Days Of Preexposure Research Articles

Pre-exposure cognitive performance variability is associated with severity of respiratory infection

Using data from a longitudinal viral challenge study, we find that the post-exposure viral shedding and symptom severity are associated with a novel measure of pre-exposure cognitive performance variability (CPV), defined before viral exposure occurs. Each individual’s CPV score is computed from data collected from a repeated NeuroCognitive Performance Test (NCPT) over a 3 day pre-exposure period. Of the 18 NCPT measures reported by the tests, 6 contribute materially to the CPV score, prospectively differentiating the high from the low shedders. Among these 6 are the 4 clinical measures digSym-time, digSym-correct, trail-time, and reaction-time, commonly used for assessing cognitive executive functioning. CPV is found to be correlated with stress and also with several genes previously reported to be associated with cognitive development and dysfunction. A perturbation study over the number and timing of NCPT sessions indicates that as few as 5 sessions is sufficient to maintain high association between the CPV score and viral shedding, as long as the timing of these sessions is balanced over the three pre-exposure days. Our results suggest that variations in cognitive function are closely related to immunity and susceptibility to severe infection. Further studying these relationships may help us better understand the links between neurocognitive and neuroimmune systems which is timely in this COVID-19 pandemic era.

Optimisation of CAFE assay for the evaluation of ethanol preference in Drosophila melanogaster

Alcohol is one of the most harmful psychoactive drugs which can cause various medical, physical, social, financial, and work-related problems. The fruit fly Drosophila melanogaster has been proposed to be a useful model to explore alcohol-induced behavioural, cellular and molecular mechanisms. The capillary feeder assay (CAFE) has been used to measure the development of preference for alcohol that is observable in Drosophila as well in mammals including humans. The aim of this study was to investigate and optimize the CAFE assay to validate further studies using this technique. The parameters that were investigated were: the ethanol concentration and length of exposure, both during pre-exposure and during the preference assay, and whether the sex of the flies affected the outcome. The results indicate that a minimum of two days of pre-exposure of 15% ethanol is required to induce preference for 15% vs 5% ethanol, while there was no significant difference in extending the preference assay beyond two hours and males and females flies behaved in similar manner. Overall these results further validate and better define the usefulness of the CAFE assay for the measurement of alcohol preference in Drosophila as a method to explore the mechanisms of preference which may apply also to higher organisms.

Medial prefrontal and ventral hippocampal contributions to incidental context learning and memory in adolescent rats.

The Context Preexposure Facilitation Effect (CPFE) is a contextual fear conditioning (CFC) paradigm in which context learning, context-shock learning, and retrieval of contextual fear occur in three distinct phases. The medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and ventral hippocampus (vHPC) are required for the acquisition and/or consolidation of a context representation during incidental context exposure (Heroux et al., 2017; Robinson-Drummer et al., 2016; Rudy & Matus-Amat, 2006). This exposure also induces the expression of the immediate early genes (IEGs) c-Fos, Arc, Egr-1, and Npas4 in these regions (Heroux et al., 2018, 2019). Despite these studies, it is still unclear how mPFC and vHPC contribute to incidental context learning and memory. The current study examined whether prefrontal or ventral hippocampal inactivation during context preexposure interferes with long-term context memory and IEG activity in the mPFC, vHPC, dHPC and the ventral midline thalamus (VMT, a region connected to both the mPFC and HPC). Adolescent Long-Evans rats were given intra-mPFC (Experiment 1) or intra-vHPC (Experiment 2) infusions of the GABAA receptor agonist muscimol or PBS prior to context preexposure, and then were sacrificed 30 min later and whole mPFC, dHPC, vHPC, and VMT were collected and assayed for IEG mRNA expression via qPCR. Prefrontal or ventral hippocampal inactivation during context exposure abolished subsequent post-shock and retention test freezing in behaviorally-tested littermates of the sacrificed groups. In Experiment 1, prefrontal inactivation reduced expression of c-Fos, Arc, Egr-1, and Npas4 in the mPFC, c-Fos, Arc, and Npas4 in the vHPC, and c-Fos in the VMT, to the level of behaviorally-naïve home-cage controls. Prefrontal inactivation did not alter IEG expression in the dHPC during context exposure. In Experiment 2, ventral hippocampal inactivation impaired expression of all IEGs in the mPFC, dHPC, and vHPC, with no effect in the VMT. Taken together, these results suggest that context memory processes on the preexposure day of the CPFE may depend on mPFC-vHPC circuitry not typically emphasized in studies of incidental or configural learning and memory.

Age and experience dependent changes in Egr-1 expression during the ontogeny of the context preexposure facilitation effect (CPFE)

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which acquisition of the contextual representation and association of the retrieved contextual memory with an immediate foot-shock are separated by 24 h. During the CPFE, learning- related expression patterns of the early growth response-1 gene (Egr-1) vary based on training phase and brain sub-region in adult and adolescent rats (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014; Chakraborty, Asok, Stanton, & Rosen, 2016). The current experiments extended our previous findings by examining Egr-1 expression in infant (PD17) and juvenile (PD24) rats during the CPFE using preexposure protocols involving single-exposure (SE) or multiple-exposure (ME) to context. Following a 5 min preexposure to the training context (i.e. the SE protocol), Egr-1 expression in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and lateral nucleus of the amygdala (LA) was differentially increased in PD24 rats relative to PD17 rats. In contrast, increased Egr-1 expression following an immediate foot-shock (2s, 1.5 mA) did not differ between PD17 and PD24 rats, and was not learning-related. Interestingly, increasing the number of exposures to the training chamber on the preexposure day (i.e. ME protocol) altered training-day expression such that a learning-related increase in expression was observed in the mPFC in PD24 but not PD17 rats. Together, these results illustrate a clear maturation of Egr-1 expression that is both age- and experience-dependent. In addition, the data suggest that regional activity and plasticity within the mPFC on the preexposure but not the training day may contribute to the ontogenetic profile of the effect. Further studies are necessary to elucidate the causal role of sub-region-specific neuroplasticity in the ontogeny of the CPFE.

Cholinergic mechanisms of the context preexposure facilitation effect in adolescent rats.

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which context learning, context-shock association, and expression of context conditioning occur in 3 separate phases-preexposure, training, and testing. During the preexposure phase, the CPFE is disrupted by hippocampal NMDA receptor blockade in juvenile rats (Schiffino et al., 2011), and a similar deficit is seen with a subcutaneous injection of the muscarinic receptor antagonist, scopolamine, in adult mice (Brown, Kennard, Sherer, Comalli, & Woodruff-Pak, 2011). As a foundation for further developmental research, the present study examined the role of cholinergic function in the CPFE in adolescent rats during each phase of the CPFE protocol. In Experiment 1, an i.p injection of either 0.5 or 1.0 mg/kg dose of scopolamine administered prior to all 3 phases of the CPFE protocol impaired the CPFE. Experiment 2 further showed that a 0.5 mg/kg injection prior to just 1 of the 3 phases of the CPFE also disrupted contextual fear conditioning. We further showed that the CPFE is impaired by localized scopolamine infusions into dorsal hippocampus on the preexposure day (Experiment 3a), training day (Experiment 3b), and test day (Experiment 3c). These findings demonstrate a role of cholinergic signaling in hippocampus during each of the 3 phases of the CPFE in adolescent rats. Implications for the development and neural basis of the CPFE are discussed. (PsycINFO Database Record

The novel dopamine D3 receptor antagonist, SR 21502, reduces cocaine conditioned place preference in rats

Research has shown that dopamine (DA) D3 receptors play a crucial role in cocaine addiction. Recently, there has been a strong focus on the development of DA D3 receptor antagonists as potential pharmacological treatments for cocaine addiction. We investigated the ability of a novel selective D3 receptor antagonist SR 21502 to block the expression of cocaine-induced conditioned place preference (CPP) in rats. CPP was determined using a two-chamber apparatus. All of the animals had free access to both chambers on day 1, followed by 4 alternating conditioning days of cocaine injection (paired chamber) and 4 alternating non-conditioning days with saline (non-paired chamber). On the test day, animals were systemically treated with 0, 3.75, 7.5 or 15mg/kg of SR 21502, 10min prior to being placed in the CPP apparatus, and the time spent in each chamber was recorded for 15min. The amount of time spent in the cocaine-paired chamber on the test and pre-exposure days was analyzed. Vehicle-treated animals spent significantly more time in the cocaine-paired side during the test than during the pre-exposure session, indicating a cocaine CPP. SR 21502 produced a dose-related significant reduction in the time spent in the cocaine-paired side compared to vehicle. The DA D3 receptor antagonist SR 21502 blocks the rat's preference for the cocaine-paired chamber, thereby attenuating the rewarding effect of the cocaine cues. This suggests that this compound may be an effective pharmacological treatment against cocaine addiction.

Chronic preexposure to methylphenidate cross-sensitizes methamphetamine in male Japanese quail

An increasing debate exists about the potential of exposure to methylphenidate increasing later risk of drug abuse. The objective of this study was to investigate whether chronic preexposure to methylphenidate would induce cross-sensitization to a subsequent methamphetamine challenge in male Japanese quail. Male quail were treated intraperitoneally with either 5, 10, or 20 mg/kg methylphenidate or saline for 14 days. After a 14-day washout period, birds were challenged with 5.6 mg/kg of methamphetamine. Methylphenidate-induced behavioral sensitization was not evident after 14 days of preexposure. However, locomotor activity was greater during the methamphetamine challenge in birds that were preexposed to a high dose of methylphenidate. The findings suggest that chronic preexposure to methylphenidate may be sufficient to alter later responding to methamphetamine, regardless of whether preexposure resulted in behavioral sensitization.

Repeated exposure to Δ 9-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

The present study examined the effect of chronic exposure to Δ 9-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats ( n = 60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups ( n = 12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups ( n = 6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naïve rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the Edinger–Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.

Nicotine-conditioned locomotor sensitization in rats: assessment of the US-preexposure effect

In rats, stimulus–nicotine associations can be altered by preexposure to the nicotine US (unconditioned stimulus). This alteration differs with the conditioning preparation. In a conditioned taste avoidance preparation, preexposure to nicotine weakens conditioning. In contrast, nicotine preexposure enhances acquisition of a nicotine-conditioned place preference. No one has examined the effects of US preexposure on nicotine locomotor conditioning. In three separate experiments, we assessed the effects of nicotine preexposure on the subsequent expression of conditioned hyperactivity produced by a nicotine US. We found evidence for nicotine-conditioned locomotor sensitization in non-preexposed rats that received repeated pairings of a distinct context with the psychomotor effects of a 0.42mg/kg dose of nicotine (free base). Conditioning was not observed at lower nicotine doses (0.18 and 0.11mg/kg) in non-preexposed rats. Preexposure to the 0.42 and 0.18mg/kg doses of nicotine (3 or 9 days) attenuated acute locomotor suppression and enhanced the development of locomotor sensitization to that same dose. Despite similar qualitative shifts in the locomotor profile induced by preexposure to the nicotine US, conditioned hyperactivity was only altered after 3 or 9 days of preexposure at the 0.18mg/kg dose. Thus, similar to place conditioning, nicotine preexposure can enhance the subsequent effectiveness of the nicotine US in a locomotor conditioning preparation.

Pre-exposure to wheel running disrupts taste aversion conditioning

When rats are given access to a running wheel after drinking a flavored solution, they subsequently drink less of that flavor solution. It has been suggested that running produces a conditioned taste aversion (CTA). This study explored whether CTA is eliminated by prior exposure to wheel running [i.e., unconditioned stimulus (UCS) pre-exposure effect]. The rats in the experimental group (UW) were allowed to wheel run for 1 h daily for seven consecutive days of pre-exposure. Rats in the two other groups had either access to locked wheels (LW group) or were maintained in their home cages (HC group) during the pre-exposure days. All rats were then exposed to four paired and four unpaired trials using a “ABBAABBA” design. Conditioning trials were composed of one flavored liquid followed by 60-min access to wheel running. For the unpaired trials, rats received a different flavor not followed by the opportunity to run. All rats were then initially tested for water consumption followed by tests of the two flavors (paired or unpaired) in a counterbalanced design. Rats in the UW group show no CTA to the liquid paired with wheel running, whereas LW and HC groups developed CTA. These results indicate that pre-exposure to wheel running (i.e., the UCS), eliminates subsequent CTA.

Chronic caffeine exposure in rats blocks a subsequent nicotine-conditioned taste avoidance in a one-bottle, but not a two-bottle test

Two experiments were conducted in order to investigate nicotine-conditioned taste avoidance (CTA) following chronic preexposure to caffeine. Rats were given daily intraperitoneal injections of caffeine anhydrous (0, 10, or 30 mg/kg) for 10 or 30 days. Training of the nicotine-CTA began after the last day of caffeine preexposure. On five separate occasions access to a saccharin solution was followed immediately by an injection of 1.2 mg/kg nicotine hydrogen tartrate salt or saline. Nicotine-CTA readily developed in saline-preexposed controls. That is, paired rats drank less saccharin solution than unpaired rats after repeated saccharin–nicotine pairings. A similar pattern of nicotine-CTA was found for rats preexposed to 30 mg/kg caffeine for 10 days. Following 10 days of preexposure to 10 mg/kg caffeine, however, CTA did not develop under standard testing conditions. Thirty days of caffeine preexposure did not affect the development of a nicotine-CTA even though the anorexic effects of caffeine were evident after exposure to 30 mg/kg for this duration. Thus, caffeine exposure appears to weaken acquisition or expression of the conditioned avoidance properties of nicotine. This effect is sensitive to the dose of caffeine and duration of preexposure. Importantly, the pattern of nicotine-CTA does not appear to be due to nonspecific effects of caffeine.

A neurotoxic lesion of serotonergic neurones using 5,7-dihydroxytryptamine does not disrupt latent inhibition in paradigms sensitive to low doses of amphetamine

Testing the effects of low doses of d-amphetamine on latent inhibition (LI) in two different conditioning paradigms, passive avoidance and conditioned taste aversion, provided evidence of their pharmacological equivalence. For passive avoidance, LI was expressed by the decreased latency to enter a shock compartment in preexposed rats placed 5 min in the compartment during 3 consecutive days before conditioning. In the conditioned taste aversion paradigm, a group of rats was preexposed to a solution of sucrose also for 3 consecutive days prior to the establishment of an association between sucrose and sickness elicited by an injection of LiCl. On the following day, the preexposed rats drunk more sucrose when allowed to choose between one tube containing water and an other containing sucrose. In both paradigms, 0.25 mg/kg d-amphetamine, injected daily on the 3 preexposure days and on the conditioning day, decreased LI. A dose of 0.5 mg/kg suppressed LI in the passive avoidance paradigm. The effect of a serotonergic lesion induced by i.c.v. injection of 5,7-dihydroxytryptamine (5,7-DHT) was evaluated in the same paradigms. The lesion procedure that lowered hippocampal serotonin and 5 HIAA levels by more than 80% did not affect LI. Taken together, the present results lessens the hypothesis that LI is prone to an opposing influence of the two monoaminergic systems considered in this work.

The Delayed Effects of Phencyclidine (Pcp) Disrupt Latent Inhibition in a Conditioned Taste Aversion Paradigm

The acute effects of a low dose of phencyclidine (PCP) and the delayed effects of a high dose of PCP on latent inhibition (LI) were assessed in a series of experiments using conditioned taste aversion paradigms. Each paradigm involved a preexposure phase in which water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with the negative reinforcer lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. The effects of low-dose PCP (2.5 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 15 min prior to the onset of the preexposure and conditioning phases. A 4-day paradigm involved 2 days of preexposure followed by a day of conditioning and a test day. This paradigm produced comparable levels of LI in vehicle and PCP-treated animals. A 5-day extinction paradigm involved 2 days of preexposure followed by 2 days of conditioning and a test day. This paradigm abolished LI in vehicle and PCP-treated animals. A 3-day paradigm involved 1 day of preexposure followed by a day of conditioning and a test day. One day of preexposure induced a modified LI effect in both in vehicle and PCP-treated animals. The delayed effects of high dose PCP (8.6 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 20 h prior to the onset of the preexposure and conditioning phases in the 4-day paradigm. PCP disrupted latent inhibition in this paradigm. The results are discussed in the context of their relevance to the ability for PCP to model schizophrenic symptomatology.

Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.

Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse.

The role of dopamine D1A receptors in mediating amphetamine-induced sensitization was investigated using the D1A-deficient mouse. During the drug pre-exposure phase, D1A-deficient and control mice were injected for five consecutive days with saline or amphetamine (2 mg/kg, i.p.). Locomotor activity was measured on the first and fifth pre-exposure day. After three abstinence days, mice were given either amphetamine or saline and locomotor activity was again assessed. Mice were then sacrificed and protein kinase A (PKA) activity was measured. In contrast to control mice, D1A-deficient mice did not show a progressive increase in locomotor activity across days. Importantly, both control and mutant mice did exhibit behavioral sensitization, because mice pre-exposed and tested with amphetamine were more active than mice acutely tested with the drug. Even so, the amphetamine-induced locomotor activity of the mutant mice was significantly reduced when compared with similarly treated control mice, indicating that the sensitized response was less pronounced in the D1A-deficient mouse. PKA activity also varied depending on genotype, since amphetamine decreased PKA activity in control but not D1A-deficient mice.

Cu uptake and turnover in both Cu-acclimated and non-acclimated rainbow trout (Oncorhynchus mykiss)

64Cu accumulation and total Cu concentration were measured in plasma, red blood cells, gills, liver, kidney and bile during 65h of exposure to 64Cu at 20μg of Cu per liter, in non acclimated and Cu acclimated (28 days of preexposure) rainbow trout (Oncorhynchus mykiss) fitted with a dorsal aortic catheter. By measuring both 64Cu accumulation and total Cu concentrations, we were able to analyse the ongoing uptake and turnover of ambient Cu, independent of any Cu already present in the fish.Plasma accounted for at least 90% of the 64Cu labelled Cu present in the blood and Cu-acclimation clearly involves changes in copper accumulation kinetics in the plasma. The acclimated fish showed a 65% reduced 64Cu accumulation after 65h and an increased turnover of Cu in the plasma compared to the non-acclimated fish. Total Cu in the plasma increased by 59% after 3h of exposure in the non-acclimated fish but was recovered during the following 24h and remained at control levels throughout 65h; even after 28 days the acclimated fish showed no increase in total plasma [Cu]. Apparently Cu acclimation involves an increased clearing of plasma Cu, primarily to the liver, stimulated during the first 12h of exposure.Acclimation did not have an unambiguous effect on branchial Cu uptake and differences in branchial uptake could not explain the reduced accumulation in the plasma. The rapidly exchangeable Cu pools were 54% in the gills and 33% in the liver, suggesting a considerable hepatic Cu elimination. No increase in the total [Cu] in the kidney was observed, but the kidney did show substantial 64Cu accumulation and thus also a potential renal Cu excretion.

Influence of preexposure to sublethal levels of copper on 64Cu uptake and distribution among tissues of the European eel ( Anguilla anguilla)

The effect of preexposure to copper was examined in European eels with respect to uptake and distribution of 64Cu among tissues. Eels were exposed in freshwater to 8 and 64 μg Cu · L −1 for 0, 6 and 28 days before 64Cu incubation. The accumulation of copper in gill, liver and muscle tissue was studied by the uptake of 64Cu during 67 hr of exposure to 8 and 64 μg · L −1. The Cu accumulation rate in muscle tissue was inversely related to bodyweight. Although the accumulation rates in liver and muscle tissues were significantly reduced after 6 and 28 days of preexposure to 64 μg · L −1 (but not to 8 μg · L −1), the accumulation rates in the gills were not affected by preexposure. We suggest that the excretion rate of copper was stimulated by the applied preexposure to 64 μg Cu · L −1.

文脈への先行さらしがラットの文脈・ショック条件づけに及ぼす効果

This experiment was conducted to examine the effects of contextual preexposure on the context-shock conditioning in rats. Seventy-two albino rats were first placed in an experimental chamber for 5 min without electric shock (contextual preexposure) for a few days (0, 1, 3 or 7 days), and then received a shock (1 mA, 2 s) with either 1 s (immediate-shock) or 180 s (delayed-shock) placement-shock internal. They were observed on the next day after the shock. The rats which experienced 3 days of preexposure exhibited freezing more frequently than those experienced 0 day and 1 day of preexposure. Seven days of preexposure decreased freezing. These results suggest the nonmonotonic effects of preexposure: the effects of facilitation and latent inhibition of conditional freezing

Role of the central benzodiazepine receptor system in behavioral habituation to novelty.

In this article we report the results of two experiments examining the role of central benzodiazepine receptor sites in the response to novelty. Animals that were food deprived and presented with food in a novel environment showed long latencies before they began eating. Pretreatment with diazepam or preexposure to the "novel" environment for 1 hr/day for 4 or 7 days before testing in that environment dramatically reduced the latency to begin eating. Administration of either the "inverse agonist," FG-7142, or an antagonist, RO15-1788, of the central benzodiazepine receptor before testing completely reversed the effects of 7 days of preexposure to the novel environment. In home-cage feeding tests, FG-7142, but not RO15-1788, increased the latency to begin feeding in food-deprived animals. These findings indicate that FG-7142 is strongly anxiogenic, whereas RO15-1788 is not anxiogenic, yet both drugs are potent in reversing the effects of habituation. The results of these experiments suggest that the normal process of habituation to novelty may involve the release of an endogenous, anxiolytic compound (an agonist) that binds to a central benzodiazepine receptor, the effects of which are blocked by RO15-1788.

Role of the central benzodiazepine receptor system in behavioral habituation to novelty.

In this article we report the results of two experiments examining the role of central benzodiazepine receptor sites in the response to novelty. Animals that were food deprived and presented with food in a novel environment showed long latencies before they began eating. Pretreatment with diazepam or preexposure to the "novel" environment for 1 hr/day for 4 or 7 days before testing in that environment dramatically reduced the latency to begin eating. Administration of either the "inverse agonist," FG-7142, or an antagonist, RO15-1788, of the central benzodiazepine receptor before testing completely reversed the effects of 7 days of preexposure to the novel environment. In home-cage feeding tests, FG-7142, but not RO15-1788, increased the latency to begin feeding in food-deprived animals. These findings indicate that FG-7142 is strongly anxiogenic, whereas RO15-1788 is not anxiogenic, yet both drugs are potent in reversing the effects of habituation. The results of these experiments suggest that the normal process of habituation to novelty may involve the release of an endogenous, anxiolytic compound (an agonist) that binds to a central benzodiazepine receptor, the effects of which are blocked by RO15-1788.