Timeout Responses Research Articles

Design and implementation of student work management system in the context of deep learning

Abstract This paper aims to analyze and design the system’s functions by student work management requirements, focusing on the business and user modules. The security testing algorithm based on the deep learning model verifies the system’s operation, analyzes the adversarial sample attack in image and text scenarios, and uses a black-box-white-box attack algorithm and defense algorithm for system security testing. Perform environment testing, compatibility testing, data response performance testing, and instance model evaluation for implementing the student work management system. Less than 500ms is the response time, over 400 requests are processed per second, and the timeout response rate is below 5%. The security evaluation coefficient was 66.982 for Example Model I and 74.628 for Example Model II, showing the system has good loadability and security.

Early environmental enrichment and impoverishment differentially affect addiction-related behavioral traits, cocaine-taking, and dopamine D2/3 receptor signaling in a rat model of vulnerability to drug abuse

RationaleRisk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D2/3-receptors (D2/3R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear.ObjectivesWe investigated the influence of early rearing environment on striatal D2/3R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in “addiction-prone” Roman high- (RHA) and “addiction-resistant” Roman low-avoidance (RLA) rats.MethodsAnimals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D2/3R availability and AMPH-induced DA release.ResultsEE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D2/3R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D2/3R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs.ConclusionOur results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D2/3R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals.

An SDN-based true end-to-end TCP for wireless LAN

Segment losses due to intermittent connectivity and mobility lead to sub optimal performance of the Transmission Control Protocol (TCP). This is due to the fact that segment loss is considered as a binary signal for triggering congestion control and retransmission mechanisms at the TCP sender. In wired networks, segments are dropped due to congestion at the routers and the strategy of taking missed acknowledgment as an implicit signal for congestion control performs well. However, in wireless networks, segment losses are primarily due to mobility and transmission errors. Unlike many previous efforts, this paper proposes the design and implementation of Software Defined Network (SDN) assisted TCP which does not require the wireless Access Points (APs) to be TCP-aware and preserves end to end semantics. Further, no changes are required to be done in TCP protocol implementation at the end-hosts. The proposed approach utilizes the programmability provided by the SDN paradigm to intelligently trigger the spurious timeout detection and response algorithms, already implemented in standard TCP. The proposed approach is compared with the standard TCP and SDN assisted Zero Window based approach on Linux kernels using virtual data-plane switches and APs provided by the Mininet-WiFi platform. The implementation results establish the applicability of the proposed approach.

Research on Multi-task Scheduling Algorithm for Integrated Energy Metering Acquisition System

With the development of the energy Internet and the construction of a new energy measurement system, it is particularly important to promote the remote automatic collection and copying of water, gas, heat and electricity. Based on the electricity information collection system, this paper designs an integrated acquisition technology architecture system for electricity, water, gas and thermal energy measurement, and clarifies the technical route of the energy measurement system. Then, through the analysis of the system task classification, a multi-task adaptive real-time scheduling method based on Spark cluster is proposed, which solves the problem that the collection system has uneven task allocation, long overall task completion time and high priority based on the existing scheduling mechanism of the Spark cluster. The task timeout response causes problems such as poor user experience. Finally, the experimental results show that the total number of 2 million collection tasks are divided into six categories, and the default scheduling methods in the text and Spark are used for comparison. The time-based and priority-critical tasks are completed earlier than the default method. The response speed greatly improves the system user experience and effectively improves the level of social public services.

Underlying and Persistence Fault Diagnosis in Wireless Sensor Networks Using Majority Neighbors Co-ordination Approach

The faults in wireless sensor network are classified according to the underlying causes, behavior, and persistence with respect to the observation time. Due to underlying causes, faults are classified as fail and stop, crash, omission, timing, and incorrect computation fault. Due to behavior, faults are classified as hard and soft fault. Due to persistence, faults are classified as permanent, intermittent, and transient fault. As the recent state-of-art fault diagnosis is a significant requirement for each application of wireless sensor network. In this research paper, we have proposed a fault diagnosis protocol using majority neighbors coordination based approach for wireless sensor network. Precisely, a multiple-hop data received technique, timeout period mechanism, timeout request and response message exchange, timeout early and delay message exchange, and degree of belongingness using Gaussian function mechanism are used for the detection of faults such as fail and stop, crash, omission, timing, and incorrect computation. The mean difference and standard error comparison with different threshold condition are used for soft (permanent, intermittent, and transient) fault detection, and timeout response mechanism with different threshold condition is used for hard (permanent, intermittent, and transient) fault detection. After fault detection, the actual fault status of the sensor node is confirmed by the one-hop majority neighbor sensor nodes. For validation of the proposed fault detection algorithms, simulation experiments are conducted by the network simulator NS-2.35. The experimental results show the substantially parameters performance such as fault detection accuracy, false alarm rate, false positive rate, and false classification rate with increasing the fault probability for different average degree of the sensor nodes in the network.

The Effects of Cariprazine and Aripiprazole on PCP-Induced Deficits on Attention Assessed in the 5-Choice Serial Reaction Time Task

RationaleAttentional processing deficits are a core feature of schizophrenia, likely contributing to the persistent functional and occupational disability observed in patients with schizophrenia. The pathophysiology of schizophrenia is hypothesized to involve dysregulation of NMDA receptor-mediated glutamate transmission, contributing to disruptions in normal dopamine transmission. Preclinical investigations often use NMDA receptor antagonists, such as phencyclidine (PCP), to induce cognitive disruptions relevant to schizophrenia. We sought to test the ability of partial dopamine D2/D3 agonists, cariprazine and aripiprazole, to attenuate PCP-induced deficits in attentional performance.ObjectivesThe objective of this study is to determine whether systemic administration of cariprazine or aripiprazole attenuated 5-choice serial reaction time task (5-CSRTT) deficits induced by repeated exposure to PCP.MethodsWe utilized a repeated PCP-treatment regimen (2 mg/kg, subcutaneous [s.c.], once daily for 5 days) in rats to induce deficits in the 5-CSRTT. Rats were pre-treated with cariprazine (0.03, 0.1, or 0.3 mg/kg, oral [p.o.]) or aripiprazole (1, 3, or 10 mg/kg, p.o.) to determine whether they prevented PCP-induced deficits in the 5-CSRTT performance.ResultsPCP treatment increased inappropriate responding in the 5-CSRTT, elevating incorrect, premature, and timeout responses. Cariprazine treatment reduced PCP-induced increases in inappropriate responding. However, at higher doses, cariprazine produced non-specific response suppression, confounding interpretation of the attenuated PCP-induced deficits. Aripiprazole treatment also attenuated PCP-induced deficits; however, unlike cariprazine treatment, aripiprazole reduced correct responding and increased omissions.ConclusionsCariprazine and aripiprazole both demonstrated potential in attenuating PCP-induced deficits in the 5-CSRTT performance. While both compounds produced non-specific response suppression, these effects were absent when 0.03 mg/kg cariprazine was administered.

Frontostriatal systems comprising connections between ventral medial prefrontal cortex and nucleus accumbens subregions differentially regulate motor impulse control in rats.

Deficits in impulse control are prevalent in several neuropsychiatric disorders that are based on impaired frontostriatal communication. The ventral medial prefrontal cortex (vmPFC) and the nucleus accumbens (NAc) are key substrates of impulse control in rats. The NAc core and shell are considered to be differentially involved suggesting a functional distinction between the connections of the vmPFC and particular NAc subregions concerning impulse control. In the present study, simultaneous inactivation of the rats' vmPFC and NAc core or shell by contralateral microinfusion of the GABAA receptor agonist muscimol was used to investigate their relevance for impulse control in the five-choice serial reaction time task (5-CSRTT). Disconnection of the vmPFC and NAc shell produced specific impairments in inhibitory control, indicated by significantly increased premature responding and an enhanced number of time-out responses, closely resembling the effects of bilateral inactivation of either the vmPFC or NAc shell previously reported using the same task. In contrast, disconnection of the vmPFC and NAc core only slightly increased the rate of omissions and latency of reward collection indicating attentional and motivational deficits. Our results extend previous findings indicating the functional specialisation of frontostriatal networks and show a differential contribution of specific vmPFC-NAc connections to behavioural control depending on the NAc subregion. We conclude that the regulation of impulse control in rats requires an intact connection between the vmPFC and the NAc shell, while the vmPFC-NAc core projection seems to be of minor importance.

Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models

There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorders and other neuropsychiatric conditions. The purpose of this study was to evaluate guanfacine for its ability to attenuate behavioral alterations associated with acute cocaine exposure in rats trained to perform a task of sustained attention, the five choice serial reaction time task (5C-SRTT) and monkeys trained to perform a task of working/short term memory, the delayed match to sample (DMTS) task. In the rodent 5C-SRTT acute intraperitoneal (i.p.) administration of cocaine (3.5–15.0mg/kg) did not affect accuracy, but was associated with dose-dependent increases in premature responses and timeout responses. Guanfacine (0.1–1.0mg/kgi.p.) dose-dependently decreased premature responses and timeout responses associated with cocaine and it attenuated similar deficits in inhibitory response control observed in a variable ITI version of the 5C-SRTT. In the DMTS task in monkeys, acute intramuscular (i.m.) administration of cocaine (4.0mg/kg) was associated with impairments in accuracy at long delay intervals, an effect that was attenuated by guanfacine (0.4mg/kg). These animal studies suggest that guanfacine may have therapeutic potential for treating impairments of executive function that are associated with the abuse of cocaine.

Repeated exposures to diisopropylfluorophosphate result in impairments of sustained attention and persistent alterations of inhibitory response control in rats

Organophosphate (OP)-based chemicals are used worldwide for many purposes and they have likely saved millions of people from starvation and disease. However, due to their toxicity they can also pose a significant environmental risk. While considerable research has focused on the acute symptoms and long-term consequences of overtly toxic exposures to OPs, less attention has been given to the subject of repeated exposures to levels that are not associated with acute symptoms (subthreshold exposures). There is clinical evidence indicating that this type of OP exposure can lead to prolonged deficits in cognition; however only a few studies have addressed this issue prospectively in animal models. In this study, repeated subthreshold exposures to the OP nerve agent diisopropylfluorophosphate (DFP) were evaluated in a 5-Choice Serial Reaction Time Task (5C-SRTT), an animal model of sustained attention. Adult rats were trained to stably perform the 5C-SRTT and then injected subcutaneously with vehicle or DFP of 0.5mg/kg every other day for 30days. Behavioral testing occurred daily during the DFP-exposure period and throughout a 45day (OP-free) washout period. Compared to vehicle-treated controls, DFP-treated rats exhibited deficits in accuracy, increases in omissions and timeout responses during the OP exposure period, while no significant effects on premature responses, perseverative responses, or response latencies were noted. While the increase in timeout responses remained detectible during washout, all other DFP-related alterations in 5C-SRTT performance abated. When the demands of the task were increased by the presentation of variable intertrial intervals, premature responses were also elevated in DFP-treated rats during the washout period. These results indicate that repeated exposures to subthreshold doses of DFP lead to reversible impairments in sustained attention as well as persistent impairments of inhibitory response control in rats.

Differential Long-Term Effects of Haloperidol and Risperidone on the Acquisition and Performance of Tasks of Spatial Working and Short-Term Memory and Sustained Attention in Rats

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the second-generation antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15-60 and 84-320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non-match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsive-type behaviors, and impair cognitive flexibility.

ASSESSING THE ROLE OF EFFORT REDUCTION IN THE REINFORCING EFFICACY OF TIMEOUT FROM AVOIDANCE

Rats responded on concurrent schedules of shock-postponement or deletion (avoidance) and timeout from avoidance. In Experiment 1, 3 rats' responses on one lever postponed shocks for 20 s and responses on a second lever produced a 1-min timeout according to a variable-interval 45-s schedule. Across conditions, a warning signal (white noise) was presented 19.5 s, 16 s, 12 s, 8 s, or 4 s before an impending shock. Raising the duration of the warning signal increased both avoidance and timeout response rates. Timeout responding, although positively correlated with avoidance responding, was not correlated with the prevailing shock rate. In Experiment 2, 3 rats' responses on one lever deleted scheduled shocks according to a variable-cycle 30-s schedule and responses on a second lever produced a 2-min timeout as described above. After this baseline condition, the avoidance lever was removed and noncontingent shocks were delivered at intervals yoked to the receipt of shocks in the baseline sessions. Timeout responding decreased when the avoidance lever was removed, even though the shock-frequency reduction afforded by the timeout remained constant. These results suggest that a key factor in the reinforcing efficacy of timeout is suspension of the requirement to work to avoid shock, rather than the reduction in shock frequency associated with timeout.

Variable prenatal stress results in impairments of sustained attention and inhibitory response control in a 5-choice serial reaction time task in rats

Rats repeatedly exposed to variable prenatal stress (PNS) exhibit schizophrenia-like behavioral signs such as social withdrawal, elevations in amphetamine-induced locomotor activity, deficits in sensory-motor gating, as well as impairments in memory-related task performance. However, to date there have been no studies designed to test the hypothesis that variable PNS would lead to disruptions in sustained attention and inhibitory response control (i.e., symptoms also commonly observed in schizophrenia and other neuropsychiatric disorders such as attention-deficit hyperactivity disorder). In the current study, the effects of variable PNS in rats were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a 5-choice serial reaction time task (5C-SRTT). In a separate series of experiments, the glutamate (N-methyl-d-aspartate [NMDA]) antagonist, MK-801 (0.025–0.05mg/kg), and the norepinephrine reuptake inhibitor, atomoxetine (0.30–3.0mg/kg), were administered acutely to assess the sensitivity of PNS subjects to glutamatergic and noradrenergic manipulations. The results indicated that exposure to variable PNS significantly impaired accuracy in the VSD version of the 5C-SRTT and increased premature and timeout responses in the VITI version. In addition, both doses of MK-801 impaired accuracy, increased premature and timeout responses in PNS, but not control subjects. In contrast, atomoxetine decreased premature and timeout responses in both PNS and control subjects in the VITI version of the task and improved accuracy in the PNS subjects. The results suggest that exposure to variable PNS in rats results in impairments of sustained attention and inhibitory response control and that these deficits can be exacerbated by NMDA antagonism and improved by a norepinephrine uptake inhibitor. Collectively, these data further support the premise that variable PNS in rats is a valid model system for the study of neuropsychiatric disorders and their treatment.

The nicotine metabolite, cotinine, attenuates glutamate (NMDA) antagonist-related effects on the performance of the five choice serial reaction time task (5C-SRTT) in rats

Cotinine, the most predominant metabolite of nicotine in mammalian species, has a pharmacological half-life that greatly exceeds its precursor. However, until recently, relatively few studies had been conducted to systematically characterize the behavioral pharmacology of cotinine. Our previous work indicated that cotinine improves prepulse inhibition of the auditory startle response in rats in pharmacological impairment models and that it improves working memory in non-human primates. Here we tested the hypothesis that cotinine improves sustained attention in rats and attenuates behavioral alterations induced by the glutamate (NMDA) antagonist MK-801. The effects of acute subcutaneous (dose range 0.03–10.0mg/kg) and chronic oral administration (2.0mg/kg/day in drinking water) of cotinine were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a five choice serial reaction time task (5C-SRTT). The results indicated only subtle effects of acute cotinine (administered alone) on performance of the 5C-SRTT (e.g., decreases in timeout responses). However, depending on dose, acute treatment with cotinine attenuated MK-801-related impairments in accuracy and elevations in timeout responses, and it increased the number of completed trials. Moreover, chronic cotinine attenuated MK-801-related impairments in accuracy and it reduced premature and timeout responses when the demands of the task were increased (i.e., by presenting VSDs or VITIs in addition to administering MK-801). These data suggest that cotinine may represent a prototype for compounds that have therapeutic potential for neuropsychiatric disorders (i.e., by improving sustained attention and decreasing impulsive and compulsive behaviors), especially those characterized by glutamate receptor alterations.

Attention, impulsivity, and cognitive flexibility in adult male rats exposed to ethanol binge during adolescence as measured in the five-choice serial reaction time task: the effects of task and ethanol challenges

Alcohol abuse is prevalent in adolescent humans, but the long-term behavioral consequences of binge alcohol drinking are unknown. This study investigated the long-term effects of adolescent intermittent ethanol (AIE) exposure on attention and impulsivity. Adolescent male rats were exposed to 5 g/kg of 25% (v/w) ethanol every 8 h for 4 days. During adulthood, rats were tested in the five-choice serial reaction time task (5-CSRTT) assessing attention, impulsivity and cognitive flexibility. There was no metabolic tolerance to ethanol in adolescent rats during AIE exposure. In the 5-CSRTT under baseline conditions, there were no differences between AIE-exposed and control rats in accuracy, omissions, or premature responses, although AIE-exposed rats tended to make more timeout responses than control rats. The short-duration stimulus challenge decreased accuracy and increased omissions and timeout responses in both AIE-exposed and control rats. The long intertrial interval challenge increased premature responses in all rats. An ethanol challenge decreased correct responses, and increased omissions in control, but not in AIE-exposed, rats. Control, but not AIE-exposed, rats exhibited decreased premature and timeout responses after ethanol administration. Response latencies were not affected in AIE-exposed or control rats indicating no sedative effects of ethanol challenge. The results indicate that ethanol binge exposure during adolescence has long-lasting neurobehavioral consequences, which persist into adulthood and can be revealed after re-exposure to ethanol. AIE-induced diminished responses to the disruptive effects of ethanol on attention, impulsivity and cognitive flexibility may lead to increased alcohol drinking and other maladaptive behaviors in adulthood.

Comparative effects of different test day challenges on performance in the 5-choice serial reaction time task.

The 5-choice serial reaction time task (5-CSRTT) is a valuable cognitive test that permits the simultaneous assessment of several different cognitive modalities, including attention, impulse control, processing speed, and cognitive flexibility. Increasing task difficulty on test days through various challenges can further enhance the versatility of this test by selectively enhancing the cognitive load on different aspects of the task. Systematic comparisons of the effects of different test day challenges on 5-CSRTT performance are essential to verify how these challenges affect different task measures and which manipulations are best suited for future studies of different aspects of cognition. We trained Wistar rats in the 5-CSRTT under standard conditions, then challenged them on the test days by (1) decreasing the duration of the stimulus to be detected, (2) increasing the time interval between trials (intertrial interval, ITI), (3) randomly varying the ITI, or (4) adding a flashing light distractor. All test day challenges produced distinct profiles of performance disruption that reflected differential effects on different cognitive modalities. Decreased stimulus duration selectively impaired attentional performance, while increased ITI increased impulsive-like premature responses and decreased trials completed. Variable ITI induced only mild, nonsignificant disruptions in response inhibition and processing speed, while the flashing light distractor produced comprehensive impairment affecting multiple aspects of 5-CSRTT performance, including disrupted attention and increased premature and timeout responses. This improved understanding of the effects of different test day challenges in the 5-CSRTT will allow researchers to use these manipulations of a valuable cognitive test to their full potential.

The modified Geller–Seifter test in rats was insensitive to GABAB receptor positive modulation or blockade, or 5-HT1A receptor activation

RationaleBoth the GABAB receptor positive modulator GS39783 and the GABAB receptor antagonist CGP46381 exhibit anxiolytic-like properties in animal models. In the present studies, the effects of GS39783 and CGP46381 in the modified Geller–Seifter task were assessed. First, the predictive validity of the task was confirmed by assessing the effects of multiple anxiolytic and non-anxiolytic compounds on punished and unpunished responding. MethodsRats were trained in the modified Geller–Seifter task. After successful acquisition of the task, chlordiazepoxide, diazepam, MPEP, haloperidol, GS39783, 8-OH-DPAT, alprazolam and CGP46381 were tested consecutively. For each test compound, doses were administered in a randomized, counter-balanced, within-subjects design. Drug tests were performed only when rats exhibited baseline performance (the punished and time-out response rates were less than 10% of the unpunished response rate). ResultsChlordiazepoxide, diazepam, alprazolam and MPEP released punished responding with variable effects on unpunished responding. Haloperidol had a small but significant effect on punished responding at an intermediate dose, and decreased unpunished responding at the highest dose tested. In contrast, administration of the GABAB receptor positive modulator GS398783 or the GABAB receptor antagonist CGP46381 at doses up to 30mg/kg had no effects on either punished or unpunished responding. The 5-HT1A agonist 8-OH-DPAT did not release punished responding, but significantly decreased unpunished responding at the highest dose tested. SummaryThe modified Geller–Seifter task generally exhibits good predictive validity for anxiolytic-like compounds. Neither GABAB receptor positive allosteric modulation nor blockade exhibited anxiolytic-like properties in the modified Geller–Seifter task. The 5-HT1A partial agonist buspirone was similarly ineffective.

Clozapine attenuates disruptions in response inhibition and task efficiency induced by repeated phencyclidine administration in the intracranial self-stimulation procedure

Currently available antipsychotic medications lack satisfactory effectiveness against several symptom clusters of schizophrenia, including affective symptoms (e.g., anhedonia) and cognitive deficits (e.g., impulsivity). Translational animal models analogous to these symptoms are necessary to provide insights into the neurobiological events underlying these impairments and allow the development of improved schizophrenia treatments. We investigated the effects of repeated administration of the psychotomimetic phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, on performance in the intracranial self-stimulation (ICSS) procedure, a test of reward function. We also explored how chronic treatment with clozapine, an atypical antipsychotic with limited effectiveness on affective and cognitive schizophrenia symptoms, would affect PCP-induced disruptions of ICSS performance. A single injection of 2 mg/kg PCP elevated ICSS thresholds, suggesting a reward deficit. Repeated PCP administration (2 mg/kg once daily for 2 consecutive days followed by a 10-day drug free period, and then 5 consecutive days of 2 mg/kg PCP daily, s.c., 30 min pretreatment) resulted in a small, but significant, lowering of ICSS reward thresholds, indicating increased reward function. Chronic clozapine did not alter the effects of repeated PCP on ICSS thresholds. Repeated PCP also increased the number of extra and timeout responses performed during the ICSS procedure, reflecting disinhibition of inappropriate responding and decreased task efficiency. Chronic clozapine attenuated the increase in extra responses induced by repeated PCP and tended to reduce the PCP-induced increase in timeout responses. These results suggest that repeated PCP administration does not produce an anhedonia-like state resembling that seen in schizophrenia. However, the increased impulsivity and reduced task efficiency seen with repeated PCP administration, and the sensitivity of these effects to attenuation with an atypical antipsychotic, suggest that repeated PCP administration may be a useful inducing condition for eliciting cognitive deficits with relevance to schizophrenia.

CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist

The present studies were designed to investigate the effects of corticotropin-releasing factor (CRF) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a discrete-trial current-intensity threshold procedure. Bipolar electrodes were implanted in the lateral hypothalamus, and cannula guides were implanted above the lateral ventricle of male Wistar rats. Dose-effect functions were established for the effects on ICSS of the competitive CRF receptor agonist h/rCRF (0–5.0 μg, i.c.v.), the CRF receptor agonist urocortin (0–5.0 μg, i.c.v.), and the CRF receptor antagonist [ d-Phe 12, Nle 21,38, C α MeLeu 37] h/rCRF 12–41 (0–5.0 μg, i.c.v.). Administration of h/rCRF or urocortin dose-dependently elevated ICSS thresholds without altering performance measures (latencies to respond to stimulation, extra and time-out responses). CRF was more potent than urocortin in terms of threshold dose-effects on ICSS thresholds compared to vehicle. Despite these apparent potency differences, percent effect sizes on ICSS thresholds were comparable at the highest doses of both peptides. In contrast to the significant threshold elevation effects of CRF and urocortin, the competitive CRF antagonist d-Phe CRF 12–41 had no effect on ICSS thresholds or performance measures. To determine the neuropharmacological specificity of the effect of CRF on brain stimulation reward, d-Phe CRF 12–41 was used to antagonize CRF-induced threshold elevations. Pretreatment with either the 5.0- or 10.0-μg doses of d-Phe CRF 12–41 effectively blocked CRF-induced reward threshold elevations (3.0 μg) without affecting other ICSS performance measures. These results indicate that CRF neurotransmission can modulate ICSS reward processes.

The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug.

In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 microg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did saline-pre-exposed rats. These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli associated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed.

D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug.

Prior exposure to amphetamine leads to sensitized locomotor responding to subsequent injections and an enhanced predisposition to self-administer low doses of the drug. Because D1 dopamine (DA) receptors have been shown to play an important role in the development of sensitized locomotor responding to amphetamine, the present experiment assessed their contribution to the development of facilitated amphetamine self-administration produced by prior exposure to the drug. During a pre-exposure phase, rats were administered two injections on each of 10 consecutive days. The first injection (saline, 1 ml/kg, i.p., or the D1 DA receptor antagonist SCH23390, 0.04 mg/kg, s.c.) preceded the second (saline or amphetamine, 1.5 mg/kg, i.p.) by 30 min. Starting 10 days after the last injection, animals were given the opportunity to lever press for a low dose of amphetamine (10 microg/kg per infusion) in a two-lever (active versus inactive) continuous reinforcement operant task, in each of seven daily sessions. Consistent with previous reports, prior exposure to amphetamine resulted in an increase in active versus inactive lever pressing. Blocking D1 DA receptors with SCH23390 prior to each of the amphetamine pre-exposure injections prevented the development of this enhanced self-administration of amphetamine. When animals were grouped according to their locomotor response to a novel environment (assessed prior to the experiment), it was found, again in agreement with previous reports, that enhanced drug self-administration (as indicated by increased active versus inactive lever pressing as well as shorter latencies to emit the first active lever press, shorter inter-response times and more time-out responses on this lever) was observed only in amphetamine pre-exposed rats that had shown a locomotor response to novelty above the median of the subject sample (high responders). Preceding the amphetamine pre-exposure injections with SCH23390 blocked the development of enhanced drug self-administration observed in these animals. These findings, indicating that manipulations known to block the induction of locomotor and dopaminergic sensitization by amphetamine also block the facilitation of drug self-administration, suggest an important and common role for D1 DA receptor activation in the development of enhanced responding to and for drug.