We showed that ‘stopping’ is directly modulated by dopamine in the striatum, but that this action is dopamine-receptor specific and anatomically constrained. Dopamine D1 and D2 receptors in the dorsomedial striatum, but not nucleus accumbens core, had clearly opposing functions to control the speed with which an action was stopped (SSRT). The DRD1 antagonist SCH 23390 decreased (i.e., speeded) SSRT, allowing faster inhibition following an instruction to stop, while having little or no effect on the speed or likelihood of action at other times. This suggests that, normally, dopamine acting at D1 receptors in the DMStr has a very specific function during response control, to retard the imposition of behavioral inhibition, thus making it more likely that a response is completed. Conversely, the DRD2 antagonist sulpiride increased (i.e., slowed) SSRT, suggesting that dopamine acting at D2 receptors accelerates braking of responding, making it more likely that a response is inhibited. Although the two higher doses of sulpiride also increased response time on go trials, there was no correlation between the two measures, confirming that SSRT and GoRT are independent measures, and that increased SSRT is unlikely to result from generalized motor slowing.
Several recent studies have linked reduced DRD2 function with impaired behavioral inhibition and with SSRT control in particular, e.g., in ADHD and chronic drug use (Hamidovic et al. 2009
; Volkow et al. 1993
). However, our study is the first to show the regional specificity with which DRD2 controls response-braking, i.e., within the dorsomedial but not ventral striatum, the latter of which is implicated in the control of some other forms of behavioral inhibition (reviewed in Eagle & Baunez 2010
). Perhaps more intriguing is that our study provides the first evidence that dopamine acting at DRD1 has an opposing action on SSRT to that of DRD2 within the same critical region of the striatum. Such a role for DRD1 is not entirely surprising, given the purported roles of DRD1 and DRD2 families of receptor subtypes in direct and indirect pathways within the basal ganglia during activation and suppression of motor behavior respectively (Alexander & Crutcher 1990
; De Long 1990
; Gerfen & Wilson 1996
). Dopamine facilitates striatonigral neurons through DRD1 and inhibits striatopallidal neurons through DRD2 (Gerfen & Wilson, 1996
). Thus, according to existing models of striatal control (Frank & O’Reilly 2006
; Frank et al. 2007
), dopamine might promote a cortically-determined action via DRD1 in the striatum, and inhibit conflicting actions via DRD2. However, we have shown an alternative mechanism for behavioral control to these existing models, which has clear anatomical specificity and may complement the existing model of behavioral control proposed by Frank and colleagues. In a system where action and inhibition processes compete, and whichever completes first is the ‘expressed’ behaviour (action or inhibition, respectively; Logan & Cowan, 1984
), dopamine acting at DRD1 within the direct pathway effectively promotes action because the competing inhibition process is slowed and may not complete in time before the action occurs. Conversely, dopamine acting at DRD2 within the indirect pathway reduces action because inhibition completes more rapidly, and response-braking is expressed. Therefore, any change in either relative DRD1/DRD2 receptor availability, or in the accessibility of dopamine to act at one or other receptor subtype, would significantly influence the balance of behavioral activation/inhibition at a striatal level. Indeed, the lowest dose of sulpiride may have impaired response-braking both by blocking dopamine binding at DRD2 and, via its action at pre-synaptic autoreceptors, by increasing dopamine availability to act at DRD1.
However, while Frank and colleagues (e.g., Frank & O’Reilly 2006
) propose that that the role of striatal dopamine in inhibitory control over behavior is more prominent for the ability
, or decision, to inhibit (more closely reflecting the ‘no-go’ form of inhibition found in go/no-go tasks), our study suggests that dopamine also plays a role in determining the speed
at which this behavioral inhibition proceeds once the decision to stop has been made (neither DRD1 nor DRD2 blockade within the DMStr affected ‘no-go’/no-delay inhibition in our study). Therefore, dopamine can influence inhibition both at the decision-making stage, and in terms of controlling the speed of processing of the behavioral output of this decision. These subtly-different models go part-way towards elucidating the complex role of the striatum in behavioral control. Furthermore, as our study provides clear evidence for regional differentiation of function within the striatum, most likely reflecting differences in its cortical innervation, it is probable that information about both behavioral activation and inhibition can be integrated at different stages in the process, possibly within the striatum itself, to be subsequently output via the motor-output circuitry of the direct and indirect basal ganglia pathways.
Although the balance of DRD1/DRD2 function in the DMStr is clearly implicated in SSRT control, the NAcbC appears to play no role in the dopaminergic modulation of SSRT. This concept of a dorsal/ventral striatal division of SSRT control replicates evidence from lesion studies (Eagle & Robbins 2003a
), despite there being a clear role for the NAcbC in other forms of behavioral inhibition, such as impulsive-choice control and ‘waiting’ (Cardinal et al. 2001
; Christakou et al. 2004
). For example, near-identical methodology to this study produced marked effects of DRD1/DRD2 antagonists within the NAcbC on 5-CSRTT performance (Pezze et al. 2007
), confirming that our methodology was sufficient to induce performance deficits on other measures of behavioural control. This may reflect discrete corticostriatal circuitry linked to response-braking.
Further evidence from rat lesion studies shows regional differentiation within the prefrontal cortex, as well as the striatum, during SSRT control, implicating the medial division of the orbitofrontal cortex (comprising medial and ventral OFC). m/vOFC lesions increased SSRT, whereas lesions within the dorsomedial (prelimbic) or ventromedial (infralimbic) prefrontal cortex did not affect SSRT, despite being critical to other forms of inhibitory control (Eagle & Robbins 2003b
; Eagle et al. 2008
; reviewed in Dalley et al. 2004
; Eagle & Baunez 2010
). The role of the rat cingulate cortex in SSRT control is not yet known. The m/vOFC projects strongly to DMStr but not NAcbC (Schilman et al. 2008
), defining a frontostriatal circuit through which response-braking may be controlled. Although the role of the OFC in behavioural inhibition is hotly debated, growing evidence points towards the m/vOFC being functionally distinct from the more “lateral” division of the OFC (including lateral OFC, dorsolateral OFC, dorsal and ventral anterior insular (AId and AIv)) (Rudebeck et al. 2008). Unlike the m/vOFC, regions within this “lateral OFC” subdivision project strongly to the core and shell of the NAcb (AId and AIv respectively), rather than the DMStr (Voorn et al. 2004
). This “lateral OFC” may have a different role from m/vOFC in behavioral control that is unrelated to behavioural inhibition per se
(reviewed in Schoenbaum et al. 2009
In human studies, ventrolateral (right inferior frontal gyrus, RIFG) and medial prefrontal (pre-SMA/cingulate) regions are important for effective behavioural inhibition. However, the precise interplay between these structures and the anatomical circuitry underlying their integration with the basal ganglia during response-braking is still not entirely clear. Several neurobehavioral and functional imaging studies proposed the ‘hyperdirect’ pathway as a candidate for rapid processing of SSRT inhibition (e.g., Aron & Poldrack 2006
). This pathway links cortical regions (probably RIFG and supplementary motor area in humans, but see recent human imaging evidence against this using a functional connectivity analysis; Duann et al. 2009
) and subthalamic nucleus (STN), each of which is implicated in SSRT control (Aron et al. 2007
). It is argued that only this pathway could maintain the necessary speed of information processing to enable rapid inhibition (reviewed in Chambers et al. 2009
). However, our study provides the first clear evidence that temporary disruption of striatal function can severely disrupt SSRT processing speed. This adds to evidence from previous lesion studies that strongly implicates the DMStr (potentially translating to the head of the caudate in humans) in SSRT control (Eagle & Robbins 2003a
), as well as from human imaging studies that implicate the caudate during stopping (Li et al. 2008
; Boehler et al. 2010
). Our evidence does not oppose the possibility of hyperdirect SSRT modulation under some special circumstances. However, a hyperdirect pathway might be unnecessary for rapid processing speed, since such speeds of information transfer can be achieved perfectly well via a striatal route (Nambu et al 2000
; discussed in Chambers et al. 2009
). We suggest that both direct and indirect routes through the basal ganglia may be as important as the hyperdirect pathway, or more so, for controlling the speed at which responses are inhibited, especially where additional information, such as context, can add to the appropriateness of a rapid braking process (Aron 2010
In summary, we have produced the first conclusive evidence that direct receptor-specific interference of dopamine transmission within the rat dorsomedial striatum affects the ability to rapidly ‘put the brakes on’ an impending response. These findings are a significant step towards understanding how the brain controls the expression of unwanted actions and may contribute to improved treatment strategies for disorders such as ADHD and drug addiction, in which behavioral inhibition is often severely compromised.