding that the escalation of cocaine intake is reliably predicted by low D2/3 receptor levels in the ventral striatum, and that the escalated intake may lead to rapid neuroadaptations including further down-regulation of D2 receptors in the ventral and dorsal striatum leading to rapid consolidation of drug-seeking habits which are more readily reinstated following abstinence (i.e. high rates of relapse) following exposure to drug-associated cues when compared to less impulsive rats (Dalley et al., 2007). Additionally, D2/3 receptor availability in the caudate and putamen (as determined by binding of the radiotracer [18F]fallypride – a highly selective D2/3 antagonist – in positron emission tomography) was shown to be strongly correlated with faster SSRTs in humans (Ghahremani et al., 2012). This indicates the importance of D2/3 receptors in modulating impulsivity via dopaminergic striatal projections (Figure 1 & 2), further supporting H2. Additional studies confirm this relationship. Methamphetamine-dependent subjects – who measured higher than controls in the Barratt Impulsiveness Scale (a self-report measure of impulsivity) – showed lower striatal D2/3 receptor availability than controls; moreover, further voxelwise analysis indicated a direct negative correlation between impulsivity and D2/3 receptor availability in the caudate and

Figure 4: Faster SSRTs correlated with greater D2/3 receptor availability
 in the caudate and putamen. Adapted from Ghahremani (2012).

putamen (Lee et al., 2009). Overall, since D2/3 receptor interaction has been strongly implicated in the addictive action of drugs such as methamphetamine (Groman, 2012; Higley, 2011), these studies further add to the evidence that chronic exposure to addictive drugs leads to a number of neurochemical changes in neural circuits modulating impulsivity, resulting in increased impulsivity and contributing to the shift from impulsive to compulsive drug use, i.e. H2. These adaptive changes may be baseline-dependent, however – Mitchell et al. (2006) showed that highly impulsive rats showed significantly greater locomotor sensitisation (a hallmark feature of addiction in rodent studies) after repeated exposure to ethanol than rats with lower baseline impulsivity, suggesting that the escalation of drug intake and switch to compulsive drug-seeking likely results from a combination of H1 and H2.

However, to fully address H2 in humans, it would be necessary to show that the increased impulsivity caused by chronic drug use returned to and remained at levels equivalent to non-users after drug use is ceased. Bickel et al. (1999) compared the delay-discounting of hypothetical monetary rewards by current, never, and ex-smokers and found precisely that; ex-smokers performed similarly to never-smokers, suggesting that cigarette smoking is associated with a reversible increase in discounting, i.e. a reversible increase in impulsivity (Bickel et al., 1999). While this appears to favour H2 over H1, the possibility of other factors affecting impulsivity and drug use (H3) should also be considered. For example, while opioid-dependent subjects discount delayed monetary rewards more than drug-naïve controls (Kirby & Petry, 2004), opioid-dependent subjects who reported having shared needles discounted delayed rewards to an even greater extent than opioid-dependent subjects who did not share needles (Odum et al., 2000). The fact the opioid addicts who shared needles showed even higher impulsivity than opioid addicts who didn’t, shows that other factors (such as poverty, homelessness, poor hygiene, access to drugs and peer pressure) are also important in the acquisition, escalation, maintenance and relapse phases of addiction. Thus there is evidence to support the importance of such external factors (H3). This also supports H1 since people scoring higher in impulsivity may be less able to resist environmental cues such as peer pressure (de Wit & Richards, 2004).

A similar example of an external factor which interacts with impulsivity to increase the likelihood of addiction is mental illness. There is a significant level of co-morbidity between substance abuse and mental disorders such as bipolar disorder, mood disorders and anxiety disorders, and such disorders are commonly referred to as risk factors for compulsive drug seeking (Swendsen et al., 2010). Since trait impulsivity is often significantly higher in patients suffering from disorders such as bipolar disorder compared to healthy controls, Swann et al. (2004) propose that impulsivity may be a predisposing link between bipolar disorder and substance abuse; indeed, substance abuse is present in most patients with bipolar disorder. Substance abuse comorbidity is also common in schizophrenia, with drug abusing schizophrenic patients scoring higher in impulsivity compared to non-drug abusing patients (Gut-Fayand et al., 2001; Dervaux et al., 2001). Furthermore, drug-addicted schizophrenic patients show significant grey matter volume reductions in the ACC, frontal and parietal regions – regions associated with impulsivity – which is negatively correlated with increased impulsivity (Schiffer et al., 2010). These studies further implicate the importance of impulsivity in compulsive drug use, while highlighting the relevance of external factors (H3).

Interestingly, while cocaine-addicted subjects (Hester & Garavan, 2004) and alcoholics (Noël et al., 2007) rate higher in stopping impulsivity on a Go/No-Go task compared to controls, there were no differences between 3,4-methylendioxymethamphetamine (MDMA) or cannabis users and non-drug users (Quednow et al., 2007). However, both of these drugs have addictive potential under certain circumstances (Jansen, 1999; Wenger et al., 2003) – although they do not interact with the mesolimbic dopamine system and impulsivity circuitry described above in the same way as typical “addictive” drugs (e.g. methamphetamine, cocaine, heroin) do. Thus, there are clearly other factors and neural networks affected by drugs which are not directly related to impulsivity.

Additionally, there are limitations of animal models of addiction as well as much of the experimental methodologies described here. For example, animal models do not consider the social aspects of addiction, such as socioeconomic status (Redonnet et al., 2012), which are important factors in the development of compulsive drug seeking (H3). Recent animal models have begun to consider factors such as craving and relapse, such as the reinstatement model (Spanagel, 2000); however further studies are needed to determine the relevance of these factors with the theories on impulsivity outlined above. The three hypotheses highlighted by Perry & Carroll (2008) (H1, H2, H3) are a useful framework for the relevance of impulsivity in compulsive drug seeking, however there remain other factors (not relevant to impulsivity) which are not considered. It is clear that impulsivity models do not fully explain the phenomenon of compulsive drug use/addiction. 

Nonetheless, the importance of the role of impulsivity in addiction is increasingly being recognised, with researchers focusing on how addictive drugs interact with the underlying neural circuitry to result in a shift from impulsive to compulsive drug use. Although it is unclear whether increased impulsivity is an inherent, predisposing factor for addiction (H1) or a consequence of repeated exposure to addictive drugs (H2), the research presented here suggests both / a combination of the two. Furthermore, the interactions between impulsivity and external factors such as mental illness, socio-economic background and peer-pressure (H3) are being increasingly documented in the literature. Ongoing studies continue to explore the relevant neural circuitry with the hope of developing more effective approaches to treating/preventing drug addiction.

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