It is never as good the second time around: Brain areas involved in salience processing habituate during repeated drug cue exposure in treatment engaged abstinent methamphetamine and opioid users.

The brain response to drug-related cues is an important marker in addiction-medicine. However, the temporal dynamics of this response in repeated exposure to cues are not well known. In an fMRI drug cue-reactivity task, the presence of rapid habituation or sensitization was investigated by modeling time and its interaction with condition (drug>neutral) using an initial discovery-sample. Replication of this temporal response was tested in two other clinical populations all abstinent during their early recovery (treatment). Sixty-five male participants (35.8 ± 8.4 years-old) with methamphetamine use disorder (MUD) were recruited as the discovery-sample from an abstinence-based residential treatment program. A linear mixed effects model was used to identify areas with a time-by-condition interaction in the discovery-sample. Replication of these effects was tested in two other samples (29 female with MUD from a different residential program and 22 male with opioid use disorder from the same residential program as the discovery sample). The second replication sample was re-tested within two weeks. In the discovery-sample, clusters within the VMPFC, amygdala and ventral striatum showed both a main effect of condition and a condition-by-time interaction, indicating a habituating response to drug-related but not neutral cues. The estimates for the main effects and interactions were generally consistent between the discovery and replication-samples across all clusters. The re-test data showed a consistent lack of drug > neutral and habituation response within all selected clusters in the second cue-exposure session. The VMPFC, amygdala and ventral striatum show habituation in response to drug-related cues which is consistent among different clinical populations. This habituated response in the first session of cue-exposure and lack of reactivity in the second session of exposure may be important for informing the development of cue-desensitization interventions.

Folic acid prevents habituation memory impairment and oxidative stress in an aging model induced by D-galactose.

The present study aimed to evaluate the effect of folic acid treatment in an animal model of aging induced by D-galactose (D-gal). For this propose, adult male Wistar rats received D-gal intraperitoneally (100 mg/kg) and/or folic acid orally (5 mg/kg, 10 mg/kg or 50 mg/kg) for 8 weeks. D-gal caused habituation memory impairment, and folic acid (10 mg/kg and 50 mg/kg) reversed this effect. However, folic acid 50 mg/kg per se caused habituation memory impairment. D-gal increased the lipid peroxidation and oxidative damage to proteins in the prefrontal cortex and hippocampus from rats. Folic acid (5 mg/kg, 10 mg/kg, or 50 mg/kg) partially reversed the oxidative damage to lipids in the hippocampus, but not in the prefrontal cortex, and reversed protein oxidative damage in the prefrontal cortex and hippocampus. D-gal induced synaptophysin and BCL-2 decrease in the hippocampus and phosphorylated tau increase in the prefrontal cortex. Folic acid was able to reverse these D-gal-related alterations in the protein content. The present study shows folic acid supplementation as an alternative during the aging to prevent cognitive impairment and brain alterations that can cause neurodegenerative diseases. However, additional studies are necessary to elucidate the effect of folic acid in aging.

Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function.

Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

Habituation of the startle reflex depends on attention in cannabis users.

BACKGROUND: Cannabis use is associated with an attention-dependent deficit in prepulse inhibition of the startle reflex (PPI). The aim of the current study was to investigate startle habituation in cannabis users and healthy controls during two attentional tasks. METHODS: Auditory startle reflex was recorded from orbicularis oculi muscle while participants (12 controls and 16 regular cannabis users) were either attending to or ignoring 100 dB startling pulses. Startle habituation was measured as the absolute reduction in startle magnitude on block 2 (last nine trials) vs. block 1 (first nine trials). RESULTS: Startle habituation with moderate effect sizes was observed in controls and cannabis users only while they were ignoring the startling pulses but not while they were attending to them. Similar results were also observed in controls (lifetime non-users of cannabis) and cannabis users with lifetime cannabis use disorders (CUD). CONCLUSION: Startle habituation appears to depend on selective attention but not on cannabis use. Startle habituation was present when attention was directed away from auditory startling pulses in healthy controls and cannabis users. Such a similar pattern of results in both groups suggests that at least a trend exists towards presence of startle habituation regardless of cannabis use or CUD in otherwise healthy members of the general population.

Neuromodulatory Regulation of Behavioral Individuality in Zebrafish.

Inter-individual behavioral variation is thought to increase fitness and aid adaptation to environmental change, but the underlying mechanisms are poorly understood. We find that variation between individuals in neuromodulatory input contributes to individuality in short-term habituation of the zebrafish (Danio Rerio) acoustic startle response (ASR). ASR habituation varies greatly between individuals, but differences are stable over days and are heritable. Acoustic stimuli that activate ASR-command Mauthner cells also activate dorsal raphe nucleus (DRN) serotonergic neurons, which project to the vicinity of the Mauthner cells and their inputs. DRN neuron activity decreases during habituation in proportion to habituation and a genetic manipulation that reduces serotonin content in DRN neurons increases habituation, whereas serotonergic agonism or DRN activation with ChR2 reduces habituation. Finally, level of rundown of DRN activity co-segregates with extent of behavioral habituation across generations. Thus, variation between individuals in neuromodulatory input contributes to individuality in a core adaptive behavior. VIDEO ABSTRACT.

The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance.

The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement.

Triptolide preserves cognitive function and reduces neuropathology in a mouse model of Alzheimer's disease.

Triptolide, a major bioactive ingredient of a widely used herbal medicine, has been shown to possess multiple pharmacological functions, including potential neuroprotective effects pertinent to Alzheimer's disease (AD) in vitro. However, the therapeutic potential of triptolide for AD in vivo has not been thoroughly evaluated. In the present study, we investigated the impact of peripherally administered triptolide on AD-related behavior and neuropathology in APPswe/PS1ΔE9 (APP/PS1) mice, an established model of AD. Our results showed that two-month treatment with triptolide rescued cognitive function in APP/PS1 mice. Immunohistochemical analyses indicated that triptolide treatment led to a significant decrease in amyloid-ß (Aß) deposition and neuroinflammation in treated mice. In contrast to previous findings in vitro, biochemical analyses showed that triptolide treatment did not significantly affect the production pathway of Aß in vivo. Intriguingly, further analyses revealed that triptolide treatment upregulated the level of insulin-degrading enzyme, a major Aß-degrading enzyme in the brain, indicating that triptolide treatment reduced Aß pathology by enhancing the proteolytic degradation of Aß. Our findings demonstrate that triptolide treatment ameliorates key behavioral and neuropathological changes found in AD, suggesting that triptolide may serve as a potential therapeutic agent for AD.

Supplemental choline does not attenuate the effects of neonatal ethanol administration on habituation of the heart rate orienting response in rats.

Several studies using rodent subjects have now shown that extra dietary choline may prevent or even reverse the deleterious effects of pre- and early post-natal ethanol administration. Choline supplementation has been shown to attenuate many, although not all, of ethanol's effects on brain development and behavior. Our laboratory has consistently reported impaired habituation of the heart rate orienting response to a novel olfactory stimulus in animals exposed to ethanol on postnatal days (PD) 4-9. Here we examine whether supplemental choline given both during and after ethanol administration could alleviate these ethanol-induced deficits. Subjects were given 5g/kg/day ethanol or sham intubations on PD 4-9. Half of the subjects in each group were given a single daily s.c. injection of choline chloride on PD 4-20, while the other half were injected daily with saline. Pups were tested for heart rate orienting and response habituation in a single test session on PD 23. Results replicated the ethanol-induced impairment in response habituation. However, choline supplementation had no effect on orienting or habituation in either neonatal treatment group. These findings indicate that habituation deficits induced by ethanol are not alleviated by extra dietary choline using these parameters. Choline holds great promise as a treatment for some fetal alcohol effects, but is not an effective treatment for all ethanol-related deficits.

Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice.

Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo.

Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD.

Clinical studies suggest that administration of ketamine hydrochloride-an antagonist at the N-methyl-d-aspartate ionophore-provides short-term amelioration for depressive symptoms. The effects of a brief course of ketamine given immediately following exposure to psychogenic stress on the behavioral stress responses were assessed in an animal model of posttraumatic stress disorder. Animals exposed to stress were treated 1h later with ketamine (0.5, 5, and 15 mg/kg) or vehicle for three days (N = 107). Outcome measures included behavior in the elevated plus maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into "extreme," "minimal," or "partial" behavioral response for analysis of prevalence rates of "PTSD-like behavior." Circulating corticosterone levels were assessed 20 min after injection of ketamine in exposed and unexposed animals (N = 62). The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Prevalence rates of extremely-, partially-, or minimally-disrupted behavior demonstrated that ketamine administered immediately following stress exposure was ineffective in alleviating "PTSD-like behavior" at day 30 after exposure. Administration of ketamine was associated with increase in freezing behavior after exposure to a trauma-cue on day 31. Corticosterone levels were significantly suppressed by ketamine only in the exposed animals. Administration of ketamine immediately following trauma-exposure may not only be ineffective but actually detrimental in the long term. A disruption of the post-stress HPA-response has been raised as a contributing factor.

Effect of ethanolic extract of Carpolobia lutea G. Don (polygalaceae) root on learning and memory in CD1 mice.

Carpolobia lutea, commonly called cattle stick or poor man's candle, is used by traditional herbalists in eastern Nigeria to treat 'madness'. It has a reported analgesic and anti-nociceptive effect. The effect of its ethanolic root extract on learning and memory was investigated. Thirty mice were divided into three groups of ten each. One group of mice served as the control and was given normal saline (p.o.) while the other two groups were given acute low dose (1500mg/kg, p.o.) and high dose (2500mg/kg, p.o.) (LD50 3338.83mg/kg). The effect of the extract on cognitive memory was investigated using the Novel Object recognition task (NORT) while the effect on visuospatial learning and memory was studied using the Morris Water maze (MWM). The results obtained in the NORT show that the index of habituation was significantly lower following acute treatment with a low dose of C. lutea extract compared to control. However, the index of habituation did not differ following treatment with a high dose of C. lutea compared to control but it was higher compared to the low dose. Following treatment with a low dose of the extract, the index of discrimination was significantly higher compared to control. The index of discrimination in the high dose treatment group did not differ from control, but it was lower compared to the low dose treatment. This indicated that there was improved cognitive memory only in the low dose treatment group. In the MWM there was no significant difference in swim latency during Acquisition and Reversal training. There also was no significant difference in quadrant duration during probe trial. The swim latency during the visible platform test showed that all mice used had good visual acuity. Therefore, the ethanolic extract of C. lutea root enhanced cognitive memory. However it did not affect visuospatial learning and memory.

Clonidine normalizes sensorimotor gating deficits in patients with schizophrenia on stable medication.

BACKGROUND: Cognitive deficits form core features in schizophrenia. Several studies have shown improvements in prefrontal cognitive function by α 2 -agonists in schizophrenia. In the present study, it was investigated whether clonidine (an α 2 -adrenoceptor agonist) could normalize sensorimotor gating deficits in schizophrenia. METHODS: In a double blind, placebo controlled, randomized, yet balanced, cross-over experiment, 20 male schizophrenia patients on stable medication were assessed in an auditory prepulse inhibition (PPI), sensitization, and habituation of the startle reflex paradigm on 5 occasions: once after oral administration of placebo and after a single dose of 25, 50, 75, and 150 µg of clonidine. Their results were compared with 20 age- and gender-matched healthy volunteers, who received no treatment. RESULTS: In the placebo treatment, patients showed deficient PPI and sensitization, yet normal habituation compared with the controls. Except the highest dose, all dosages of clonidine significantly increased percentage PPI in the patients compared with placebo, to such levels that it no longer differed significantly from the healthy controls. However, none of the dosages increased sensitization or influenced habituation. CONCLUSIONS: This is the first study to show that even a single low dose of clonidine added to the medical treatment of patients with schizophrenia who are clinically stable on their antipsychotic medication not only significantly ameliorates their PPI deficits, but also normalizes them. The results have a potentially high clinical relevance for the medical treatment of schizophrenia.

Pyruvate and creatine prevent oxidative stress and behavioral alterations caused by phenylalanine administration into hippocampus of rats.

Phenylketonuria is characterized by a variable degree of mental retardation and other neurological features whose mechanisms are not fully understood. In the present study we investigated the effect of intrahippocampal administration of phenylalanine, isolated or associated with pyruvate or creatine, on rat behavior and on oxidative stress. Sixty-day-old male Wistar rats were randomly divided into 6 groups: saline; phenylalanine; pyruvate; creatine; phenylalanine + pyruvate; phenylalanine + creatine. Phenylalanine was administered bilaterally in the hippocampus one hour before training; pyruvate, at the same doses, was administered in the hippocampus one hour before phenylalanine; creatine was administered intraperitoneally twice a day for 5 days before training; controls received saline solution at same volumes than the other substances. Parameters of exploratory behavior and of emotionality were assessed in both training and test sessions in the open field task. Rats receiving phenylalanine did not habituate to the open field along the sessions, indicating deficit of learning/memory, but parameters of emotionality were normal, not interfering in the habituation process. Pyruvate or creatine administration prevented the lack of habituation caused by phenylalanine. Pyruvate and creatine also prevented alterations provoked by phenylalanine on lipid peroxidation, total content of sulfhydryls, total radical-trapping antioxidant potential and total antioxidant reactivity. The results suggest that the behavioral alterations provoked by intra-hippocampal administration of phenylalanine may be caused, at least in part, by oxidative stress and/or energy deficit. If this also occurs in PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric patients.

Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction.

Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.

Chemical modulation of memory formation in larval zebrafish.

Whole organism-based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis-dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.

MK-801 increases the baseline level of anxiety in mice introduced to a spatial memory task without prior habituation.

C57BL/6J mice were introduced to a nine arm radial maze without prior habituation and trained in the acquisition of a working memory task in 16 sessions, one session per day. In this maze mice need to climb onto an upward inclined bridge in order to reach and cross onto an arm. They received in each session an i.p. injection of MK-801 (0.1 mg/kg) 30 min before training or immediately after training. MK-801 pre-treated mice made significantly more entries onto the bridges, fewer entries onto the arms and took significantly longer time to make a first arm visit compared to saline and MK-801 post-treated mice during the first 3 session blocks (4 sessions per block). These results indicate that MK-801 induced anxiety which was extended throughout the first 3 session blocks. MK-801 pre-treated mice made also significantly more errors and required more sessions to reach the criterion compared to saline and MK-801 post-treated mice. Administration of MK-801 after training did not affect the acquisition of the task. The present results indicate that MK-801 pre-treatment impaired the acquisition of a spatial task and this can be accounted for by its effect on the baseline level of anxiety which was elevated. The introduction of mice to the acquisition of the task without prior habituation demonstrates that a drug treatment can affect learning and memory by increasing and/or prolonging anxiety. Such effect may be confounded with learning and memory performance and not detected with pre-habituation training procedures, particularly when the number of sessions is determined a-priori.

Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.

Glycine inhibits startle-mediating neurons in the caudal pontine reticular formation but is not involved in synaptic depression underlying short-term habituation of startle.

The mammalian startle response is controlled by glycine inhibition in the spinal cord. Evidence for additional glycine inhibition on the level of the brainstem, namely in the caudal pontine reticular nucleus (PnC), is controversial. Startle mediating PnC neurons receive fast input from sensory pathways and project to cranial and spinal motoneurons. Synaptic depression in the sensory synapses in the PnC has been indicated as underlying mechanism of short-term habituation of startle. We here performed patch-clamp recordings of PnC giant neurons in rat brain slices to test the hypothesis that the activation of glycine receptors inhibits PnC neurons and that this inhibition is involved in synaptic depression in the PnC. Glycine strongly inhibited PnC neuron activity and synaptic signalling, indicating that functional glycine receptors mediate a powerful inhibition of PnC neurons over a wide range of glycine concentrations. Strychnine reversed all glycine effects, but had no effect on PnC neurons itself. Thus, we found no evidence for a tonic glycine inhibition or for glycine activation within the primary startle pathway indicating that baseline startle reactions are unlikely to be controlled by glycine in the PnC. Most importantly, synaptic depression underlying short-term habituation was not affected by glycine or strychnine.

(-)-Linalool, a naturally occurring monoterpene compound, impairs memory acquisition in the object recognition task, inhibitory avoidance test and habituation to a novel environment in rats.

It is known that (-)-linalool is a competitive antagonist of NMDA receptors, which play a key role in the learning and memory processes; however, only a few studies have reported a possible interference of (-)-linalool in memory. The purpose of this study was to investigate the (-)-linalool effects on acquisition of short- and long-term memories through the objects recognition task, inhibitory avoidance test and habituation to a novel environment. Furthermore, the open field test was used to investigate the interference of (-)-linalool in motivation, locomotion and exploration by animals. Wistar male adult rats received an intraperitoneal injection (i.p.) of saline (NaCl 0.9%), tween 5% or (-)-linalool (50 or 100 mg/kg) before training in the tasks; MK-801 (0.1 mg/kg), a glutamate antagonist, was used as positive control. Short-term (STM) and long-term (LTM) memories were tested 1.5 and 24 h after training, respectively, in the inhibitory avoidance and recognition objects. The results suggested that (-)-linalool (as 50- and 100-mg/kg doses) impaired LTM acquisition, but not STM acquisition, in the object recognition task. In the inhibitory avoidance test, animals receiving linalool (both doses) showed impairment in acquisition of both memories measured. In the open field test, the animals that received (-)-linalool showed no significant difference in the crossings and latency to start the locomotion in any of the doses tested, although (-)-linalool 100 mg/kg reduced rearing behavior. When re-exposed to open field 24 h after training, the rats that received (-)-linalool 100mg/kg showed no habituation. Taken together, these data suggested that (-)-linalool was able to impair the acquisition of memory in rats, which can be associated to (-)-linalool antagonist capacity as regards NMDA glutamatergic receptors, since other glutamate antagonists also seem to affect memory.

Somatic and neuroendocrine responses to standard and biologically salient acoustic startle stimuli in monkeys.

The startle response, a simple defensive response to a sudden stimulus signaling proximal threat, has been well studied in rodents and humans, but has been rarely examined in monkeys. The first goal of the present studies was to develop a minimally immobilizing startle measurement paradigm and validate its usefulness by testing two core features of the startle response (habituation and graded responsivity) in squirrel monkey subjects. Two different types of startle stimuli were used: standard broad-band noise bursts, and species-specific alarm vocalizations ("yaps") which are elicited in response to threat in both wild and captive animals. The second goal of the present studies was to test whether yaps produce enhanced startle responsivity due to their increased biological salience compared to simple, non-biologically relevant noise bursts. The third goal of the present studies was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis response to startle stimuli, as little is known about the stress-activating role of startle stimuli in any species. These experiments determined that the whole-body startle response in relatively unrestrained squirrel monkeys habituates across repeated stimulus presentations and is proportional to stimulus intensity. In addition, differential habituation was observed across biologically salient vs. standard acoustic startle stimuli. Responses to "yaps" were larger initially but attenuated more rapidly over trials. Responses to "yaps" were also larger in the early subepochs of the response window but then achieved a lower level than responses to noise bursts in the later subepochs. Finally, adrenocorticotropic hormone and cortisol concentrations were significantly elevated above baseline after startle stimuli presentation, though monkeys did not exhibit differential HPA axis responses to the two types of startle stimuli. The development of monkey startle methodology may further enhance the utility of this paradigm in translational studies of human stress-related psychiatric disorders.