Dissociable dopaminergic and pavlovian influences in goal-trackers and sign-trackers on a model of compulsive checking in OCD.

RATIONALE: Checking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D2 receptor agonist quinpirole, is unknown. OBJECTIVES: We tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers. METHODS: Sign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested. RESULTS: Prior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active. CONCLUSIONS: The results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D2 receptors.

Behavioural characterisation of high impulsivity on the 5-choice serial reaction time task: specific deficits in 'waiting' versus 'stopping'.

Impulsivity is a core deficit of a number of neuropsychiatric disorders including attention-deficit hyperactivity disorder (ADHD), anti-social conduct disorder and drug addiction. Recent research has highlighted the multifaceted nature of impulsivity and the myriad of putative neural and psychological mechanisms thought to underpin behavioural syndromes of impaired self-control. Here we report a novel conceptualisation of impulsivity based on 'waiting' and 'stopping' efficiency with explanatory value in defining the psychological and neural basis of impulsivity and the high co-morbidity of brain disorders such as ADHD and drug addiction. Rats selected for high levels of impulsivity on a reaction time task analogous to the continuous performance test in humans exhibited correspondingly high levels of impulsive decision-making on a delay-of-reward task. The same rats, however, were unimpaired on a stop-signal task requiring inhibition of an already initiated motor response. The specific nature of this deficit in 'waiting impulsivity' was confirmed by unimpaired acquisition of appetitive Pavlovian conditioning, a putative ancillary measure of impulsive behaviour. These findings are significant in light of recent evidence linking impulsivity in rats to high levels of cocaine self-administration and development of compulsive cocaine seeking behaviour. We thus suggest that an inability to bridge delays to future rewards and reward-related stimuli is a candidate behavioural endophenotype that pre-disposes to clinical psychopathology.

Inhibitory control in rats performing a stop-signal reaction-time task: effects of lesions of the medial striatum and d-amphetamine.

The stop-signal task measures the ability to inhibit a response that has already been initiated, that is, the ability to stop. Imaging studies have implicated frontostriatal circuitry in the mediation of this form of response control. The authors report inhibition functions of normal rats and those with medial striatal damage performing the stop-signal task. Excitotoxic lesions of the medial striatum produced significant deficits on task performance, including increased omissions on the go task and flattened inhibition function, possibly as a result of increased reaction-time mean and variability. Medial striatal lesions also significantly slowed stop-signal reaction time. Subsequent treatment with d-amphetamine removed (0.3 mg/kg) or exacerbated (1.0 mg/kg) this deficit.

Lesions of the medial prefrontal cortex or nucleus accumbens core do not impair inhibitory control in rats performing a stop-signal reaction time task.

The 'stop-signal' task measures the ability to inhibit a response that has already been initiated, i.e. the ability to stop. Human subjects who have been classified as 'impulsive', for example, those with attention-deficit/hyperactivity disorder (ADHD), are slower to react to the stop signal, and are often less sensitive to changes in the timing of signals to stop. Imaging studies have implicated fronto-striatal circuitry in the mediation of this form of response control. We report inhibition functions on the stop-signal reaction time (SSRT) task for normal rats, and following damage to the medial prefrontal cortex or to the nucleus accumbens core. Neither group of excitotoxic lesions produced significant deficits on task performance. Subsequent treatment with D-amphetamine (0.3 and 1.0mg/kg) resulted in quicker go-trial reaction times (mRT) overall, but had no significant effect on SSRT. Neither medial prefrontal cortex nor nucleus accumbens lesions had any differential effects on performance following D-amphetamine. These results are discussed with respect to the fronto-striatal circuitry involved in the mediation of behavioural inhibition.

Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection.

The subthalamic nucleus (STN) is a key structure within the basal ganglia, inactivation of which is a current strategy for treating parkinsonism. We have previously shown that bilateral lesions of the STN or pharmacological inactivation of this structure in the rat induce multiple deficits in serial reaction time tasks. The aim of the present study was to investigate further a possible role for the STN in response preparatory processes by using simple (SRT) and choice (CRT) reaction time tasks. In contrast to the CRT procedure, the information related to the location of where the response had to be made was given in advance in the SRT procedure. Accurate performance on these tasks requires not only the selection of the correct response (i.e. which response), but also preparation in order to perform when required. A comparison between the two tasks allows assessment of whether STN lesions affect which response ("which") or when to perform it ("when"). As previously observed in these procedures, the responses were faster as a function of the variable foreperiod preceding the trigger stimulus. This well-known effect, termed "motor readiness, was maintained after STN lesions, suggesting that STN lesions did not affect the "when" phase of action preparation. However, while performance on the SRT was faster than on the CRT task preoperatively, STN lesions slowed RTs and abolished the beneficial effect of advance information, suggesting a deficit in the selection ("which") phase of response preparation. This deficit in the selection phase was further supported by deficits in accuracy of responding after STN lesions, as well as increases in mislocated premature responding in the SRT condition. Together, these results suggest that the STN plays an important role in response preparatory processes, including response selection and inhibitory control processes.

Effects of regional striatal lesions on motor, motivational, and executive aspects of progressive-ratio performance in rats.

The striatum is implicated in response selection and performance, the dorsal striatum in sensorimotor control and habit learning, and the ventral striatum in motivation and rewarded behaviors. Ventral striatal lesions produce performance changes on food-reinforced, progressive-ratio (PR) schedules, but the effects of dorsal striatal lesions on this task are not known. In this study, neither medial nor lateral dorsal striatal lesions produced deficits on the main motivational indices of PR performance. In contrast, significant impairments were observed in motoric or "executive" aspects of performance. Motivationally related manipulations of the task (food deprivation and reward magnitude) produced some subtle lesion-specific changes in behavior on these motoric or executive aspects of performance. Findings are discussed in relation to the roles of the dorsal and ventral striatum in reward-related behaviors.