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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.

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.

Do gestures merely reflect problem-solving processes, or do they play a functional role in problem solving? We hypothesized that gestures highlight and structure perceptual-motor information, and thereby make such information more likely to be used in problem solving. Participants in two experiments solved problems requiring the prediction of gear movement, either with gesture allowed or with gesture prohibited. Such problems can be correctly solved using either a perceptual-motor strategy (simulation of gear movements) or an abstract strategy (the parity strategy). Participants in the gesture-allowed condition were more likely to use perceptual-motor strategies than were participants in the gesture-prohibited condition. Gesture promoted use of perceptual-motor strategies both for participants who talked aloud while solving the problems (Experiment 1) and for participants who solved the problems silently (Experiment 2). Thus, spontaneous gestures influence strategy choices in problem solving.

The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic α2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity α1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that α1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while α2 and α1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in ‘focused’ vs. ‘flexible’ cognitive processes. Translationally, this information indicates that: 1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and 2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes.

Background At low and clinically-relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention deficit hyperactivity disorder (ADHD) as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH; Ritalin®) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory. Methods Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (0.03-8.0 μg/500 nl) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic) and the dorsomedial striatum of rats (n=69). Results MPH infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted-U shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable to that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance. Conclusions These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants.

Substantial experimental evidence exists suggesting a critical role for dopamine in reinforcer-related processes, such as learning and drug addiction. Dopamine receptors, and in particular D1 receptors, are widely considered as modulators of synaptic plasticity. The amygdala contains both dopamine terminals and dopamine D1 receptors and is intimately involved in motivation and learning. However, little is known about the involvement of D1 receptor activation in two subnuclei of the mammalian amygdala, the central nucleus and basolateral complex in instrumental learning. Following recovery from surgery and preliminary training, rats with bilateral indwelling cannulae aimed at the central nucleus or basolateral complex were trained to lever-press for sucrose pellets over 12 sessions. Infusion of the selective D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (0.3 nmol and 3.0 nmol) prior to the first five training sessions dose-dependently impaired instrumental learning when compared with vehicleinfused controls. All rats were then exposed to five sessions drug-free; lever-pressing quickly reached equal levels across groups. A drug infusion prior to an 11th session revealed no effect on performance. Control experiments indicated that basic motivational processes and general motor responses were intact, such as spontaneous feeding and locomotor activity. These results show an essential role for D1-receptor activation in both the central nucleus and basolateral complex on the acquisition of lever pressing for sucrose pellets in rats, but not the performance of the behavior once conditioned. We propose that instrumental learning is dependent on plasticity in the central nucleus and basolateral complex amygdala, and that D1 receptor activation participates in transcriptional processes that underlie this plasticity.Keywords instrumental learning; amygdala; dopamine; D1; plasticity; rats Biologically important events, such as procurement of food, escape from predation, and access to sexual partners, often require flexible patterns of behavior in order to produce themforaging, vigilance, and defense, for example. Important biological reinforcers (Reinf), in turn, change the behavior that produced them, illustrating a form of adaptability termed "instrumental learning." Many Reinf-related processes are mediated by the mesocorticolimbic dopamine (DA) system, consisting of DA neurons in the ventral tegmental area and their projections to the nucleus accumbens, medial prefrontal cortex, striatum, amygdala and other *Corresponding author. Tel: +1-608-262-9332. E-mail address: mandrzejewsk@wisc.edu (M. E. Andrzejewski). (Beninger and Miller, 1998;Cardinal et al., 2002;Kelley and Berridge, 2002). Specifically, studies have shown that D1 receptor activation throughout this corticolimbicstriatal network plays a critical role in learning (Beninger and Gerdjikov, 2004). Indeed, D1 receptor activation is thought to serve a crucial modulatory function in the induction o...

A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC).