Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory.

The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical role in executive cognitive processes that guide goal-directed behavior. Dysregulation of frontostriatal-dependent cognition is implicated in a variety of cognitive/behavioral disorders, including addiction and attention deficit hyperactivity disorder (ADHD). Psychostimulants exert dose-dependent and opposing actions on frontostriatal cognitive function. Specifically, low and clinically-relevant doses improve, while higher doses associated with abuse and addiction impair, frontostriatal-dependent cognitive function. Frontostriatal cognition is supported by the coordinated activity of neurons across this circuit. To date, the neural coding mechanisms that support the diverse cognitive actions of psychostimulants are unclear. This represents a significant deficit in our understanding of the neurobiology of frontostriatal cognition and limits the development of novel treatments for frontostriatal cognitive impairment. The current studies examined the effects of cognition-enhancing and cognition-impairing doses of methylphenidate (MPH) on the spiking activity of dorsomedial PFC (dmPFC) and dorsomedial striatal (dmSTR) neurons in 17 male rats engaged in a working memory task. Across this frontostriatal circuit, we observed opposing actions of low- and high-dose MPH on the population-based representation of delay: low-dose strengthened, while high-dose weakened, representation of this event. MPH elicited a more complex pattern of actions on reward-related signaling, that were highly dose-, region- and neuron-dependent. These observations provide novel insight into the neurophysiological mechanisms that support the cognitive actions of psychostimulants.

Stress degrades working memory-related frontostriatal circuit function.

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.

Prefrontal corticotropin-releasing factor neurons impair sustained attention via distal transmitter release.

The prefrontal cortex (PFC) supports cognitive processes critical for goal-directed behavior. Although the PFC contains a high density of corticotropin-releasing factor (CRF) neurons, their role in cognition has been largely unexplored. We recently demonstrated that CRF neurons in the caudal dorsomedial PFC (dmPFC) of rats act to impair working memory via activation of local CRF receptors. However, there is heterogeneity in the neural mechanisms that support the diversity of PFC-dependent cognitive processes. Currently, the degree to which PFC CRF neurons impact other forms of PFC-dependent cognition is unknown. To address this issue, the current studies examined the effects of chemogenetic manipulations of PFC CRF neurons on sustained attention in male rats. Similar to working memory, activation of caudal dmPFC CRF neurons impaired, while inhibition of these neurons or global CRF receptor antagonism improved, sustained attention. However, unlike working memory, the sustained attention-impairing effect of PFC CRF neurons was not dependent on local CRF receptors. Moreover, CRF infusion into the caudal dmPFC or other medial PFC subregions had no effect on task performance. Together, these observations demonstrate that while caudal dmPFC CRF neurons impair both working memory and sustained attention, these actions involve distinct neural circuits (local CRF release for working memory and extra-PFC release for sustained attention). Nonetheless, the procognitive actions of systemically administered CRF antagonists across both tasks are similar to those seen with attention deficit hyperactivity disorder-related treatments. Thus, CRF antagonists may have potential for use in the treatment of PFC cognitive dysfunction.

Harmonization of Biosafety and Biosecurity Standards for High-Containment Facilities in Low- and Middle-Income Countries: An Approach From the Perspective of Occupational Safety and Health.

Following the global-level Ebola virus disease (EVD) outbreak during 2014-2016, international collaboration with multiorganizational participation has rapidly increased. Given the greater priorities for research and development (R&D) outcomes despite the quantitative and qualitative lack of high-containment laboratory facilities in low- and middle-income countries (LMICs), where biological targets for investigation are located near their natural habitats, occupational readiness for health workers' safety has not been well-addressed, where limited global expert human resources are being deployed to high-containment laboratories including biosafety level 4 (BSL-4) facilities for case management and medical investigations. Pursuing scientific and managerial success to make laboratories efficient and productive, most laboratory safety policies have focused on the functionality of technical skills or performance, procedural methodologies, and supervision over the employees to collaborate in LMICs. The experts dispatched from advanced countries bring a long list of scientific tasks with high-tech devices, supplies, and training programs to introduce their collaboration with local partners in LMICs. However, the dispatched experts would subsequently realize their list becomes endless to establish their basic functions required in high-containment laboratories to ensure qualified scientific outcomes in LMICs. Under such circumstances where dual or multiple policies and standards accommodated pose dilemmas for operational procedures to ensure biosafety and biosecurity, all the frontline experts from both LMICs and advanced countries may be exposed to significant risks of life-threating infection of highly pathogenic agents like EVD, without any pragmatic measures or road maps to establish valued international collaboration, pursuing its sustainability. Given the fact mentioned above, we conducted a quick review of the key biosafety and biosecurity management documents, relevant policy analyses, and research to understand the current status and, if any, measures to dissolve critical dilemmas mentioned above. As a result, we found that occupational safety and health (OSH) aspects had not been sufficiently addressed, particularly in the context of international BSL-4 collaboration in LMICs. Moreover, consideration of OSH can be one of the key drivers to make such collaborative interventions more pragmatic, safer to reorient, harness disease-based vertical approaches, and harmonize policies of biosafety and biosecurity, particularly for collaborations organized in resource-limited settings.

Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants.

Psychostimulants, including methylphenidate (MPH), improve cognitive processes dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. In both humans and animals, systemic MPH improves certain cognitive processes, such as working memory, in a narrow inverted-U-shaped manner. In contrast, other processes, including attention-related, are improved over a broader/right-shifted dose range. The current studies sought to elucidate the potential circuit and receptor mechanisms underlying the divergent dose-dependent procognitive effects of psychostimulants. We first observed that, as with working memory, although sustained attention testing was highly dependent on multiple frontostriatal regions, only MPH infusion into the dorsomedial PFC improved task performance. Importantly, the dose-response curve for this action was right-shifted relative to working memory, as seen with systemic administration. Additional studies examined the receptor mechanisms within the PFC associated with the procognitive actions of MPH across working memory and sustained attention tasks. We observed that PFC α2 and D1 receptors contributed to the beneficial effects of MPH across both cognitive tasks. However, α1 receptors only contributed to MPH-induced improvement in sustained attention. Moreover, activation of PFC α1 receptors was sufficient to improve sustained attention. This latter action contrasts with the impairing actions of PFC α1 receptors reported previously for working memory. These results provide further evidence for a prominent role of the PFC in the procognitive actions of MPH and demonstrate the divergent dose sensitivity across cognitive processes aligns with the differential involvement of PFC α1 receptors.

Stress Degrades Prefrontal Cortex Neuronal Coding of Goal-Directed Behavior.

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, stress elicits a profound collapse of task representations across the broader population of PFC neurons.

Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex.

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. This article is part of a Special Issue entitled SI: Noradrenergic System.

GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding.

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).

The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex.

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 effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats.

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.

Comparison of a frozen human foreskin fibroblast cell assay to an enzyme immunoassay and toxigenic culture for the detection of toxigenic Clostridium difficile.

This study set out to validate the Hs27 ReadyCell assay (RCCNA) as an alternative CCNA method compared against a commonly used commercial enzyme immunoassay (EIA) method and toxigenic culture (TC) reference standard. A total of 860 samples were identified from those submitted to the Health Protection Agency microbiology laboratories over a 30-week period. RCCNA performed much better than EIA when using TC as a gold standard, with sensitivities of 90.8% versus 78.6% and positive predictive value of 87.3% to 81.9%, respectively. The Hs27 Human Foreskin Fibroblast ReadyCells are an easy-to-use and a sensitive CCNA method for the detection of toxigenic Clostridium difficile directly from stool. A turnaround time of up to 48 h for a negative result and possible need for repeat testing make it an unsuitable method to be used in most clinical laboratory setting.

Psychostimulants act within the prefrontal cortex to improve cognitive function.

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, 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 (.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: Methylphenidate 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 with 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.

Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α1 - and α2-receptors.

BACKGROUND: Psychostimulants improve a variety of cognitive and 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) versus classroom/overt behavior (broad inverted U) in children with ADHD. Recent work in rodents demonstrates 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 (.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, whereas α2-receptors improve, working memory. In contrast, attentional set shifting is improved with α1-receptor activation, whereas 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- versus α2-receptors in these processes. These observations have significant preclinical and clinical implications.

Spontaneous gestures influence strategy choices in problem solving.

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.

Use of performance-based contracting to improve effective use of resources for publicly funded residential services.

This article details the process that was undertaken to convert the financing mechanism for publicly funded mental health residential programs in a large urban setting from nonincentivized agreements to performance-based contracts. The initial target for change was improving occupancy rates for residential services targeted to persons with serious and persistent mental illness. Improving occupancy rates enhanced efficiency such that 25 additional cents for every dollar spent on mental health residential services went to direct care. Challenges met in the process of effecting the contracting conversion of this expansive system are addressed. The importance of centralized gatekeeping, stakeholder involvement, and setting modest expectations are emphasized as keys to success. Although the system still has less capacity than client demand warrants, existing beds are no longer underutilized. Recent efforts to expand contracting targets beyond efficiency goals to include improved quality and effectiveness are also discussed.

The management of Clostridium difficile infection.

INTRODUCTION/BACKGROUND: Clostridium difficile is the commonest cause of nosocomial diarrhoea. The epidemiology and clinical phenotype of the disease has dramatically changed with the global emergence of a virulent strain of C. difficile. SOURCE: This review was compiled using data from individual studies and review articles identified from PubMed. The retrieved articles were also examined for additional references. AREAS OF AGREEMENT: Appropriate and timely infection control measures are required to control C. difficile infection (CDI) in the hospital environment, and either oral metronidazole or vancomycin remains the mainstay of treatment depending on the severity of infection. AREAS OF CONTROVERSY: The optimal method for diagnosing CDI remains unclear, as does the best therapeutic strategy for the management of multiple relapses. GROWING POINTS/AREAS TIMELY FOR DEVELOPING RESEARCH: Studies of new antimicrobial agents with activity against C. difficile are required to improve the management of multiply relapsing disease. The use of novel therapeutic approaches that do not require antimicrobials requires urgent research, including the use of immunological or vaccine-based regimen, bacteriotherapy or C. difficile-specific bacteriophages.

Muscarinic receptor antagonism of the nucleus accumbens core causes avoidance to flavor and spatial cues.

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.

Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.

BACKGROUND: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown. METHODS: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal, .25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory. RESULTS: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux. CONCLUSIONS: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.

Dissociating ventral and dorsal subicular dopamine D1 receptor involvement in instrumental learning, spontaneous motor behavior, and motivation.

A series of experiments investigating the role of dopamine D1 receptors in the ventral subiculum (vSUB) and dorsal subiculum (dSUB), 2 subregions of the hippocampal formation, found that D1 receptor antagonism (3.0 nmol/0.5 microl SCH-23390 bilaterally) in the vSUB impaired instrumental learning and performance, reduced break point in progressive ratio (PR) tests, and produced an intrasession decline in responding during test sessions, but had no effect on spontaneous motor or food-directed behavior. In contrast, D1 receptor blockade in the dSUB had no effect on instrumental learning, performance, PR break point, or food-directed behavior, but reduced spontaneous motor behavior. These results suggest a dissociation between the vSUB and dSUB with respect to the role of dopamine in various aspects of motivated and motor behavior. Further, D1 activation in the vSUB may be a critical component of motivational arousal associated with learned contextual cues.