The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed ... more 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 rel...
Goal-directed behavior is dependent on neuronal activity in the prefrontal cortex (PFC) and exten... more Goal-directed behavior is dependent on neuronal activity in the prefrontal cortex (PFC) and extended frontostriatal circuitry. Stress and stress-related disorders are associated with impaired frontostriatal-dependent cognition. Our understanding of the neural mechanisms that underlie stress-related cognitive impairment is limited, with the majority of prior research focused on the PFC. To date, the actions of stress across cognition-related frontostriatal circuitry are unknown. To address this gap, the current studies examined the effects of acute noise-stress on the spiking activity of neurons and local field potential oscillatory activity within the dorsomedial PFC (dmPFC) and dorsomedial striatum (dmSTR) in rats engaged in a test of spatial working memory. Stress robustly suppressed responses of both dmPFC and dmSTR neurons strongly tuned to key task events (delay, reward). Additionally, stress strongly suppressed delay-related, but not reward-related, theta and alpha spectral power within, and synchrony between, the dmPFC and dmSTR. These observations provide the first demonstration that stress disrupts the neural coding and functional connectivity of key task events, particularly delay, within cognition-supporting dorsomedial frontostriatal circuitry. These results suggest that stress-related degradation of neural coding within both the PFC and striatum likely contributes to the cognition-impairing effects of stress.
Cerebral cortex (New York, N.Y. : 1991), May 25, 2016
Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processe... more Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processes, an action implicated in multiple psychopathologies and estimated to contribute to nearly half of all work place accidents. However, the neurophysiological bases for stress-related impairment of PFC-dependent function remain poorly understood. The current studies examined the effects of stress on PFC neural coding during a working memory task in rats. Stress suppressed responses of medial PFC (mPFC) neurons strongly tuned to a diversity of task events, including delay and outcome (reward, error). Stress-related impairment of task-related neuronal activity included multidimensional coding by PFC neurons, an action that significantly predicted cognitive impairment. Importantly, the effects of stress on PFC neuronal signaling were highly conditional on tuning strength: stress increased task-related activity in the larger population of PFC neurons weakly tuned to task events. Combined, str...
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-m... more 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. 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), versus switching between ingestive and non-ingestive (e.g., exploratory-like) behavioral repertoires (vmPFC).Neuropsychopharmacology accepted article preview online, 23 July 2015. doi:10.1038/npp.2015.222.
Do gestures merely reflect problem-solving processes, or do they play a functional role in proble... more 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.
Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed ... more Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD.
Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and... more Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and instrumental behaviors that are reinforced by food delivery. Nucleus accumbens muscarinic antagonism may specifically suppress the hedonic or reinforcing effects of food, thus blocking its capacity to direct behavior. Alternatively, muscarinic receptor blockade may cause a negative hedonic state that interferes with appetitive learning and food intake. In these experiments, rats received infusions of scopolamine methyl bromide (10 microg/0.5 microl) into the nucleus accumbens core, following exposure to a novel flavor of liquid diet (Experiment 1) or prior to being placed into a place preference apparatus (Experiment 2). In both experiments, nucleus accumbens muscarinic receptor antagonism caused subsequent avoidance of the paired cue (flavor or spatial location). This effect was specific to cholinergic manipulation; no conditioned taste avoidance was observed after pairing the novel flavor with nucleus accumbens core antagonism of N-methyl-D-aspartate, dopamine D-sub-1, or opioid receptors (Experiment 3). These experiments confirm previous reports of a critical role for striatal acetylcholine in modulating goal-directed behaviors, but suggest caution when interpreting behavioral effects of pharmacological manipulation of striatal acetylcholine.
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed ... more 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 rel...
Goal-directed behavior is dependent on neuronal activity in the prefrontal cortex (PFC) and exten... more Goal-directed behavior is dependent on neuronal activity in the prefrontal cortex (PFC) and extended frontostriatal circuitry. Stress and stress-related disorders are associated with impaired frontostriatal-dependent cognition. Our understanding of the neural mechanisms that underlie stress-related cognitive impairment is limited, with the majority of prior research focused on the PFC. To date, the actions of stress across cognition-related frontostriatal circuitry are unknown. To address this gap, the current studies examined the effects of acute noise-stress on the spiking activity of neurons and local field potential oscillatory activity within the dorsomedial PFC (dmPFC) and dorsomedial striatum (dmSTR) in rats engaged in a test of spatial working memory. Stress robustly suppressed responses of both dmPFC and dmSTR neurons strongly tuned to key task events (delay, reward). Additionally, stress strongly suppressed delay-related, but not reward-related, theta and alpha spectral power within, and synchrony between, the dmPFC and dmSTR. These observations provide the first demonstration that stress disrupts the neural coding and functional connectivity of key task events, particularly delay, within cognition-supporting dorsomedial frontostriatal circuitry. These results suggest that stress-related degradation of neural coding within both the PFC and striatum likely contributes to the cognition-impairing effects of stress.
Cerebral cortex (New York, N.Y. : 1991), May 25, 2016
Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processe... more Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processes, an action implicated in multiple psychopathologies and estimated to contribute to nearly half of all work place accidents. However, the neurophysiological bases for stress-related impairment of PFC-dependent function remain poorly understood. The current studies examined the effects of stress on PFC neural coding during a working memory task in rats. Stress suppressed responses of medial PFC (mPFC) neurons strongly tuned to a diversity of task events, including delay and outcome (reward, error). Stress-related impairment of task-related neuronal activity included multidimensional coding by PFC neurons, an action that significantly predicted cognitive impairment. Importantly, the effects of stress on PFC neuronal signaling were highly conditional on tuning strength: stress increased task-related activity in the larger population of PFC neurons weakly tuned to task events. Combined, str...
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-m... more 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. 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), versus switching between ingestive and non-ingestive (e.g., exploratory-like) behavioral repertoires (vmPFC).Neuropsychopharmacology accepted article preview online, 23 July 2015. doi:10.1038/npp.2015.222.
Do gestures merely reflect problem-solving processes, or do they play a functional role in proble... more 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.
Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed ... more Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD.
Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and... more Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and instrumental behaviors that are reinforced by food delivery. Nucleus accumbens muscarinic antagonism may specifically suppress the hedonic or reinforcing effects of food, thus blocking its capacity to direct behavior. Alternatively, muscarinic receptor blockade may cause a negative hedonic state that interferes with appetitive learning and food intake. In these experiments, rats received infusions of scopolamine methyl bromide (10 microg/0.5 microl) into the nucleus accumbens core, following exposure to a novel flavor of liquid diet (Experiment 1) or prior to being placed into a place preference apparatus (Experiment 2). In both experiments, nucleus accumbens muscarinic receptor antagonism caused subsequent avoidance of the paired cue (flavor or spatial location). This effect was specific to cholinergic manipulation; no conditioned taste avoidance was observed after pairing the novel flavor with nucleus accumbens core antagonism of N-methyl-D-aspartate, dopamine D-sub-1, or opioid receptors (Experiment 3). These experiments confirm previous reports of a critical role for striatal acetylcholine in modulating goal-directed behaviors, but suggest caution when interpreting behavioral effects of pharmacological manipulation of striatal acetylcholine.
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorde... more Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
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Papers by Robert Spencer
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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.