Fronto-striatal circuits in response-inhibition: Relevance to addiction

Abstract

Disruptions to inhibitory control are believed to contribute to multiple aspects of drug abuse, from preexisting vulnerability in at-risk individuals, through escalation to dependence, to promotion of relapse in chronic users. Paradigms investigating the suppression of actions have been investigated in animal and human research on drug addiction. Rodent research has focused largely on impulsive behaviors, often gauged by premature responding, as a viable model highlighting the relevant role of dopamine and other neurotransmitters primarily in the striatum. Human research on action inhibition in stimulant dependence has highlighted impaired performance and largely prefrontal cortical abnormalities as part of a broader pattern of cognitive abnormalities. Animal and human research implicate inhibitory difficulties mediated by fronto-striatal circuitry both preceding and as a result of excessive stimulus use. In this regard, response-inhibition has proven a useful cognitive function to gauge the integrity of fronto-striatal systems and their role in contributing to impulsive and compulsive features of drug dependence.

Keywords: Addiction; Cognitive control; Drug use; Relapse; Stimulant dependence; Stop-signal.

Fig. 1

Panel 1a. Schematic representation of a single trial in the 5-CSRT task. The rat begins the trial with a nose poke in the food magazine. Following an intertrial interval (ITI), a brief light appears in one of the apertures and the rat must make a nose poke response in the appropriate hole in order to subsequently collect its reward. Premature responding occurs when the rat responds with a nose poke during the ITI rather than waiting (1). Error responding occurs when the rat responds to the wrong hole (2) and preservative responding occurs when it continues to respond rather than collect its reward. Panel 1b. Schematic representation of a sequence of trials in the go/no-go task. Subjects respond to one set of stimuli (‘A’) while withholding responses to another set (‘B’). Commission errors occur when subjects respond to no-go stimuli (4). Panel 1c. Schematic representation of a sequence of trials in the stop signal task. Subjects respond to go stimuli (‘A’ and ‘B’) presented on each trial. On a minority of trials a stop signal (in this case a visual ‘X’) indicates the prepotent response is to be withheld. As stop signal (SS) delay is varied so is the resulting probability of successfully inhibiting a response (6). Errors occur when subjects respond to a go stimulus by selecting the wrong key (5). By using a race horse model in combination with mean reaction time on go trials as well as the proportion of successful inhibitions and SS delay, an estimate of the latency to inhibit responding can be calculated (stop signal reaction time).

Fig. 2

Schematic representation of circuitry involved in response inhibition including interactions between cortical areas as well as interactions with basal ganglia structures projecting via the thalamus back to the prefrontal cortex. M1 primary motor cortex; dmPFC dorsomedial prefrontal cortex (including the supplementary motor area); vlPFC ventrolateral prefrontal cortex (including the anterior insula and inferior frontal gyrus); ACC anterior cingulate, Globus pallidus pars externa GPe; Globus pallidus pars interna/reticular substantia nigra GPi/SN; subthalamic nucleus STN.