Behavioural Brain Research

Published by Elsevier
Online ISSN: 0166-4328
Publications
Article
Inverse agonism at the benzodiazepine site of α(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for α(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an α(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2, 5 and 10mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2mg/kg) also successfully reversed the 0.3mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5, 10 and 15mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10mg/kg) also proved to be ineffective in the reversal of the 1mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective α(5) GABA(A) inverse agonists.
 
Article
The 5-HT(6) receptor antagonist Ro-04-6790 or 8-OH-DPAT injection improved learning consolidation on an autoshaping task, while mCPP, scopolamine and dizocilpine decreased the performance. The effect induced by scopolamine, but not that induced by mCPP, was reversed completely by Ro-04-6790, while dizocilpine effect was antagonized partially. Nevertheless, ritanserin or WAY 100635, but not Ro 04-6790, antagonized the 8-OH-DPAT facilitatory effects on learning consolidation. As WAY 100635 did not modify the Ro 04-6790 facilitatory effect, hence 5-HT(1A), and/or 5-HT(7), but not 5-HT(6), receptors might mediate the 8-OH-DPAT facilitatory effect on learning consolidation. Since, the Ro 04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A)/(2B)/(2C), 5-HT(3) or 5-HT(4) receptor blockade, thereby, the facilitatory effect induced by Ro 04-6790 involved specifically 5-HT(6) receptors. Indeed, the present data provide further support to the notion that, 5-HT(6) receptors play a significant part in the learning consolidation under normal and dysfunctional memory conditions.
 
Article
There are experimental evidences indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies and ataxia). The present study was designed to investigate the efficacy of the selective 5-HT(6) receptor antagonist Ro 04-6790 in counteracting these MK-801-induced behavioural effects in the rat. The effects of Ro 04-6790 in antagonizing MK-801-induced memory deficits were assessed using the object recognition task. The ability of this 5-HT(6) receptor antagonist in counteracting hypermotility, stereotypies and ataxia produced by MK-801 were evaluated in a motor activity cage. Post-training administration of Ro 04-6790 (10 and to some extent also 3mg/kg) antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, Ro 04-6790 (3 and 10 mg/kg) reversed hypermotility and ataxia produced by MK-801. This 5-HT(6) receptor antagonist also alleviated MK-801-induced certain stereotypies. Our findings indicate that Ro 04-6790 attenuates behavioural effects related to the hypofunction of the NMDA receptor suggesting that this compound might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.
 
Article
Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (Abeta) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble Abeta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Abeta is therapeutically attractive, as Abeta aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of Abeta oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit Abeta(1-42) fibrillogenesis and protect against Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human Abeta on behaviour and dose dependently reduced the behavioural effects of Abeta oligomers, with the highest dose, 10microM, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD.
 
Article
The amygdala is a crucial brain site for acquisition and expression of conditioned fear. Neuropeptides such as somatostatin play a critical role in regulating the activity of the amygdala. In the present study, the specific somatostatin receptor type 2 (SSTR2) agonist L-054,264 was injected into the amygdala of rats either before fear acquisition or before the expression test on conditioned fear measured by fear-potentiated startle. L-054,264 injections strongly attenuated fear expression but did not affect fear acquisition. This suggests that amygdaloid SSTR2 plays an important role in the modulation of fear memory expression.
 
Representative images of coronal frontal lobe sections showing mRNA expression of GluN10XX (A, D, G, J), GluN11XX (B, E, H, K) and GAPDH (C, F, I, L) following treatment with GluN10XX siRNA (A, B, C), vehicle (D, E, F), control siRNA (G, H, I) or no treatment (J, K, L). (M). Image of the region of brain where the injections were applied. Solid vertical lines indicate needle placement. Numbers indicate regions where mRNA analysis was performed (regions 1 = deep (cortical layers IV-VI) ventral orbital, 2 = superficial (II-III) ventral orbital, 3 = deep lateral orbital and 4 = superficial lateral orbital. (N) Diagramatic representation of evidence of the injection site needle tracks (vertical solid lines from top) and the spread of grossly visible reduction of mRNA for GluN10XX subunit splice variants (stippled area) from rostral to caudal. Distances rostral to Bregma are indicated below each diagram (N). Image M and N were adapted from Paxinos et al. [28] (A-L) Standard images and the equivalent pmol of labeled 33 P/mm 2 tissue are shown to the right of each section image.
Article
The GluN1 subunit of the N-methyl-D-aspartate (NMDA) receptor shows age-related changes in its expression pattern, some of which correlate with spatial memory performance in mice. Aged C57BL/6 mice show an age-related increase in mRNA expression of GluN1 subunit splice variants that lack the N terminal splice cassette, GluN1(0XX) (GluN1-a). This increase in expression is associated with good performance in reference and working memory tasks. The present study was undertaken to determine if GluN1(0XX) splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN1(0XX) splice variants, control siRNA or vehicle alone into ventro-lateral orbital cortices. A fourth group of mice did not receive any injections. Starting five days post-injection, mice were tested for their performance in spatial reference memory, associative memory and cognitive flexibility tasks over four days in the Morris water maze. There was a 10-19% reduction in mRNA expression for GluN1(0XX) splice variants within the ventro-lateral orbital cortices in mice following GluN1(0XX) siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN1(0XX) splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN1(0XX) splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.
 
Article
Evidence exists that some abused solvents have N-methyl-D-aspartic acid (NMDA) antagonist activity, although which of their effects may be related to this mechanism is not well understood. The effects of toluene and 1,1,1-trichloroethane (TCE) on NMDA-induced seizures in mice were studied using three experimental protocols: (a) animals injected i.p. with 120 or 170 mg/kg NMDA and immediately afterwards exposed to solvent vapors or air for 30 min (co-exposure protocol); (b) mice exposed for 30 min to solvent or air, then injected with NMDA and placed in the chamber for a second 30-min exposure (pre-exposure+co-exposure protocol); and (c) mice that inhaled 4000 ppm toluene or air for 30 min twice a day, 6 h apart, for 7 days, and were injected with 120 mg/kg NMDA immediately before a 30-min toluene exposure (repeated exposure protocol). When given acutely, toluene, but not TCE, produced concentration-dependent protection against NMDA-induced seizures. Higher concentrations of toluene were also effective against the lethal effects produced by 170 mg/kg NMDA. Clearer effects were seen when the pre-exposure+co-exposure protocol was followed. Under these conditions the IC(50) for toluene was 739 ppm (653-825) against seizure occurrence and 2127 ppm (1966-2288) against lethality. Repeated exposure to toluene did not result in tolerance to its anticonvulsant effects. These results are consistent with the in vitro effects described for toluene as a noncompetitive NMDA antagonist and as a compound that enhances GABAergic transmission. The lack of protective effects of TCE is not consistent with its in vitro actions.
 
Article
In Parkinson's disease (PD) compensatory mechanisms such as an increase of the de novo biosynthesis of dopamine (DA) are thought to delay the onset of motor impairment. Here, we investigated whether the tyrosine hydroxylase (TH) inhibitor alpha-methyl-para-tyrosine (AMPT) affects behavioral deficits in the running wheel activity induced by the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immediately after MPTP treatment C57bl/6 mice showed reduced running wheel activity which lasted during the entire active phase (20:00 to 08:00 h), recovered to baseline levels in the following 2 days and remained stable up to the end of the experiment. AMPT challenge significantly reduced wheel running activity in MPTP-treated mice in the first 3 h after treatment. Post mortem HPLC analysis detected mean striatal DA levels in saline + saline and saline + AMPT-treated mice of 14.32 and 9.83 ng/mg, respectively and in MPTP + saline and MPTP + AMPT-treated mice of 1.73 and 0.69 ng/mg, respectively. Taken together, de novo biosynthesis of DA is a crucial component of the compensatory mechanisms which contributes to masking long-term behavioral deficits in the MPTP mouse model. Additionally, wheel running activity might provide a useful tool to study MPTP-induced behavioral deficits, shifts in circadian rhythmicity, and further compensatory mechanisms relevant to PD.
 
Article
We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects.
 
Article
We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) display time-dependent impairments in olfactory, emotional, cognitive and motor functions associated with disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, lithium (Li) and valproate (VPA) are two primary drugs used to treat bipolar mood disorder that have recently emerged as promising neuroprotective agents. The present data indicates that the pretreatment with Li (47.5 mg/kg) or VPA (200 mg/kg) by intraperitoneal route during 7 consecutive days was able to prevent olfactory discrimination and short-term memory impairments evaluated in the social recognition and step-down inhibitory avoidance tasks in rats infused with a single intranasal (i.n.) administration of MPTP (0.1 mg/nostril). Despite the absence of clear depressive-like responses following the current MPTP dose, Li and VPA treatment presented an antidepressant profile reducing the immobility time in the forced swimming test. Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, Li and VPA prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats. These results provide new insights in experimental models of PD, indicating that Li and VPA may represent new therapeutic tools for the management of olfactory and cognitive symptoms associated to early preclinical phases of PD, together with their neuroprotective potential demonstrated in previous research.
 
Article
Adenosine A(1) receptor antagonists are of potential value in the treatment of cognitive dysfunction. We have developed compound AJ23 (7-methyl-1-phenyl-1,8-dihydro-pyrazolo-(3,4d)(1,2,4)-triazolo(1,5a)-pyrimidin-4-one) as a novel, non-xanthine based antagonist at A(1) receptors. It has micromolar affinity at human A(1) receptors with a 45-fold selectivity for A(1) over A(2A) receptors and little affinity for many other receptors and transporters tested in a screening panel. AJ23 blocks A(1) receptors in the rat hippocampus, increasing the baseline size of excitatory post-synaptic potentials and blocking the inhibitory effects of adenosine. When administered directly into the rodent hippocampus this compound improves consolidation in a step-down avoidance learning task. The results suggest that AJ23 or derivatives may represent possible leads for further chemical development towards a chemically novel group of antagonists at A(1) receptors with potential value as cognitive enhancers.
 
Article
In the brain, the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is a major subtype of receptors for inositol 1,4,5-trisphosphate, which mediates the release of calcium from intracellular stores. The motor function of knockout mice heterozygous for IP3R1 (IP3R1+/-) was assessed. An impairment of motor coordination was observed in IP3R1+/- mice in the rotating rod test. There was no observable difference between genotypes in spontaneous motor activity, grip strength, the hanging test, or walking pattern. These results suggest that IP3R1 plays a substantial role in motor coordination.
 
Article
Anabolic androgenic steroids and high testosterone doses have been reported to induce impulsive behavior in man and behavioral disinhibition in rats. The purpose of the present study was to investigate whether aromatization of testosterone to estradiol is of importance for the behavioral disinhibiting effect of a high testosterone dose in adult male rats. Testosterone administered via five testosterone-filled silastic capsules implanted subcutaneously (s.c.) to non-castrated, group-housed rats for six days induced behavioral disinhibition in a modified Vogel's drinking conflict model and yielded supraphysiological serum levels of testosterone and increased accessory sex organ weights. Moreover, concurrent administration of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD; 60 mg/kg/day s.c.) decreased behavioral disinhibition in testosterone-treated rats (without affecting accessory sex organ weights) while behavior was not significantly affected in sham-treated animals. Since some reports indicate that ATD, in addition to inhibit aromatase, also may affect the binding of testosterone to the androgen receptor, the effect of the non-steroidal androgen receptor antagonist flutamide was investigated. Flutamide treatment did not affect disinhibited behavior in testosterone-treated rats. However, in sham-treated animals, flutamide (50mg/kg/day) produced behavioral disinhibition. These results suggest that estradiol is of importance in the mechanisms underlying behavioral disinhibition in non-castrated rats treated with a high testosterone dose. Speculatively, aromatization may be involved in pro-impulsive effects of high testosterone doses in humans.
 
Article
Pharmacological application of broad agonists and antagonists has supported the notion of a potential role of metabotropic glutamate receptors (mGluRs) in learning and memory formation, but the specific function of the different classes or individual subtypes remains elusive. Furthermore, our knowledge with respect to different learning mechanisms is still fragmentary. In an attempt to clarify further the function of mGluRs in learning, rats were trained in various paradigms in the presence/absence of the specific class I antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA). Intraperitoneal application of AIDA prior to training led to enhanced within-session performance in animals trained in a positively reinforced reference memory task in a three-choice maze. However, this enhancement did not result in increased retention as measured by the number of correct responses during the first four trials of each session on subsequent days. The increase was purely an enhancement in within-session performance, required doses higher than 2 mg/kg, and was not accompanied by an unspecific increase in activity as monitored in the open field. By contrast, AIDA animals trained in a combined shock-reinforced contextual and cue conditioning paradigm demonstrated a pronounced retention deficit compared with controls in conditioning to the context, but not the cue (a high-frequency tone). Although within-session performance during context and cue periods was slightly increased in the AIDA group, the difference did not reach significance. Drug-induced hyperactivity, which could account for the memory deficit, was excluded by recordings of activity in specific activity cages. These results shed new light on the possible function of class I mGluRs in learning and memory formation and imply that systemic blockade of class I mGluRs may enhance short-term memory under certain learning conditions.
 
Article
Latent inhibition (LI), a measure of the ability to learn to ignore irrelevant stimuli, is disrupted in acute schizophrenics and in rats treated with amphetamine; antipsychotics prevent amphetamine disruption of LI in rats. The 5-HT2A/C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has hallucinogenic properties in humans, and evidence suggests that 5-HT2 antagonism is an important component of atypical antipsychotic activity. Therefore, the ability of DOI to disrupt LI in rats was tested, and the ability of clinically-used and putative antipsychotics to reverse DOI disruption of LI was assessed. The method consisted of four phases. After habituation to the apparatus, thirsty rats underwent preexposure to a tone stimulus 24 h prior to two tone-shock conditioning trials. LI was demonstrated at testing (an additional 24 h later) by reduced lick suppression during tone presentation. When administered at the preexposure phase only, DOI disrupted LI. However, when administered at both preexposure and conditioning phases, DOI did not disrupt LI except at the highest dose, where lick suppression itself was also disrupted. Therefore, disruptive effects of DOI on LI are not easily dissociated from state-dependent learning effects. Additional experiments demonstrated that haloperidol, clozapine, risperidone, and the selective 5-HT2A antagonist MDL 100,907 prevented the disruptive effects of DOI on LI when administered at preexposure only. These results agree with findings that these compounds can also prevent other behavioral effects of DOI. Further experiments will be required to explore the possible involvement of state-dependent learning effects in the present results. However, if the disruptive effects of DOI on LI are due to an influence on attentional processes rather than state-dependent learning, this procedure may have potential as a method for detection of antipsychotic activity.
 
Article
MDL 100,907 is a potent and selective antagonist of the 5-HT2A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT2C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT2 receptor antagonists as a novel therapeutic strategy for schizophrenia.
 
Article
The effects of flesinoxan, a selective 5-HT1A receptor agonist, and of WAY 100635, a selective high affinity 5-HT1A receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. Systemic administration of flesinoxan (0.03 and/or 0.06 micromol/kg, s.c.) increased waking (W) and sleep latencies and reduced REM sleep (REMS) and the number of REM periods during the first and/or second 2-h period after treatment. Systemic injection of WAY 100635 (0.46 and/or 0.92 micromol/kg, s.c.) augmented W and REMS latency and reduced REMS and the number of REM periods during the 6-h recording period. Microinjection of flesinoxan (0.03, 0.06 and/or 0.12 nmol) into the laterodorsal tegmental nucleus (LDT) reduced REMS and the number of REM periods, and augmented REMS latency during the first, second, and/or third 2-h recording period. Direct infusion of WAY 100635 (0.06 and/or 0.12 nmol) into the LDT increased REMS and the number of REM periods during the first and/or second 2 h of recording. It is proposed that the activation by flesinoxan of postsynaptic 5-HT1A receptors located in the LDT could be responsible for the REMS suppression. The increase in REMS after the blockade of postsynaptic 5-HT1A receptors in the LDT by WAY 100635 further supports our proposal. The effects of systemic flesinoxan on sleep variables may depend mainly on the activation of postsynaptic 5-HT1A receptors, whereas the effects corresponding to systemic WAY 100635 may be predominantly related to the blockade of presynaptic somatodendritic 5-HT1A autoreceptors.
 
Article
An increase in the extracellular dopamine (DA) concentration is generally accepted as an important neurochemical mediator of the behavioral effects of cocaine. Cocaine induced increases in serotonergic (5-HT) activity also appears to be involved in these effects. Here we describe the effects of the 5-HT(1A)-receptor antagonist WAY 100635 on the behavioral and neurochemical effects of cocaine. In-vivo microdialysis was used in behaving rats to measure extracellular concentration of DA in the nucleus accumbens (Nac). Four groups of animals received one of the following drug combinations: WAY 100635 (0.4 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), WAY 100635 (0.4 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 20 min apart. The pretreatment with WAY 100635 significantly attenuated the locomotor stimulant effects of cocaine without altering the DA overflow in the Nac. WAY 100635 itself did not modify locomotion or the extracellular DA concentration in the Nac. These results indicate that (1) the 5-HT(1A)-receptor is an important component in the mediation of cocaine locomotor stimulant effects, and (2) an increase in the extracellular DA concentration in the Nac might be a necessary but is not a sufficient condition for the locomotor stimulant effects of cocaine.
 
Article
Although considerable progress has been made in characterising the 5-HT1A receptor using agonists, partial agonists or non-selective antagonists, further studies of 5-HT1A receptor function have been hindered by the lack of highly selective antagonists. The term 'silent' antagonist has been used for such compounds in order to distinguish them unequivocally from several 5-HT1A receptor partial agonists which were initially designated 'antagonists'. In this report we provide a comprehensive review of the biochemical, pharmacological and behavioural properties of the first potent, selective and silent 5-HT1A receptor antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride). WAY-100635 had an IC50 (displacement of specific [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus) of 1.35 nM and was > 100-fold selective for the 5-HT1A site relative to a range of other CNS receptors. [3H]WAY-100635 was also characterised as the first 5-HT1A antagonist radioligand, displaying the same regional distribution of binding sites as [3H]8-OH-DPAT in rat brain. As would be expected for the binding of an antagonist to a G-protein-coupled receptor, the Bmax of [3H]WAY-100635 specific binding was consistently 50-60% greater than that of the agonist radioligand, [3H]8-OH-DPAT. Mn2+, but not guanine nucleotides, inhibited [3H]WAY-100635-specific binding. [3H]WAY-100635 was also shown to bind selectively to brain 5-HT1A receptors in vivo, following intravenous administration to mice. In vitro electrophysiological studies demonstrated that WAY-100635 had no 5-HT1A receptor agonist actions, but dose-dependently blocked the effects of agonists at both the postsynaptic 5-HT1A receptor in the CA1 region of the hippocampus, and the somatodendritic 5-HT1A receptor located on dorsal raphe 5-HT neurones. In vivo, WAY-100635 also dose-dependently blocked the ability of 8-OH-DPAT to inhibit the firing of dorsal raphe 5-HT neurones, and to induce the '5-HT syndrome', hypothermia, hyperphagia and to elevate plasma ACTH levels. In the mouse light/dark box anxiety model, WAY-100635 induced anxiolytic-like effects. WAY-100635 had no intrinsic effect on cognition in the delayed-matching-to-position model of short-term memory in the rat, but reversed the disruptive effects of 8-OH-DPAT on motor motivational performance. These data clearly demonstrate that WAY-100635 is the first potent, selective and silent 5-HT1A receptor antagonist. Furthermore, [3H]WAY-100635 is the first antagonist radioligand to become available for 5-HT1A receptor binding studies both in vitro and in vivo. The positive effects of WAY-100635 in an anxiety model also indicate that a postsynaptic 5-HT1A receptor antagonist action may contribute to the anxiolytic properties of 5-HT1A receptor partial agonists.
 
Article
S-100 beta, a gene triplicated in Down Syndrome (DS), is thought to play a role in development of the brain in general, and in the serotonergic neuronal system in particular. We have been studying an animal model of DS, based on overexpression of this gene. In the current study, we report on the social behaviors of these animals, both in same-strain and mixed-strain pairings. In addition, as the neuropeptide oxytocin is often thought to be involved in social behaviors, we have looked at oxytocin-containing cells. In non-social behaviors, such as grooming and line-crossing, the S-100 beta animals were more active than the CD-1 control animals and showed significantly less social sniffing. In mixed-strain studies, these differences became more pronounced, with the CD-1 animals showing significantly greater levels of sniffing and anogenital sniffing. As well, the CD-1 animals showed more rearing and an increase in line crossings, suggesting a heightened level of vigilance or awareness of novelty. The S-100 beta animals, conversely, did not appear to respond to the novelty of the CD-1 animals. In mixed pair studies, the S-100 beta animals more frequently took submissive postures, while the CD-1 animals more frequently took dominant postures, and showed a significant increase in biting the S-100 beta partner. The S-100 beta animals showed less rearing, perhaps a further indication that they were inhibited by the CD-1 animals. Analysis of oxytocin-containing neurons showed comparable levels in the supraoptic and paraventricular nuclei of the hypothalamus, but significantly reduced numbers of cells in the bed nucleus of the stria terminalis of the S-100 beta animals. These results are discussed in terms of oxytocin contributions to socialization and fear responding and the significance of these findings to DS.
 
Article
This study was conducted to characterize female behavioral response to acute 'binge' pattern cocaine administration (15 mg kg(-1) i.p., three times a day, at 1 h intervals) during the different stages of the estrous cycle in Fischer rats. Cocaine administration significantly increased stereotypic behavior and locomotion in females. Animals in estrus showed significantly higher cocaine-induced stereotypic and locomotive behavioral responses than those in other stages of the cycle. Plasma levels of the cocaine metabolite benzoylecgonine during metestrus diestrus were significantly higher than during estrus and proestrus probably reflecting more rapid biotransformation of cocaine. Therefore, it is likely that the hormonal fluctuations associated with the estrous cycle modulate both cocaine metabolism and the behavioral responses to cocaine in female rats. This in turn may have important implications in gender differences in behavioral responses to cocaine.
 
Article
Repeated administration of psychomotor stimulants may produce an impulsive state that could contribute to the cycle of drug abstinence and relapse seen in human drug addicts. We have previously reported that the inhibitory effects of dopamine (DA) on the firing rate of medial prefrontal cortex (mPFC) neurons were reduced in rats after repeated amphetamine treatment suggesting impaired mPFC DA function. Here, we used a differential reinforcement of low rates of responding (DRL) operant conditioning task, which is dependent on mPFC DA, to test impulsivity and inhibitory control. Food-restricted rats were trained to inhibit a nose poke response for 30s before a subsequent nose poke would result in a food reward (DRL 30). Once training was completed, rats received 5 days of no treatment, daily i.p. saline injections or daily i.p. injections of 5mg/kg amphetamine. Nine days of DRL 30 test performance began following a 3-day withdrawal from treatment. The percent of training active hole nose pokes was significantly increased and the percent of training efficiency was significantly decreased in rats withdrawn from repeated amphetamine administration as compared to saline or nai;ve rats. This suggests that impulsivity is increased during amphetamine withdrawal, which we hypothesize is associated with disrupted DA function in the mPFC.
 
Effects of N/OFQ (0.3 nmol) or PBS injection into the lateral ventricle 1 min before administration of UFP-101 (1.0 nmol) or PBS on inhibitory avoidance (A) and escape (B) latencies measured in the elevated T-maze. Bars represent the mean ± S.E.M. Latencies to leave the enclosed arm (BASELINE, AVOID 1–2) or one of the open arms (ESCAPE 1–3) were measured sequentially at 30 s intervals beginning 5 min after the last treatment. Twenty-four hours before the test, all animals were exposed to one of the open arms for 30 min. * P < 0.05, ** P < 0.01 vs. PBS + PBS. ˛ P < 0.05 vs. PBS + UFP-101 (1.0 nmol) (Duncan's test). n = 9.  
Effects of UFP-101 (1.0, 3.0 or 10.0 nmol) or PBS injection into the lateral ventricle on inhibitory avoidance (A) and escape (B) latencies measured in the elevated T-maze. Bars represent the mean ± S.E.M. Latencies to leave the enclosed arm (BASE- LINE, AVOID 1–2) or one of the open arms (ESCAPE 1–3) were measured sequentially at 30 s intervals beginning 5 min after treatment. Twenty-four hours before the test, all animals were exposed to one of the open arms for 30 min. * P < 0.05, ** P < 0.01 vs. PBS (Duncan's test). n = 8–9.  
Article
Depression and anxiety disorders present several genetic and neurobiological similarities. Drugs with antidepressant activity are effective in the treatment of a wide spectrum of anxiety disorders. Preclinical results showed that acute and chronic treatment with the NOP antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101) produced antidepressant-like effects in rodents. Thus, the present study aimed to investigate the effect of central administration of UFP-101 on the anxiety-related behavior in rats as evaluated in the elevated T-maze (ETM) test. Our results showed that UFP-101 reduced the latency of inhibitory avoidance in the ETM, indicating an anxiolytic-like effect. The endogenous peptide N/OFQ prevented this anxiolytic-like action of UFP-101, demonstrating its modulation via central NOP receptors. However, UFP-101 failed to interfere with the latency to escape. No change was observed in locomotor activity after UFP-101 treatment, ruling out any nonspecific motor effect. In conclusion, our results showed that the central administration of UFP-101 presents an anxiolytic-like effect in rats evaluated in the ETM test, providing new insights for drug development to treat anxiety disorders targeting the N/OFQ-NOP receptor system.
 
Article
The augmented tyrosine phosphorylation of NR2B subunit of N-methyl-D-aspartate receptors (NMDAR) dependent on Fyn kinase has been associated with levodopa (L-dopa)-induced dyskinesia (LID). CP-101,606, one selective NR2B subunit antagonist, can improve dyskinesia. Yet, the accurate action mechanism is less well understood. In the present study, the evidences were investigated. Valid 6-hydroxydopamine-lesioned parkinsonian rats were treated with L-dopa intraperitoneally for 22 days to induce LID rat model. On day 23, rats received either CP-101,606 (0.5mg/kg) or vehicle with each L-dopa dose. On the day of 1, 8, 15, 22, and 23 during L-dopa treatment, we determined abnormal involuntary movements (AIMs) in rats. The levels of NR2B phosphorylation at tyrosine-1472 (pNR2B-Tyr1472) and interactions of NR2B with Fyn in LID rat model were detected by immunoblotting and immunoprecipitation. Results showed that CP-101,606 attenuated L-dopa-induced AIMs. In agreement with behavioral analysis, CP-101,606 reduced the augmented pNR2B-Tyr1472 and its interactions with Fyn triggered during the L-dopa administration in the lesioned striatum of parkinsonian rats. Moreover, CP-101,606 also decreased the level of Ca(2+)/calmodulin-dependent protein kinase II at threonine-286 hyperphosphorylation (pCaMKII-Thr286), which was the downstream signalling amplification molecule of NMDAR overactivation and closely associated with LID. However, the protein level of NR2B and Fyn had no difference under the above conditions. These data indicate that the inhibition of the interactions of NR2B with Fyn and NR2B tyrosine phosphorylation may contribute to the CP-101,606-induced downregulation of NMDAR function and provide benefit for the therapy of LID. Copyright © 2015 Elsevier B.V. All rights reserved.
 
Article
A distinct environment associated with psychomotor stimulants like cocaine and amphetamine can elicit conditioned locomotion in rats. This study examined the contribution of CART 55-102 peptide in the NAcc core to the expression of conditioned locomotion in a cocaine-associated environment. Rats in different groups were administered injections in five 2-day blocks: Paired, cocaine (15 mg/kg, IP) in locomotor activity boxes on day 1 and saline in their home cages on day 2; Unpaired, saline in the activity boxes on day 1 and cocaine in their home cages on day 2; or Control, saline in both environments. One week after the last conditioning block, all rats were tested for their conditioned locomotor response in the activity boxes for 1h following an IP saline injection, which was preceded by a bilateral microinjection into the NAcc core of saline or CART 55-102 (1.0 and 2.5 microg/side). As expected, Paired rats showed both increased locomotor activity and rearing compared to rats in either the Unpaired or Control groups. However, the expression of this conditioned hyper-locomotion was inhibited by microinjection into the NAcc core of CART 55-102. These results suggest that CART 55-102 peptide in the NAcc plays a role in the expression of conditioned locomotion in an environment associated with cocaine, and further extends the notion that CART 55-102 plays an important regulatory role in psychomotor stimulants actions in the NAcc.
 
Article
We report a functional magnetic resonance imaging (fMRI) study of 102 healthy participants who completed a demanding Go/NoGo task. The primary purpose of this study was to delineate the neural systems underlying responses to errors in a large sample. We identified a number of regions engaged during error processing including the anterior cingulate, left lateral prefrontal areas and bilateral inferior frontal gyrus, and the subthalamic nucleus. The power afforded by the large cohort enabled identification of regions not consistently measured during Go/NoGo tasks thus helping to incrementally refine our understanding of the neural correlates of error processing. With the present fMRI results, in combination with our previous exploration of response inhibition (Steele et al. [1]), we outline a comprehensive set of regions associated with both response inhibition and error processing.
 
Article
In this review we discuss the evidence that drug addiction, defined as a maladaptive compulsive habit, results from the progressive subversion by addictive drugs of striatum-dependent operant and Pavlovian learning mechanisms that are usually involved in the control over behaviour by stimuli associated with natural reinforcement. Although mainly organized through segregated parallel cortico-striato-pallido-thalamo-cortical loops involved in motor or emotional functions, the basal ganglia, and especially the striatum, are key mediators of the modulation of behavioural responses, under the control of both action-outcome and stimulus-response mechanisms, by incentive motivational processes and Pavlovian associations. Here we suggest that protracted exposure to addictive drugs recruits serial and dopamine-dependent, striato-nigro-striatal ascending spirals from the nucleus accumbens to more dorsal regions of the striatum that underlie a shift from action-outcome to stimulus-response mechanisms in the control over drug seeking. When this progressive ventral to dorsal striatum shift is combined with drug-associated Pavlovian influences from limbic structures such as the amygdala and the orbitofrontal cortex, drug seeking behaviour becomes established as an incentive habit. This instantiation of implicit sub-cortical processing of drug-associated stimuli and instrumental responding might be a key mechanism underlying the development of compulsive drug seeking and the high vulnerability to relapse which are hallmarks of drug addiction.
 
Article
Orphanin FQ/nociceptin (OFQ/N) has been shown to modulate mesolimbic dopaminergic neurotransmission. Repeated administration of OFQ/N into the ventral tegmental area results in a sensitized locomotor response to subsequent peripheral cocaine administration. The aim of the present study was to examine the potential for OFQ/N to produce a sensitized locomotor response to cocaine after a single intra-VTA administration and to determine if this effect of OFQ/N extrapolates to other points along the mesolimbic or nigrostriatal dopaminergic axes. Bilateral administration of OFQ/N (30 microg/side) into the VTA on day 1 to male Sprague--Dawley rats resulted in an enhanced locomotor response to cocaine (10 mg/kg i.p) administered on day 2. However, OFQ/N (3, 10 and 30 microg per side) administered on day 2, 5 mins prior to the administration of cocaine (10 mg/kg i.p), in animals treated with aCSF or OFQ/N on day 1, similarly blocked the action of cocaine, suggesting that the sensitized response was not due to tolerance to the effect of endogenously released OFQ/N. The administration of OFQ/N into the substantia nigra or nucleus accumbens failed to produce a significant sensitized response to a cocaine challenge 24 h later. A significant increase in cocaine stimulated locomotor response on day 2 was observed after injection of OFQ/N into the striatum on day 1. These results demonstrate the ability of a single intra-VTA or intra-striatal administration of OFQ/N to produce increases in the sensitivity to cocaine and may indicate a role for endogenous OFQ/N systems in regulating responses to psychostimulant drugs.
 
Article
Microdialysis is a sampling method that is used to determine the extracellular concentration of neurotransmitters in the brain. The method can be applied to conscious and unrestrained animals and is very suitable for the study of the chemistry of endogenous behaviour. This article reviews the contribution that microdialysis made to our understanding of the chemistry of behaviour. Methodological and practical considerations such as the implantation time and the use of guide cannulas are reviewed. The question whether neurotransmitters and related metabolites in dialysates reflect true synaptic release is critically discussed. There is much evidence that dopamine, noradrenaline, acetylcholine and serotonin in dialysates are related to neurotransmission, but there is serious doubt whether this is the case with amino acid transmitters such as GABA, glutamate and aspartate. Until now far over 100 papers appeared that used microdialysis in behavioural studies. Behavioural activation, the sleep-awake cycle and diurnal rhythms were subject of several of these studies. Various workers have described neurochemical changes in the brain that are related to feeding. Other studies were concerned with sexual behaviour and the sexual cycle in females. Parturition, maternal behaviour and offspring recognition have been studied in a series of microdialysis studies carried out in sheep. An overview is given of the microdialysis studies that were carried out to understand the biochemistry of stress. In this respect dopamine and noradrenaline have received much attention. A great number of microdialysis studies dealt with the role of dopamine in self-stimulation, reward and aversive emotions. It is concluded that microdialysis is at presently the most versatile and practical method to study the chemistry of behaviour and it is to be expected that it will soon be a routine methodology in behavioural research. Finally, perspectives and possible future developments of the methods are discussed.
 
Article
In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.
 
Article
A major goal of translation research in autism is to characterize the physiological and psychological processes underlying behavioral abnormalities. Since autism reflects impairments in social motivation, we modified the mouse three-chamber social approach apparatus for use as a social conditioned place preference arena. We paired one of two unique contexts with social interactions in juvenile mice for five or ten conditioning sessions in BTBR T+tf/J mice and a control strain with normal approach behaviors (C57BL/6J) since the BTBR T+tf/J inbred mouse strain displays a variety of behavioral alterations analogous to symptoms of autism spectrum disorders. While C57BL/6J mice formed a conditioned place preference to the context associated with social interactions, particularly those receiving ten days of conditioning, BTBR T+tf/J mice did not. Neither absence of social proximity nor avoidance due to high rates of autogrooming appeared to underlie the impaired positive incentive value of the unconditioned social stimulus in the BTBR T+tf/J strain. These data contribute to a growing body of evidence suggesting that the BTBR T+tf/J strain shows impairments in all diagnostic domains of autism including social motivation. Additionally, social conditioning testing might provide an important social motivation measure in other rodent models of neuropsychiatric disorders characterized by social abnormalities.
 
Rat brain regional distribution of cAMP level after PDE inhibitors treatment. Cyclic AMP level was measured on hippocampal and striatal extracts 30 min (left) and 24 h (right) after injection of indicated PDE inhibitor types and doses (mg/kg). The data reported are the means of three independent experiments run in duplicate (±S.E.M.). ( * ): significantly different from control level.
Hippocampal PDE activity of inhibitors treated rat after 24 h. PDE activity was assayed on hippocampus of treated rat using 1 M cAMP as substrate concentrations. ( * ): significantly different from control level.
Immunoblots of PDE4D isoform in hippocampus of control and treated rats. Fifty micrograms of total protein extracts were loaded in each lanes. C: hippocampus from control rat; D: hippocampus from rat treated with DC-TA 46 20 mg/kg; R: hippocampus from rat treated with rolipram 30 mg/kg. Densitometric analysis and relative intensity of immunostained bands was showed below. The values are means (±S.E.M.) of three different immunoblot experiments.
RT-PCR analysis of PDE4D isoform in hippocampus of control and treated rats. RNAs were isolated from C: hippocampus from control rat; D: hippocampus from rat treated with DC-TA 46 20 mg/kg; R: hippocampus from rat treated with rolipram 30 mg/kg. An increased expression of the PDE4D specific fragment is evident in both treated samples and was quantified by densitometric evaluation. The values are means (±S.E.M.) of three different experiments.
Article
In this study, the effects on memory of intraperitoneal post-training administration of cyclic nucleotide phosphodiesterase (PDE) inhibitors, DC-TA 46 and rolipram, were tested using a visible/hidden-platform water maze task. The effects of these compounds on cyclic nucleotide levels in the hippocampal formation (HF) and striatum (CP) were also assessed, by enzymatic immunoassay (EIA). The results obtained from rats trained in the visible-platform task were not significantly different from controls. On the contrary, the animals trained in the hidden-platform water maze task showed a memory impairment, when injected with DC-TA 46 at maximal dose of 20mg/kg and with rolipram at 3 and 30 mg/kg doses. The effects of these drugs on cyclic nucleotide levels in HF and CP were observed at 30 min and at 24h after drug administration. Thirty minutes after drug injection, we observed an increase of cAMP level, both in HF and in CP. Twenty-four hours after the retention test, we observed that in CP the cAMP intracellular level remained high, while in the HF at effective doses both inhibitors induced cAMP PDE activity, determining a decrease of cyclic nucleotide. Semi-quantitative RT-PCR analysis, together with Western blot immunodetection, showed a mRNA and protein induction of PDE4D PDE isoforms, that may account for the increase of PDE activity observed. Our data suggest that, despite cyclic nucleotide increase at 30 min, the fundamental event causing memory impairment, came from the subsequent long time decrease of cAMP levels, due to the post-translational PDE4D induction.
 
Article
The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) possesses clear anxiolytic-like effects. Other neurosteroids namely pregnenolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEA-S) influence anxiety-related behavior differently. In the present study, the implication of the amygdala, a key structure in mechanisms of fear and anxiety, was investigated as a potential neural substrate for the effects of neurosteroids on anxiety-like behavior in rat. Animals implanted with bilateral cannulae aimed at the central nucleus of the amygdala (CeA) and infused with neurosteroids, were tested in two animal models of anxiety. Allopregnanolone (8 microg/side) produced a significant increase in responding suppressed by punishment in the conflict test. In the elevated plus maze, allopregnanolone (8 microg/side) induced a significant increase in the time spent and the number of entries in open arms compared with the vehicle-infused controls. No significant changes in punished and unpunished responding of the conflict test were observed with PREG-S (0.001-8 microg/side) and DHEA-S (2-8 microg/side) administered into the CeA or into the lateral ventricle (1-20 microg). The results reveal the lack of activity of PREG-S and DHEA-S in the operant conflict test, but suggest that the central nucleus of the amygdala is a key region involved in the mechanisms underlying the anxiolytic-like action of allopregnanolone.
 
Article
The effects of CGS 10746B, a dopamine release inhibitor, on spontaneous locomotor activity, morphine-induced hyperactivity, acquisition of conditioned place paradigm and morphine-induced conditioned place preference (CPP) was evaluated in male mice. In experiment 1, animals treated with CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg) were placed in an actimeter during a period of 90 min. In experiment 2, animals treated with CGS 10746B (0.5, 1, 3 and 10 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 3 and 10 mg/kg) were conditioned following a procedure unbiased in terms of initial spontaneous preference. In experiment 1, it was found that a decrease in spontaneous locomotor activity was produced between 0 and 45 min after administration of 24 and 32 mg/kg of CGS 10746B. In contrast, morphine induced hyperactivity between 45 and 90 min after administration. CGS 10746B reduced morphine-induced hyperactivity with doses of 2 mg/kg and higher. In experiment 2, CGS 10746B did not produce any effect on place conditioning but blocked morphine-induced CPP with doses from 1 mg/kg upwards. Our results confirm that an intact dopamine neurotransmission is critical for the manifestation of the motor and place preference conditioning effects of morphine.
 
Article
CGS 10746B is an imidazole-derivative related to the atypical antipsychotic clozapine which produces a decrease in dopamine release without altering dopamine metabolism or occupying D2 receptors. Rats were trained on an appetitively-motivated, two-choice, operant task to discriminate 20.0 mg/kg CGS 10746B from its vehicle. CGS 10746B was highly discriminable, producing rapid acquisition of the discrimination, and its effects were dose-responsive allowing generation of an ED50 value of 6.16 mg/kg. Substitution tests were conducted with other typical and atypical antipsychotic compounds: haloperidol, chlorpromazine, clozapine and SCH 23390. Additional tests examined generalization from the CGS 10746B stimulus properties to the calcium channel blocker isradipine, as well as to the anticholinergics atropine, scopolamine and methylscopolamine, as well as to the serotonergic agonist DOI. Clozapine and SCH 23390 were the only substances to substitute for the CGS 10746B stimulus cue. Results are discussed in terms of potential D1 receptor selectivity of CGS 10746B.
 
Article
Endogenous processes referred to as circadian oscillators generate many of the daily rhythms in physiology and behavior of a variety of animals including humans. We investigated the possible circadian regulation of acquisition, recall and extinction in two strains of mice (C-57/6J and C-3H). Mice were trained in either the day or night with a tone and context fear conditioning protocol. The mice were then tested over the course of several days for their ability to recall the training. When comparing the performance of animals in the day and night, the mice acquired the conditioning faster in the day than in the night. Furthermore, the recall for context and tone consistently peaked during the day for at least 3 days after training, irrespective of the time of training. Finally, the loss of this training (or extinction) exhibited a rhythm in that mice trained in night exhibited a greater degree of extinction than mice trained in the day. For all of these rhythms in acquisition, recall, and extinction the phase of the rhythm was controlled by the prior light-dark (LD) cycle. When we reversed the phase of the LD cycle, the phase of the rhythm also reversed. Importantly, all three of the rhythms also continued in constant darkness demonstrating the endogenous, and presumably circadian nature, of the rhythms.
 
Article
Trace conditioning of the nictitating membrane response (NMR) was examined in rabbits with lesions of the dorsal hippocampus and fimbria-fornix. Using a white noise conditional stimulus and an electrical shock unconditional stimulus, the number and amplitude of conditional responses (CRs) was similar in hippocampus-lesioned and control subjects. At some stages of conditioning, the latencies of CRs from hippocampus-lesioned subjects were slightly shorter than those of the controls. We suggest that the hippocampus is not essential for trace conditioning but may exert a modulatory influence on the timing of the CR.
 
Article
Postnatal lesion with ibotenic acid in the ventral hippocampus produces several behavioural effects that resemble the symptoms of schizophrenia. In the present study, we tested neonatally lesioned 1-year-old Sprague-Dawley rats for their social memory. It was found that social memory is worsened in lesioned rats. Subchronic treatment with haloperidol (0.025 mg/kg body weight) partly ameliorated this impairment. It was suggested that social memory might be a useful paradigm to test clinically used and potential antipsychotic drugs for their effects on learning and memory processes.
 
Article
Ultrasonic vocalization (USV) in the 50-kHz range occurs in rats immediately upon first-time exposure to cocaine or amphetamine, and rapidly increases with repetitive drug exposure at the same dose. This sensitized positive-affect response to these drugs of abuse is persistent in that the peak level of USVs again appears when the drug is reintroduced after several weeks of drug discontinuation. The present study explored whether with enough experience USVs might be elicited, and gradually escalate, in anticipation of impending drug delivery. Rats were trained to self-administer (SA) cocaine intravenously by lever pressing 5 days per week for 4 weeks. Yoked rats received experimenter-delivered cocaine matching that of SA rats. USVs and locomotor activity were recorded during each 10-min period prior to 60-min drug access sessions. Extinction trials in which drug access was denied were then carried out over an additional 4-week period. After about a week of cocaine experience, both the SA and yoked groups began to progressively increase USVs when placed in an environment that predicted forthcoming drug exposure. Extinction of anticipatory calls and locomotion occurred over days after drug access ended. USVs may be a useful model for specifically investigating the neural basis of drug anticipation and aid in developing and assessing new addiction treatment strategies for reducing craving and relapse.
 
Article
Previous studies have shown memory enhancing effects of phosphodiesterase type 5 (PDE5) inhibitors in rats. However, differences in nitric oxide (NO)-mediated cyclic GMP (cGMP) signaling in the hippocampus have been described between rats and mice. In the present study we investigated the memory enhancing effects of the PDE5 inhibitor, sildenafil on memory performance in Swiss mice using the object recognition task. Sildenafil (0.3, 1 and 3 mg/kg) was administered orally directly after the first trial. The memory for the objects was retested 24 h later when mice show no memory for the familiar object. Sildenafil improved the object discrimination performance of Swiss mice at a dose of 1 mg/kg. Hippocampal slices of Swiss mice incubated with sildenafil (10 microM) increased cGMP levels in varicosities in the CA3 region of the hippocampus and a number of short, thin fibers. Addition of DEA/NO, an NO donor (10 microM), in the presence of sildenafil (10 microM) strongly increased cGMP immunoreactivity of varicosities in the CA3 region. Double immunostaining of cGMP with the presynaptic marker synaptophysin did not reveal any co-localization of these markers under any circumstance. Taken together, inhibition of PDE5 improves object recognition memory in mice. Furthermore, a postsynaptic role of cGMP could be involved in this respect.
 
Article
A scaling approach was introduced recently to assess sequential and geometrical aspects of animal behavior. This study describes the relationship between different measures of unconditioned motor activity of rats. Specifically, the amount of motor activity was assessed using both a traditional photobeam break measure, counts, and the temporal scaling exponent, alpha, which describes the ratio of fast to slow behavioral micro-events. The sequential characteristics of the behavior were assessed by the dynamical entropy, h, describing the degree of unpredictability of future movements. The geometrical characteristics of rat motor activity were quantified by the spatial scaling exponent, d. Exploratory activity was measured by counting rearings and holepoking responses. A factor analysis of these measures was conducted based on results from 137 drug-naive animals that were tested for 1 h in the Behavioral Pattern Monitor. Three independent factors account for 77% of the variance. These factors can be described as the 'amount of activity', 'sequential response organization', and 'exploratory activity'. The factor loadings support the initial hypothesis that the geometrical structure of rat motor activity, i.e. the spatial scaling exponent d, varies independently from the amount of activity, i.e. counts. In addition, the distribution of these measures did not deviate significantly from normality suggesting that the z-scores of these variables, which have been used previously in the d-alpha plane description, are able to indicate significant changes of behavior. These results suggest that unconditioned motor activity is influenced by at least three independent factors. The independent assessment of these factors may contribute significantly to the understanding of the neural substrates involved in the organization of unconditioned behavior.
 
Article
Recent evidence suggests that progesterone (P) may have behaviorally relevant actions on neuronal membranes in the ventral midbrain. In the present experiments, we exploited the rapid time course predicted for non-genomic actions of steroid hormones. Ovariectomized hamsters were implanted with chronic guide cannulae, one aimed above the ventromedial hypothalamus (VMH) and the other over the contralateral ventral tegmental area (VTA). The following week animals were estrogen-primed (10 micrograms estradiol benzoate) and pre-tested for sexual receptivity 2 h after a P or P conjugated to the macromolecule bovine serum albumin (P-3-BSA) containing tube was applied to the VMH. P-3-BSA binds well to neuronal membranes, but does not penetrate them because of the large size of the BSA molecule. After the pre-test, the opposite hormone-containing insert was applied to the VTA and hamsters were tested again for sexual receptivity 5 min after this implantation. The following week, the contents of the tubes were reversed. Receptivity only occurred when P was applied to the VMH and 2 h later P-3-BSA was applied to the VTA; the reverse treatment was ineffective. These data indicate that P is capable of rapidly facilitating receptivity by actions on cell membranes in the VTA if P has been applied to the hypothalamus 2 h earlier. Progesterone conjugated to BSA at carbon 11 (P-11-BSA) was ineffective compared to P-3-BSA using the same paradigm. This suggests that the mechanism which responds to P in the ventral midbrain may require the 11 region.
 
Article
The goal of this work was to identify the distribution of serotonin transporters in the human brain with [11C](+)McN5652/PET. Four healthy volunteers were studied. To determine non-specific binding, a PET study was also performed with the inactive enantiomer [11C](-)McN5652 as well as with [11C](+)McN5652 after pretreatment with fluoxetine. For pattern extraction the PET data sets were analyzed by a back-propagation neural network. Two pharmacokinetic patterns and two characteristic images were separated; one representing specific binding, the other representing non-specific binding. The specific binding image showed characteristic distribution of serotonin transporters with [11C](+)McN5652. The pattern images demonstrated an improvement in image quality compared to the original PET images (reduced variance, higher region-to-cerebellum ratio, good correlation with known density of serotonin transporters). The non-specific binding images extracted from [11C](-)McN5652/PET were similar to those of [11C](-)McN5652 and [11C](-)McN5652 with fluoxetine. Thus, PET studies obtained with [11C](+)McN5652 largely represent the regional distribution of the serotonin transporters and the inactive enantiomer [11C](-)McN5652 shows the distribution of its nonspecific binding.
 
Article
This review examines the relationship between exploration and contextual fear conditioning. The fear acquired to places or contexts associated with aversive events is a form of Pavlovian conditioning. However, an initial period of exploration is necessary to allow the animal to form an integrated memory of the features of the context before conditioning can take place. The hippocampal formation plays a critical role in this process. Cells within the dorsal hippocampus are involved in the formation, storage and consolidation of this integrated representation of context. Projections from the subiculum to the nucleus accumbens regulate the exploration necessary for the acquisition of information about the features of the context. This model explains why electrolytic but not excitotoxic lesions of the dorsal hippocampus cause enhanced exploratory activity but both cause deficits in contextual fear. It also explains why retrograde amnesia of contextual fear is greater than anterograde amnesia.
 
Article
Pavlovian fear conditioning procedures have been a fruitful means of exploring the neural substrates of associative learning. There is now substantial evidence suggesting that many aspects of conditioned fear depend critically upon the integrity of the amygdala and the perirhinal cortex. Recent studies in our laboratory examining the contributions of these areas to olfactory and contextual fear conditioning are reviewed; collectively the results of these studies suggest that the amygdala participates critically in the acquisition and expression of fear conditioned to both an olfactory conditioned stimulus (CS) and to the training context, while the perirhinal cortex contributes to olfactory, but not contextual, fear conditioning. Moreover, it appears that perirhinal cortex may play a prominent role in recognition of the CS following conditioning. These results are discussed in light of the extent to which they replicate and extend previous research examining the contributions of these areas to fear conditioned to auditory and visual CSs.
 
Article
This paper describes the neural basis and the role of Pavlovian conditioning in the modification of blood glucose and related endocrine parameters after repeated insulin and glucose administration. Pavlovian conditioning requires that conditioned stimulus (CS) and unconditioned stimulus (US) are both detected in the central nervous system (CNS), where the CS-US association takes place. We will therefore elucidate the detectability of insulin and glucose in the CNS. Since current data focus almost exclusively on animals, we conducted a placebo-controlled insulin conditioning experiment in humans (Experiment 1). Compared with the control group with CS-placebo pairings throughout, the experimental group with previous CS-insulin pairings in the acquisition phase showed a conditioned decrease in blood glucose and a trend for a conditioned baseline insulin increase, and an increase in cortisol levels relative to baseline and cumulative number of neuroglycopenic symptoms in the CS-placebo test session. The conditionability of glucose administration also had to be examined; experiments using an arbitrary CS and glucose are extremely rare, even in animals. Glucose is the natural stimulus for endogenous insulin secretion, so studies on cephalic-phase insulin release (CPIR) will be reviewed in this paper. We implemented a placebo-controlled three-group design (Experiment 2): Subjects received either CS-insulin, CS-glucose or CS-placebo pairings during the acquisition. Together, our results demonstrate the conditionability mainly of insulin, but also of glucose effects in healthy humans. The clinical relevance and future research perspectives are outlined with an emphasis on insulin in the brain and its role in learning and memory.
 
Article
The Ts65Dn mouse is the most commonly used model of Down syndrome. This mouse shows many phenotypic characteristics present in people with Down syndrome, including behavioral and cognitive deficits. SGS-111 is a novel analogue of the nootropic piracetam, which prevents oxidative damage and apoptosis in both normal and Down syndrome human cortical neurons. In this work we tested the ability of chronic administration of SGS-111 to adult Ts65Dn mice to reverse the cognitive deficit found in these mice. Moreover, since oxidative stress has been reported as early as the fetal stage, SGS-111 was also administered to pregnant Ts65Dn females from the day of conception throughout the pregnancy and to Ts65Dn pups during their entire life (5 months), from birth to the end of the behavioral testing period. A characterization of the effects of SGS-111 treatment on Ts65Dn and control mice sensorimotor abilities, motor coordination, spontaneous activity, activity in the open field, exploration, anxiety and spatial and non-spatial short- and long-term learning and memory was performed. The behavioral characterization showed that chronic administration of the antioxidant SGS-111 reduced the hyperactivity shown by Ts65Dn mice in their home cage, in the open field and in the hole board test. SGS-111 administration during adulthood improved performance in the first session in the Morris water maze in control mice, and when administered during the pre- and post-natal periods, improved spatial learning in the control mice but not in Ts65Dn mice. Chronic SGS-111 administration failed to affect behavior and cognition in Ts65Dn mice.
 
Top-cited authors
Ian Whishaw
  • University of Lethbridge
Trevor W Robbins
  • University of Cambridge
Abdel Ennaceur
  • University of Sunderland
Bryan Kolb
  • University of Lethbridge
Ilan Golani
  • Tel Aviv University