Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

Abstract

The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

“…C957T is also likely to be in linkage disequilibrium with Taq1A polymorphism of ANKK1 gene (Frank & Hutchison, 2009). What is more, DRD2 affects other aspects of behavior not investigated in this study, such as reward, addiction (Volkow, Fowler, Wang, & Swanson, 2004) and impulsivity (White, Lawford, Morris, & Young, 2009), suggesting that the effect of C957T on behavior and its interactions with other gene polymorphisms and environmental stressors are more complex than observed in this study. We also acknowledge that a subset of the participants may have been experiencing current adversity, and a small number of individuals ( n  =   6) reported a history of mental health disorder, but these participants were not disproportionately distributed between genotype groups and it is therefore unlikely that these cases were driving the significant effects seen in our study.…”

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…2016) which is consistent with previous neuroimaging findings showing that Drd2 receptor levels are lower in opioid‐dependent subjects (Volkow et al. 2004). Interestingly, although VPA treatment increased Drd2 expression in DA neurons derived from all four iPSC lines, the amount of increase in both of the opioid‐dependent lines were higher compared to both of the control iPSC lines (2.59‐ and 2.30‐fold of increases for opioid‐dependent lines vs. 1.42‐ and 1.35‐fold of increases in control iPSC lines).…”

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

“…The dopaminergic system is believed to modulate a range of cognitive processes, including response inhibition (Brozoski et al, 1979;Mehta et al, 1999;Cropley et al, 2006). Both the striatum (especially the caudate) and prefrontal cortex have been identified as regions important for response inhibition (Lawrence et al, 1998;Volkow et al, 1998Volkow et al, , 2004Aron and Poldrack, 2005;Cropley et al, 2006). Impaired response inhibition has frequently been described in schizophrenia (Roberts and Pennington, 1996;Badcock et al, 2002;Henik et al, 2002) and is associated with abnormal striatal activation in both those with schizophrenia and their first-degree relatives (Vink et al, 2006).…”

“…In addition, we repeated all analyses excluding eight control subjects who were not matched on the basis of age and sex and found that all interactions remained significant. The lack of correlation between smoking history and medication effect is important as impairments in inhibitory function resulting from frontostriatal dysfunction have been described in chronic drug abuse (Jentsch and Taylor, 1999;Volkow et al, 2004). Furthermore, in a recent study in smokers without psychiatric disorder, smoking abstinence resulted in impairments in response inhibition that were reversed by nicotine administration (Dawkins et al, 2007).…”