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1.  Prefrontal and monoaminergic contributions to stop-signal task performance in rats 
Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal sub-regions in the rat by means of muscimol microinfusions on SST performance. We found that dorso-medial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different sub-regions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects we infused the α2-adrenergic agonist guanfacine and the D1/D2 antagonist α-flupenthixol in dorsal prelimbic in order to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by α-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.
doi:10.1523/JNEUROSCI.1543-11.2011
PMCID: PMC3145112  PMID: 21697375
2.  Contrasting roles for dopamine D1- and D2-receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats 
Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to ADHD, schizophrenia, obsessive-compulsive disorder and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition (stop-signal reaction time, SSRT), psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear.
This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions, into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC), of the dopamine D1-receptor (DRD1) antagonist SCH 23390 or dopamine D2-receptor (DRD2) antagonist sulpiride. DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation.
doi:10.1523/JNEUROSCI.6182-10.2011
PMCID: PMC3173842  PMID: 21593319
stopping; SSRT; caudate; ADHD; schizophrenia; OCD
3.  Dissociable effects of lesions to orbitofrontal cortex subregions on impulsive choice in the rat. 
The orbitofrontal cortex (OFC) is implicated in a variety of adaptive decision-making processes. Human studies suggest that there is a functional dissociation between medial (mOFC) and lateral OFC (lOFC) subregions when performing certain choice procedures. However, little work has examined the functional consequences of manipulations of OFC subregions on decision-making in rodents. In the present experiments, impulsive choice was assessed by evaluating intolerance to delayed, but economically-optimal, reward options using a delay-discounting paradigm. Following initial delay-discounting training, rats received bilateral neurotoxic or sham lesions targeting whole OFC (wOFC) or restricted to either mOFC or lOFC subregions. A transient “flattening” of delay-discounting curves was observed in wOFC-lesioned animals relative to shams –differences that disappeared with further training. Stable, dissociable effects were found when lesions were restricted to OFC subregions: mOFC-lesioned rats showed increased, whereas lOFC-lesioned rats showed decreased, preference for the larger-delayed reward relative to sham-controls –a pattern that remained significant during retraining after all delays were removed. When locations of levers leading to small-immediate versus large-delayed rewards were reversed, wOFC- and lOFC-lesioned rats showed retarded, while mOFC-lesioned rats showed accelerated, trajectories for reversal of lever preference. These results provide the first direct evidence for dissociable functional roles of the mOFC and lOFC for impulsive choice in rodents. The findings are consistent with recent human functional-imaging studies and suggest that functions of mOFC and lOFC subregions may be evolutionarily-conserved and contribute differentially to decision-making processes.
doi:10.1523/JNEUROSCI.6620-10.2011
PMCID: PMC3183455  PMID: 21525280
cognitive; medial orbitofrontal cortex; lateral orbitofrontal cortex; impulsivity; delay discounting; decision making; intertemporal choice
4.  Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition 
Many common psychiatric conditions, such as attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Parkinson's disease, addiction and pathological gambling are linked by a failure in the mechanisms that control, or inhibit, inappropriate behavior. Models of rat behavioral inhibition permit us to study in detail the anatomical and pharmacological bases of inhibitory failure, using methods that translate directly with patient assessment in the clinic. This review updates current ideas relating to behavioral inhibition based on two significant lines of evidence from rat studies:
(1) To integrate new findings from the stop-signal task into existing models of behavioral inhibition, in particular relating to ‘impulsive action’ control. The stop-signal task has been used for a number of years to evaluate psychiatric conditions and has recently been translated for use in the rat, bringing a wealth of new information to behavioral inhibition research.
(2) To consider the importance of the subthalamic nucleus (STN) in the neural circuitry of behavioral inhibition. This function of this nucleus is central to a number of ‘disinhibitory’ disorders such as Parkinson's disease and OCD, and their therapies, but its role in behavioral inhibition is still undervalued, and often not considered in preclinical models of behavioral control.
Integration of these findings has pinpointed the orbitofrontal cortex (OF), dorsomedial striatum (DMStr) and STN within a network that normally inhibits many forms of behavior, including both impulsive and compulsive forms. However, there are distinct differences between behavioral subtypes in their neurochemical modulation.
This review brings new light to the classical view of the mechanisms that inhibit behavior, in particular suggesting a far more prominent role for the STN, a structure that is usually omitted from conventional behavioral-inhibition networks. The OF–DMStr–STN circuitry may form the basis of a control network that defines behavioral inhibition and that acts to suppress or countermand many forms of inappropriate or maladaptive behavior.
doi:10.1016/j.neubiorev.2009.07.003
PMCID: PMC2789250  PMID: 19615404
Dopamine; Serotonin; Noradrenaline; Atomoxetine; Orbitofrontal; Subthalamic nucleus; Dorsomedial striatum; Nucleus accumbens; SSRT; Premature response; Perseverative response
5.  Dissociable effects of noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in rats 
Psychopharmacology  2009;205(2):273-283.
Rationale
The stop-signal paradigm measures the ability to stop a motor response after its execution has been initiated. Impairments in inhibiting inappropriate behavior and prolonged stop-signal reaction times (SSRTs) are characteristic of several psychiatric disorders, most notably attention deficit/hyperactivity disorder. While there is relative consensus regarding the anatomical substrates of behavioral inhibition, the neurochemical imbalance responsible for the deficits in stopping displayed by impulsive individuals is still a matter of debate.
Objective
The aim of this study was to investigate the effects of manipulating brain monoamine levels on stop task parameters.
Methods
Lister-hooded rats were trained on the rodent version of the stop-signal task and administered different monoamine transporter inhibitors: citalopram, which selectively blocks the serotonin transporter; atomoxetine, which selectively blocks the noradrenaline transporter; and GBR-12909, which selectively blocks the dopamine transporter (DAT), and the alpha-2 adrenergic agonist guanfacine.
Results
Atomoxetine speeded SSRT and increased accuracy for go-trials. Citalopram slowed go reaction time and decreased go accuracy at the highest dose (1 mg/kg). GBR-12909 speeded go reaction time and impaired both go and stop accuracy. Guanfacine negatively modulated all principal stop and go measures at the highest dose used (0.3 mg/kg).
Conclusions
The results suggest that atomoxetine exerts its beneficial effects on SSRT via its action on noradrenaline re-uptake, as the specific DAT blocker GBR-12909 and serotonin reuptake blockade had only minor effects on SSRT. The speeding of the go reaction time by dopamine reuptake blockade is consistent with the hypothesis that the hypothetical stop and go processes are modulated by distinct monoaminergic systems.
doi:10.1007/s00213-009-1537-0
PMCID: PMC2705723  PMID: 19404616
Stop-signal task; Response inhibition; SSRT; Dopamine; Noradrenaline; Serotonin; GBR-12909; Atomoxetine; Citalopram; Guanfacine
6.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical psychology review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine
7.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical Psychology Review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine

Results 1-7 (7)