Research report
Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task

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Abstract

Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive–compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D1 and D2 receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D1 receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D2 agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D1 agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamine's actions selectively at the D1 or D2 receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D2-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour.

Introduction

Understanding how changes in orbitofrontal cortex (OFC) function influences reward-related behaviour is becoming a research goal of ever-increasing importance. Dysfunction within this region is thought to critically contribute to both obsessive–compulsive disorder (OCD) and bipolar disorder [1], [2], and the observation that the OFC is hypoactive in cocaine addicts has lead to the suggestion that this region likewise plays a key role in mediating substance abuse [3], [4]. There is a clear need for improved treatments for such disorders, and important new leads could arise through studying the neurochemical regulation of the OFC.

Patients with OFC damage display a pattern of aberrant social behaviour and maladaptive decision-making which is often described as impulsive, and such patients score highly on questionnaire-based measurements of impulsivity [5]. Deficits in impulse control are manifest in both bipolar disorder, substance abuse disorder and, to some extent, OCD, and it has been hypothesized that these deficits may be attributable to OFC dysfunction [6], [7], [8]. Impulsivity can contribute to the making of unwise or poorly reasoned choices, such as the selection of small immediate rewards over larger but more delayed ones [9]. Given the apparent importance of OFC input for reward-related decision-making, it is perhaps unsurprising that data from studies using both humans and rodents implicate the OFC in the making of such delay-discounting judgements [10], [11], [12], [13].

However, impulsivity can also reflect deficits in response inhibition, as exemplified by difficulties in inhibiting a prepotent motor response either in anticipation of a reward signal (“waiting”) or in cancelling a motor act once it has been engaged (“stopping”) [14]. Although the OFC is not considered a primary area in the regulation of inhibitory processes, a growing body of evidence suggests that this region does contribute to these aspects of behaviour, perhaps due to its more general role in processing negative feedback [15]. For example, reductions in OFC grey matter are correlated with poor performance on the stop-signal reaction time test of motor impulsivity observed in OCD patients and their relatives [16], [17]. Damage to the OFC in rats likewise slowed stop-signal reaction time, indicative of an impairment in stopping ability, and transiently increased premature responding on the five-choice serial reaction time task (5CSRT), suggestive of a deficit in waiting for the appropriate signal before emitting a response [18], [19]. Recent work in rats also suggests that high levels of premature responding are predictive of future cocaine dependency, and that changes in gene transcription within the OFC can exacerbate withdrawal-induced increases in this form of motor impulsivity [20], [21].

Abnormalities in dopaminergic neurotransmission are thought to contribute to bipolar disorder [22], OCD [23] and substance abuse [24]. It is therefore possible that changes in dopamine (DA) signaling within the OFC may contribute to the impulsive symptoms associated with these illnesses. In terms of impulsive-decision-making, it has been observed using in vivo microdialysis that DA selectively increases within the OFC while rats are performing a delay-discounting task [25]. In addition, local inhibition of dopaminergic neurotransmission leads to decreases in impulsive choice [26], further suggesting that DA could be a key modulator of impulsive decision-making of this kind. However, whether DA within the OFC contributes to the regulation of more motor aspects of impulse control has yet to be determined. Systemic administration of the DA D1 receptor antagonist SCH23390 decreases premature responding on the 5CSRT, whereas the D2 receptor antagonist eticlopride has no effect on this measure of impulsivity [27], [28]. A similar pattern of behaviour is observed when these drugs are infused directly into the nucleus accumbens [29]. However, both receptor antagonists have been found to reduce the increase in impulsive responding observed in this task after administration of the psychostimulant d-amphetamine [28].

In terms of cortical function, DA's effects could be baseline-dependent in keeping with the prevailing hypothesis that the relationship between DA levels and behavioural performance follows an inverted U-shaped curve [30]. Although infusion of dopaminergic agents into the medial prefrontal cortex (mPFC) did not affect impulsive responding on the 5CSRT, compounds active at the D1 receptor differentially affected animals ability to accurately detect the location of the light stimulus: poor performers showed an improvement after infusions of the D1 receptor agonist while highly accurate rats became worse after infusions of the D1 receptor antagonist [31]. The aim of the current experiment was therefore to determine whether modulating DA signaling within the OFC through local infusions of DA agonists and antagonists would affect performance of the 5CSRT, and whether any effects were dependent on baseline levels of impulsivity.

Section snippets

Subjects

Subjects were 41 male Long-Evans rats (Charles River Laboratories, St. Constant, Canada). Rats weighed 275–300 g at the start of the experiments and were food-restricted to 85% of their free-feeding weight and maintained on 14 g rat chow per day. Water was available ad libitum. All animals were pair-housed in a colony room under a reverse 12 h light–dark cycle (lights off at 8:00 a.m.) maintained at a temperature of 21 °C. Testing and housing was in accordance with the Canadian Council of Animal

Results

The projected location of the injector tips, based on the placement of the guide cannulae, is shown in Fig. 1. All data included in the analyses was obtained from rats in which the injector tips targeted the ventral or lateral OFC.

Discussion

Here we show that direct infusions of dopaminergic agents into the OFC can affect multiple aspects of 5CSRT performance. The administration of a DA receptor antagonist into the OFC reduced impulsivity in HI rats, but did not affect the behaviour of LI rats. Such findings are in accordance with previous reports showing that the effects of changing cortical dopamine levels depend on the subject's baseline behaviour [31], [39], [40], and further indicate that dopaminergic activity within the OFC

Acknowledgements

This research was supported by operating and infrastructure grants to CAW from the Canadian Institutes for Health Research (CIHR), the National Sciences and Engineering Research Council, and the Canadian Foundation for Innovation. CAW also receives salary support from the Michael Smith Foundation for Health Research and CIHR. No authors have any financial disclosures to make or conflicts of interest to disclose.

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