No abstract

Psychostimulants exert behavioral-calming and cognition-enhancing actions in the treatment of attention deficit hyperactivity disorder (ADHD). Contrary to early views, extensive research demonstrates that these actions are not unique to ADHD. Specifically, when administered at low and clinically-relevant doses, psychostimulants improve a variety of behavioral and cognitive processes dependent on the prefrontal cortex (PFC) in subjects with and without ADHD. Despite the longstanding clinical use of these drugs, the neural mechanisms underlying their cognitionenhancing/therapeutic actions have only recently begun to be examined. At behaviorallyactivating doses, psychostimulants produce large and widespread increases in extracellular levels of brain catecholamines. In contrast, cognition-enhancing doses of psychostimulants exert regionally-restricted actions, elevating extracellular catecholamine levels and enhancing neuronal signal processing preferentially within the PFC. Additional evidence suggests a prominent role of PFC α 2 -and D1 receptors in the behavioral and electrophysiological actions of low-dose psychostimulants. These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing and therapeutic actions of psychostimulants as well as other drugs used in the treatment of ADHD. This information may be particularly relevant for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation. KeywordsADHD; Prefrontal Cortex; Cognition; Norepinephrine; Dopamine; Stimulants Psychostimulants are a class of drugs most commonly associated with potent arousing and behaviorally-activating actions as well as the significant potential for abuse (1-6). Nonetheless, these drugs, particularly methylphenidate and amphetamine, are widely used to calm behavior and improve cognitive function in children, adolescents and adults with attention deficit hyperactivity disorder (ADHD; 7-13). These seemingly contradictory actions of psychostimulants were initially thought to reflect unique and 'paradoxical' effects in individuals with ADHD. However, subsequent work unambiguously demonstrated that the cognition-enhancing and behavioral-calming actions of psychostimulants are not limited to ADHD. Thus, when administered at low and clinically-relevant doses, psychostimulants

In mammals, the pontine nucleus locus ceruleus (LC) is the sole source of norepinephrine (NE) projections to the forebrain. Increasing tonic discharge of LC neurons elevates extracellular levels of NE in the cortex and thalamus. Tonic LC discharge is linked to the level of wakefulness and behavioral performance, demonstrating an optimal firing rate during sustained attention tasks. Iontophoretic application of NE to target neurons in the forebrain has been shown to produce a diverse set of neuromodulatory actions, including augmentation of synaptically evoked discharge as well as suppression of spontaneous and stimulus-evoked firing patterns. Iontophoretic studies cataloged potential NE effects; however, the context in which such actions could occur in awake behaving animals remained controversial. To address this issue, the current study examined the effects of increasing tonic LC output on spontaneous and stimulus-evoked discharge of neurons within the ventroposterior medial (VPM) thalamus and barrel field (BF) somatosensory cortex of awake animals using multichannel extracellular recording strategies. The present findings indicate two primary outcomes that result from increasing frequencies of LC stimulation, either an inverted-U facilitating response profile or monotonic suppression of sensory-evoked neuronal responses. Increased tonic LC output generally decreased neuronal response latency measures for both BF cortical and VPM thalamic cells. LC-mediated effects on target VPM and BF cortical neuron sensory processing are consistent with previous demonstrations of NE modulatory actions on central neurons but indicate that such actions are cell specific. Moreover, clear differences were observed between the modulation of VPM and BF cortical cells. These data suggest that sensory signal processing is continually altered over the range of tonic LC discharge frequencies that occur in the waking animal. Such changes may account for LC-mediated shifts in sensory network performance across multiple stages of arousal and attention.

Psychostimulants are highly effective in the treatment of attention deficit hyperactivity disorder (ADHD). The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2- and dopamine D1 receptors. In contrast, while the striatum is a critical participant in ‘PFC-dependent’ cognition, where examined, psychostimulant action within the striatum is not sufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear to improve PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g. working memory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 vs. α1 receptors. Collectively, this evidence indicates that at low, clinically-relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation.

Substantial evidence indicates that the locus ceruleus (LC)-norepinephrine (NE) projection system regulates behavioral state and statedependent processing of sensory information. Tonic LC discharge (0.1-5.0 Hz) is correlated with levels of arousal and demonstrates an optimal firing rate during good performance in a sustained attention task. In addition, studies have shown that locally applied NE or LC stimulation can modulate the responsiveness of neurons, including those in the thalamus, to nonmonoaminergic synaptic inputs. Many recent investigations further indicate that within sensory relay circuits of the thalamus both general and specific features of sensory information are represented within the collective firing patterns of like-modality neurons. However, no studies have examined the impact of NE or LC output on the discharge properties of ensembles of functionally related cells in intact, conscious animals. Here, we provide evidence linking LC neuronal discharge and NE efflux with LC-mediated modulation of single-neuron and neuronal ensemble representations of sensory stimuli in the ventral posteriomedial thalamus of waking rats. As such, the current study provides evidence that output from the LC across a physiologic range modulates single thalamic neuron responsiveness to synaptic input and representation of sensory information across ensembles of thalamic neurons in a manner that is consistent with the well documented actions of LC output on cognition.

Background-Despite widespread use of low-dose psychostimulants for the treatment of attention deficit hyperactivity disorder (ADHD), the neural basis for the therapeutic actions of these drugs are not well-understood. We recently demonstrated that low-dose methylphenidate (MPH) increases catecholamine efflux preferentially within the prefrontal cortex (PFC), suggesting the PFC is a principal site of action in the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants. To better understand the neural mechanisms involved in the behavioral actions of low-dose stimulants, the current study examined the effects of low-dose MPH on the discharge properties of individual and ensembles of PFC neurons.

Background Psychostimulants improve a variety of cognitive/behavioral processes in patients with attention deficit hyperactivity disorder (ADHD). Limited observations suggest a potentially different dose-sensitivity of prefrontal cortex (PFC)-dependent function (narrow inverted-U-shaped dose-response curves) vs. classroom/overt behavior (broad inverted-U) in children with ADHD. Recent work in rodents observed that methylphenidate (MPH; Ritalin®) elicits a narrow inverted-U shaped improvement in performance in PFC-dependent tests of working memory. The current studies first tested the hypothesis that PFC-dependent tasks, in general, display narrow dose sensitivity to the beneficial actions of MPH. Methods The effects of varying doses of MPH were examined on performance of rats in two tests of PFC-dependent cognition, sustained attention and attentional set shifting. Additionally, the effect of pretreatment with the α1-antagonist, prazosin (0.5 mg/kg), on MPH-induced improvement in sustained attention was examined. Results MPH produced a broad inverted-U-shaped facilitation of sustained attention and attentional set shifting. Prior research indicates α1-receptors impair, while α2-receptors improve, working memory. In contrast, attentional set shifting is improved with α1-receptor activation, while α2-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set shifting tasks, additional studies examined whether α1-receptors promote sustained attention, similar to attentional set shifting. In these studies MPH-induced improvement in sustained attention was abolished by α1-receptor blockade. Conclusions PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α1- vs. α2-receptors in these processes. These observations have significant preclinical and clinical implications.

Devilbiss DM, Waterhouse BD. Phasic and tonic patterns of locus coeruleus output differentially modulate sensory network function in the awake rat. J Neurophysiol 105: 69 -87, 2011. First published October 27, 2010 doi:10.1152/jn.00445.2010. Neurons of the nucleus locus coeruleus (LC) discharge with phasic bursts of activity superimposed on highly regular tonic discharge rates. Phasic bursts are elicited by bottom-up input mechanisms involving novel/salient sensory stimuli and top-down decision making processes; whereas tonic rates largely fluctuate according to arousal levels and behavioral states. Although it is generally believed that these two modes of activity differentially modulate information processing in LC targets, the unique role of phasic versus tonic LC output on signal processing in cells, circuits, and neural networks of waking animals is not well understood. In the current study, simultaneous recordings of individual neurons within ventral posterior medial thalamus and barrel field cortex of conscious rats provided evidence that each mode of LC output produces a unique modulatory impact on single neuron responsiveness to sensory-driven synaptic input and representations of sensory information across ensembles of simultaneously recorded cells. Each mode of LC activation specifically modulated the relationship between sensory-stimulus intensity and the subsequent responses of individual neurons and neural ensembles. Overall these results indicate that phasic versus tonic modes of LC discharge exert fundamentally different modulatory effects on target neuronal circuits within the rodent trigeminal somatosensory system. As such, each mode of LC output may differentially influence signal processing as a means of optimizing behaviorally relevant neural computations within this sensory network. Likely the ability of the LC system to differentially regulate neural responses and local circuit operations according to behavioral demands extends to other brain regions including those involved in higher cognitive functions.