Faculty Bibliography

Safety signals (SSs) have been shown to reinforce instrumental avoidance behavior due to their ability to signal the absence of an aversive event; however, little is known of their neural mediation. This study investigated whether infusions of d-amphetamine in the nucleus accumbens (Nac), previously shown to potentiate responding for appetitive conditioned reinforcers (CRfs), also regulate avoidance responding for a SS. Rats were trained on a free-operant task in which lever-press responses avoided shock and were reinforced with an auditory SS. Rats were then cannulated in the Nac core (NacC) or shell (NacS) and infused with d-amphetamine and, in separate NacS groups, other drugs, before extinction sessions with the SS present or absent following responding. Selective effects of d-amphetamine were found in the NacS, but not in the NacC, when the SS was present in the session. A significant increase in response rate during the presentation of the SS reflected a disruption of its fear-inhibiting properties. In parallel, a decrease in avoidance response rate reflected the reduced influence of the SS as a CRf. Inactivation of the NacS reduced avoidance responding only when the SS was present in the session, whereas the D1-D2 DA receptor antagonist alpha-flupenthixol reduced responding both before and during the SS regardless of the presence of the SS. Atomoxetine (ATO), a selective noradrenaline reuptake inhibitor, had no effect on responding. These results indicate a role for the NacS in the mediation of the conditioned reinforcing properties of a SS. These effects appear to be modulated by dopaminergic mechanisms but seem distinct from those previously reported with food-related CRfs.

RATIONALE: Serotonin-1A (5-HT1A) receptors modulate the stress response and have been implicated in the etiology and treatment of depression and anxiety disorders. A reduction in postsynaptic 5-HT1A receptor function in limbic areas has consistently been observed following exposure to chronic stress. OBJECTIVES: To investigate the hypothesis that increased activation of 5-HT1A receptors in rats having reduced 5-HT function may improve stress adaptation and the behavioral sequelae commonly associated with chronic stress. METHODS: One hundred forty-four Sprague-Dawley rats received injections of para-chlorophenylalanine to partially deplete 5-HT then were given daily systemic pretreatment with the 5-HT1A receptor agonist, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), the antagonist, WAY 100635, or vehicle prior to either restraint stress (6 h/day for 10 daily sessions) or control conditions. Anxiety- and depressive-like behaviors were then assessed using the open field and sucrose preference tests. Protein level of hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors was detected by immunohistochemistry and brain-derived neurotrophic factor (BDNF) was determined by in situ hybridization. RESULTS: 8-OH-DPAT pretreatment prior to stress exposure attenuated later stress-induced anxiety- and depression-like behaviors and increased GR and BDNF mRNA expression in the hippocampus relative to vehicle- and WAY 100635-pretreated, stressed animals. CONCLUSION: The stress-related impairments associated with 5-HT deficiency can be improved by 8-OH-DPAT pretreatment prior to stress exposure and are associated with an augmentation of GR-like immunoreactivity and BDNF mRNA expression in the hippocampus. It suggested that selective activation of 5-HT1A receptors may be a potential treatment strategy for stress-related disorders such as anxiety and depression.

The associative processes that support free-operant instrumental avoidance behavior are still unknown. We used a revaluation procedure to determine whether the performance of an avoidance response is sensitive to the current value of the aversive, negative reinforcer. Rats were trained on an unsignaled, free-operant lever press avoidance paradigm in which each response avoided or escaped shock and produced a 5 s feedback stimulus. The revaluation procedure consisted of noncontingent presentations of the shock in the absence of the lever either paired or unpaired with systemic morphine and in a different cohort with systemic d-amphetamine. Rats were then tested drug free during an extinction test. In both the d-amphetamine and morphine groups, pairing of the drug and shock decreased subsequent avoidance responding during the extinction test, suggesting that avoidance behavior was sensitive to the current incentive value of the aversive negative reinforcer. Experiment 2 used central infusions of D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO), a mu-opioid receptor agonist, in the periacqueductal gray and nucleus accumbens shell to revalue the shock. Infusions of DAMGO in both regions replicated the effects seen with systemic morphine. These results are the first to demonstrate the impact of revaluation of an aversive reinforcer on avoidance behavior using pharmacological agents, thereby providing potential therapeutic targets for the treatment of avoidance behavior symptomatic of anxiety disorders.

The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu) meeting. A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits.

The automated touchscreen operant chamber for rats and mice allows for the assessment of multiple cognitive domains within the same testing environment. This protocol presents the location discrimination (LD) task and the trial-unique delayed nonmatching-to-location (TUNL) task, which both assess memory for location. During these tasks, animals are trained to a predefined criterion during approximately 20-40 daily sessions. In LD sessions, touching the same location on the screen is rewarded on consecutive trials, followed by a reversal of location-reward contingencies. TUNL, a working memory task, requires animals to 'nonmatch' to a sample location after a delay. In both the LD and TUNL tasks, spatial similarity can be varied, allowing assessment of pattern separation ability, a function that is thought to be performed by the dentate gyrus (DG). These tasks are therefore particularly useful in animal models of hippocampal, and specifically DG, function, but they additionally permit discernment of changes in pattern separation from those in working memory.

This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents. Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies.

RATIONALE: Although high anxiety is commonly associated with drug addiction, its causal role in this disorder is unclear. OBJECTIVES: In light of strong evidence for dissociable neural mechanisms underlying heroin and cocaine addiction, the present study investigated whether high anxiety predicts the propensity of rats to lose control over intravenous cocaine or heroin self-administration. METHODS: Sixty-four rats were assessed for anxiety in the elevated plus-maze, prior to extended access to intravenous cocaine or heroin self-administration. RESULTS: High-anxious rats, identified in the lower quartile of the population, showed a greater escalation of cocaine, but not heroin, self-administration compared with low-anxious rats selected in the upper quartile of the population. Anxiety scores were also positively correlated with the extent of escalation of cocaine self-administration. CONCLUSIONS: The present data suggest that high anxiety predisposes rats to lose control over cocaine-but not heroin-intake. High anxiety may therefore be a vulnerability trait for the escalation of stimulant but not opiate self-administration.

RATIONALE: Previous work has demonstrated a profound effect of N-methyl-D: -aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear. OBJECTIVES: This series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output. METHODS: Drugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL. RESULTS: Systemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-L: -phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor DL: -threo-beta-benzyloxyaspartate as well as local alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABA(A) receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABA(A) receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL. CONCLUSIONS: These findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism.

Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the alpha2-adrenergic agonist guanfacine and the D(1)/D(2) antagonist alpha-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by alpha-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.

RATIONALE: Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking ('sensation seeking') are also widely present. However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood. OBJECTIVE: The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats. METHODS: Rats were screened on the five-choice serial reaction time task (5-CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR). Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure. Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats. RESULTS: SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats. However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels. By contrast, diazepam (0.3-3 mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals. CONCLUSIONS: This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction.