RationaleImpulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.ObjectiveThe objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).MethodsWe examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ‘HI’ and low impulsive ‘LI’, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.ResultsLow doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.ConclusionsThese findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.
Safety signals are learned cues that predict the non-occurrence of an aversive event. As such, safety signals are potent inhibitors of fear and stress responses. Investigations of safety signal learning have increased over the last few years due in part to the finding that traumatized persons are unable to utilize safety cues to inhibit fear, making it a clinically relevant phenotype. The goal of this review is to present recent advances relating to the neural and behavioral mechanisms of safety learning and expression in rodents, non-human primates and humans.
We survey the utility of animal models of mental illness, based on the identification of possible neurocognitive or neurobehavioral endophenotypes. Three broad clusters of neuropsychiatric disorder are discussed: (a) impulsive-compulsive syndromes, comprising drug addiction, attention deficit/hyperactivity disorder, gambling, obsessive-compulsive disorder, and compulsive eating; (b) disorders at the cognitive-emotional interface, comprising anxiety, depression, and schizophrenia; and (c) disorders purely of cognition, which contribute to the third cluster, cognitive disorders. The emphasis is thus on modeling symptoms rather than disorders per se. We also distinguish between two main aspects of any validated model: the precise neurobehavioral or neurocognitive processes implicated from detailed study of the clinical phenotype, and the perturbations, whether typically genetic, environmental, pharmacological, or neurodevelopmental, that are designed to simulate relevant neural, neurochemical, or molecular aspects of particular neuropsychiatric disorders.
SummaryFeeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans.
RationalePrevious work has demonstrated a profound effect of N-methyl-d-aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear.ObjectivesThis series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output.MethodsDrugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL.ResultsSystemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor dl-threo-β-benzyloxyaspartate as well as local α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABAA receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABAA receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL.ConclusionsThese findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism.
Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.
The amygdala has traditionally been associated with fear, mediating the impact of negative emotions on memory. However, this view does not fully encapsulate the function of the amygdala, nor the impact that processing in this structure has on the motivational limbic corticostriatal circuitry of which it is an important structure. Here we discuss the interactions between different amygdala nuclei with cortical and striatal regions involved in motivation; interconnections and parallel circuitries that have become increasingly understood in recent years. We review the evidence that the amygdala stores memories that allow initially motivationally neutral stimuli to become associated through pavlovian conditioning with motivationally relevant outcomes which, importantly, can be either appetitive (e.g. food) or aversive (e.g. electric shock). We also consider how different psychological processes supported by the amygdala such as conditioned reinforcement and punishment, conditioned motivation and suppression, and conditioned approach and avoidance behavior, are not only psychologically but also neurobiologically dissociable, being mediated by distinct yet overlapping neural circuits within the limbic corticostriatal circuitry. Clearly the role of the amygdala goes beyond encoding aversive stimuli to also encode the appetitive, requiring an appreciation of the amygdala's mediation of both appetitive and fearful behavior through diverse psychological processes.
RationalePreviously we demonstrated reduced D2/3 receptor availability in the ventral striatum of hyper-impulsive rats on the five-choice serial reaction time task (5-CSRTT). However, the anatomical locus of D2/3 receptor dysfunction in high impulsive (HI) rats is unknown.ObjectiveIn the present study, we investigated whether D2/3 receptor dysfunction in HI rats is localised to the core or shell sub-regions of the nucleus accumbens (NAcb).MethodsRats were selected for low (low impulsive, LI) and high impulsivity on the 5-CSRTT and implanted with guide cannulae targeting the NAcb core and shell. The D2/3 receptor agonist quinpirole was locally injected in the NAcb (0.1, 0.3 and 1 μg per infusion) and its effects investigated on the performance of LI and HI rats on the 5-CSRTT as well as spontaneous locomotor activity in an open field.ResultsIntra-NAcb core quinpirole increased premature responding in HI rats but not in LI rats. In contrast, intra-NAcb shell quinpirole strongly increased locomotor activity in HI rats, unlike LI rats. This effect was blocked by intra-NAcb shell infusions of the D2/3 receptor antagonist nafadotride (0.03 μg). However, nafadotride was ineffective in blocking the effects of intra-NAcb core quinpirole on premature responding in HI rats.ConclusionsThese findings indicate that impulsivity and hyperactivity are separately regulated by core and shell sub-regions of the NAcb and that HI rats show an enhanced response to D2/3 receptor activation in these regions. These results suggest that the symptom clusters of hyperactivity and impulsivity in attention-deficit hyperactivity disorder may be neurally dissociable at the level of the NAcb.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-013-3010-3) contains supplementary material, which is available to authorized users.
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