Dopamine and impulsivity — more is less or more is more?
Apr 19, 2021
A great number of psychiatric disorders share impulsivity as a salient feature: substance use disorders, attention deficit hyperactivity disorder, borderline personality disorder, antisocial personality disorder, binge eating disorder, etc (Amlung et al., 2017; Jackson & MacKillop, 2016; Barker et al., 2015; Steward et al., 2017). As in the case of drug/behavioral addiction, reducing impulsive behavior is often the central priority of any treatment plan and the key to breaking undesired patterns.
To be clear, there are many facets to impulsive behavior, and many psychological mechanisms may underlie it. For example, delay discounting refers to one’s tendency to devalue future rewards relative to immediate ones. One might also systematically underestimate the likelihood of uncertain outcomes (probability discounting). Finally, one may exhibit varying degrees of loss aversion or gamble-seeking—the tendency to risk or avoid potential losses. These among other kinds of impulsivity may be explained by differences in learning (via reward prediction error), valuation, executive control, and emotional arousal/regulation.
A 2019 study by Petzold et al. extends work from a paper published earlier that year by the same authors. The more recent study draws from the prior subject pool and makes use of previously collected behavioral data, reapplied to shed light on substrate neural mechanisms (Petzold et al., 2019b).
The earlier study employed a randomized, double-blinded, placebo-controlled, crossover design (Petzold et al., 2019a). It examined the relationship between self-reported trait impulsivity as measured by the Barrett Impulsiveness Score (BIS-15) and the effect of L-DOPA, an amino acid precursor of dopamine used to treat Parkinson’s disease, on performance in four decision-making tests—one for each of the aforementioned manifestations of trait impulsivity: delay discounting, probability discounting for gains, probability discounting for losses, and mixed gambles. The authors found that the size and direction of the treatment effect depended on baseline impulsivity scores. For those with higher self-reported impulsivity, L-DOPA appeared to induce decreased discounting and increased loss aversion. Those with lower impulsivity scores showed the opposite effect.
This finding is broadly consistent with the hypothesis that the relationship between impulsive choice and dopaminergic activity is best modelled by an inverted U-shaped curve; low and high extremes of activity predict high impulsivity, and near-median levels predict low impulsivity. It remained to be seen was whether BIS-15 scores reflected differences in baseline dopaminergic activity—whether it was these neural differences that account for the differential effects of L-DOPA administration on impulsive choice.
Addressing this crucial question, the more recent study used positron emission tomography (PET) and administered [18F]fluorodopa-traced L-DOPA to measure presynaptic dopamine function in the striatum (Petzold et al., 2019b). The influx rate of [18F]DOPA and washout rate of [18F]dopamine were used to compute the effective distribution volume ratio (EDVR), which reflects the steady state level of dopamine available for vesicular storage. The authors find that EDVR in the whole striatum and the ventral striatum were significantly correlated with self-reported impulsivity. Moreover, independently of BIS-15 scores, presynaptic dopamine function was predictive of delay discounting under the placebo condition as well as L-DOPA-induced effects on delay discounting. EDVR was not significantly predictive of L-DOPA induced effects nor placebo-specific behavior as pertaining to probability discounting or loss aversion.
Multiple key conclusions emerge. Most notably, the study provides further evidence in favor of the inverted U-shaped curve hypothesis. Low EDVR in the whole striatum—specifically in the caudate nucleus and putamen—predicted a negative effect of L-DOPA administration on delay discounting (reduced impulsivity). Conversely, median to high EDVR predicted a slight to moderate increase in delay discounting (increased impulsivity).
This hypothesis has important pharmacological implications. If true, it suggests that dopamine agonists are only suitable for impulse-control disordered patients who exhibit low baseline dopaminergic activity. Dopamine agonists are often prescribed for several impulsivity-related disorders. Dextroamphetamines (Adderall, Dexedrine) and lisdexamfetamine (Vyvanse) are used in treating ADHD and binge eating disorder. Ropinirole, pramipexole, and levodopa are used in treating Parkinson’s disease. Multiple studies have shown that a substantial percentage of patients (~17-18%) experience greater impulsivity after being prescribed dopamine agonists—often in the form of gambling or sexual behavior (Weintraub et al., 2010; Bostwick et al., 2009). Findings such as these highlight the need for neural diagnostics or suitable proxies that may inform better treatments or dosing. Moreover, illicit uses of amphetamines prescribed to treat ADHD are prolific, especially in college settings. Though some (mis)users may be seeking cognitive improvements, this study may serve as a warning of possible impulsivity-related side effects for those with near- or above-median dopaminergic functioning.
The opposite conclusion applies for those who exhibit insufficient delay discounting, as may be the case with patients suffering from anorexia nerviosa (Steinglass et al, 2017). For such patients, perhaps an increase in dopaminergic activity would induce a downward shift along the inverted U-shaped curve (heighted delay discounting). The efficacy of dopamine agonists in these cases merits further analysis.
Another noteworthy result is the correlation between BIS-15 scores and striatal dopamine availability (p < 0.05). This finding suggests that BIS-15 may be a suitable though imperfect proxy for striatal dopamine availability at steady state. If this result is shown to be replicable and robust, one possible implication is that BIS-15 may be a viable proxy for striatal dopaminergic function that avoids the need for brain scans. Such a diagnostic could perhaps improve doctors’ diagnoses and prescription decisions without requiring costly equipment.
Numerous limitations are also apparent and acknowledged by the authors. Each offers possible directions for future research. For one, no statistically significant relationship was observed between dopamine availability in the ventral striatum and L-DOPA induced impulsivity effects. The authors attribute this finding to the limited spatial resolution of a PET scan; it cannot separate conflicting signals in undistinguished parts of the nucleus accumbens. NAcc component signals are known to be influenced by different neurotransmitters and are viable subjects for further research (Dalley & Robbins et al., 2017).
Additional measurements of impulsivity (probability discounting and loss aversion) were not significantly associated with striatal dopamine availability. The correlation between these parameters and self-reported impulsivity remains to be explained in neural terms. Other mechanisms influencing impulsivity are also not dealt with, and knowledge about these are key to designing alternative treatments for impulse-control disorders.
Finally, this paper vindicates the suggestion that research on delay discounting could unearth widely applicable psychopathological insights (Lempert et al., 2018). As has been emphasized, impulsivity and extreme delay discounting are not specific to any one condition, so dopaminergic treatments may have value across many categorical diagnoses. Serotonin is also thought to play a role in impulsive behavior, and the interactions between serotonergic and dopaminergic mechanisms are likely pharmacologically relevant (Miyazaki et al., 2011; Winstanley et al., 2003). As Lempert et al. note, non-pharmacological treatments have also shown promise in multiple behavioral experiments (Lempert et al., 2018). While the Petzold et al. papers focused on the effects of L-DOPA administration, the neural patterns uncovered could be similarly influenced by cognitive training. Future research may shed light on this possibility.
In sum, this paper shores up hypotheses about the relationship between striatal dopaminergic function and impulsivity while highlighting promising research avenues with clinical implications.
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