UCLA

Addictions are multi-dimensional disorders, consisting of several behavioral, affective and cognitive dysfunctions that contribute to the compulsive and persistent drug-seeking and taking that is common to them. Cognitive control, which includes the ability to flexibly and adaptively inhibit undesirable actions (including drug-seeking), is a particularly relevant dimension of addiction, with deficits in cognitive control occurring in response to experience with drugs of abuse, as well as predicting the susceptibility for future drug-taking behaviors. The bi-directional relationship between cognitive control and substance dependence raises the possibility that these processes are governed by a common neural circuitry and emerging evidence indicates that the dopamine D2-like receptor system may be the point of convergence of these phenomena.

To determine the influence of the dopamine D2-like receptor system on cognitive control processes within the context of addictions, neuroimaging, behavioral and biochemical techniques were used to interrogate how naturally occurring and drug-induced variation in D2-like receptor system may alter cognitive-control processes. Individual differences in D2-like receptor availability, assessed with positron emission tomography, was positively related to adaptive responding following the reversal of stimulus-reward contingencies and to the sensitivity of individuals to positive feedback. Exposure to an escalating dose regimen of methamphetamine reduced D2-like receptor availability, and the degree of D2-like receptor dysfunction was correlated with the change in positive-feedback sensitivity. Cross-dimensional measurement of the D2-like receptor systems using in vivo and in vitro techniques provided evidence that deviations in D2-like receptor availability reflected actions on functionally and behaviorally relevant pools of D2-like receptors. Finally, evidence supporting the utility of spontaneous eye blink rate as a non-invasive measure of D2-like receptors was obtained from studies of rodents.

These studies provide converging support, at multiple levels of analyses, that the D2-like receptor is a common molecular determinant of addiction and cognitive control, providing a mechanistic explanation for the bi-directional relationship between these processes.