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PubMed2001

Striatal dopamine sensitization to D-amphetamine in periadolescent but not in adult rats.

The neurobiological and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants. Periadolescent (33-43 days) and adult (>70 days) Sprague-Dawley rats underwent a 3-day treatment history with D-amphetamine (AMPH) at 0, 2, or 10 mg/kg (once a day). After a short 5-day-long withdrawal interval, freely moving animals were challenged with a 2-mg/kg AMPH dose and their behavior as well as in vivo intrastriatum dopamine (DA) release in the CNS were assessed. Microdialysis data indicated that AMPH-history periadolescent rats showed a prominent sensitization of AMPH-stimulated DA release, whereas no such change was found in adult subjects. As expected, acute AMPH administration strongly reduced time spent lying still and increased levels of cage exploration in animals of both ages. A treatment history of high AMPH dosage was associated with a marked sensitization of the exploratory behavior in adults, whereas it induced a quite opposite profile in periadolescents. The latter group only was also characterized by a compulsive involvement in the stereotyped head-bobbing response. These results indicate that differently from adults, marked alterations in neurobiological target mechanisms are observed in rats around periadolescence as a consequence of a quite mild regimen of intermittent AMPH exposure. Thus, a neurobiological substrate for an age-related increased vulnerability towards the addictive risks of these drugs is suggested.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor.

The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem structures that regulate anxiety-related behavior and hypothalamic-pituitary-adrenal (HPA) activity, but its role in regulating anxiety-related behaviors is equivocal, and evidence for its role in regulating HPA activity is limited. Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these issues. Behavior in the elevated plus maze, open field, light-dark box and after Pavlovian fear conditioning was examined in addition to HPA activity under basal and acute stress conditions. Compared to age-matched adult male wild-type (WT) controls, adult male KO mice exhibited increased distance traveled in the open arms of the elevated plus maze, consistent with decreased measures of anxiety. There were no differences between the two genotypes in exploratory behavior in the open field or light-dark test. KO mice displayed enhanced fear conditioning indexed by fear-induced freezing behavior. KO mice displayed lower adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In addition, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the central amygdala were observed in KO compared to WT mice. Therefore, deletion of the 5-HT-3A receptor revealed an important role for this receptor in regulating HPA responses to acute stress and a potential interaction between the 5-HT-3A receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A receptor does not have a unitary role in the regulation of anxiety- and fear-related behaviors but has a potentially substantial role in the regulation of HPA activity.

Amygdala↗

PubMed1989

Brain 5-HT1 and 5-HT2 binding sites following portacaval shunt in the rat.

Brain serotonin 5-HT1 and 5-HT2 binding properties were investigated in experimental chronic portal-systemic encephalopathy (PSE). End-to-side portacaval shunted (PCS) rats were subjected to open field behavioral testing (spontaneous activity and exploration) 3 weeks after the shunt procedure. Each individual animal was then assayed for 5-HT1 and 5-HT2 binding properties (Bmax and KD) in the cortex + hippocampus by the use of radioligand binding and rapid filtration technique. (3H)serotonin was used to label 5-HT1 binding sites and (3H)ketanserin to label 5-HT2 binding sites. Results revealed that the PCS rats exhibited significant behavioral changes with decreased spontaneous activity and exploratory behavior as compared with sham-operated controls (sham). The affinity for, and the number of, 5-HT1 and 5-HT2 binding sites, respectively, were not different between PCS and sham rats. The brain 5-HT1 and 5-HT2 binding properties were within the range of Bmax and KD previously reported for normal rats when similar techniques are used. This first report in PCS rats on the subject of brain 5-HT1 and 5-HT2 binding properties demonstrates that no major alterations are likely to occur. This contrasts the knowledge of a markedly increased brain serotonin synthesis rate in the PCS rat, suggesting minor functional relevance of the perturbed brain serotonin metabolism associated with chronic PSE.

Animals↗

PubMed1997

Searching for spatial unit firing in the prelimbic area of the rat medial prefrontal cortex.

The prelimbic area of the rat medial prefrontal cortex is anatomically connected to the CA1 layer of the temporal hippocampus. As cells recorded from this region of the hippocampus act as place cells (i.e., their firing is related to the animal's location in the environment), the possibility arises that the prefrontal recipients of hippocampal efferences also display spatial firing patterns. To examine this hypothesis, recordings were made from prelimbic frontal units while the position and head direction of the freely moving rat were simultaneously recorded by tracking two lights mounted on the rat's head. Of 42 cells recorded in this situation, none was found to have a firing pattern bearing a significant relationship to the animal's position or to its head direction. Rather, cell activity was modulated during specific behaviors such as food-searching or exploratory behaviors.

Animals↗

PubMed2003

Severe cognitive and motor coordination deficits in tenascin-R-deficient mice.

The extracellular matrix molecule tenascin-R (TN-R), predominantly expressed in the central nervous system, has been implied in a variety of functions, e.g. during myelination, cerebellar neurite fasciculation and hippocampal long-term potentiation. In this study, we investigated in detail the impact of TN-R deficiency on the living animal by analyzing the behavior of TN-R-deficient mice. The general state, gross sensory functions, reflexes and motoric capabilities appeared normal. In contrast, motor coordination on the rota-rod was compromised in these mice, indicating a deficit in cerebellar functions. In the open field and the hole board, the mutants interact differently with their environment, probably due to differences in their exploratory behavior. TN-R-deficient mice were able to learn a reference memory task in the Morris water maze. In contrast to wild-type mice, the mutants displayed an alternative strategy; swimming around the pool using a stereotypical circling pattern, crossing all possible platform positions after relocation of the escape platform (reversal). These results, confirmed by relocating the platform in the center of the pool, suggest that TN-R-deficient mice may be impaired in constructing a goal-independent representation of space. In addition, a two-way active avoidance test (shuttle box) revealed a severe deficit in associative learning in TN-R-deficient mice. Our results support important functions of TN-R in vivo in the central nervous system, in particular in the cerebellum and the hippocampus.

Animals↗

PubMed2005

Spatial exploration-induced Arc mRNA and protein expression: evidence for selective, network-specific reactivation.

The immediate-early gene Arc is transcribed in neurons that are part of stable neural networks activated during spatial exploratory behaviors. Arc protein has been demonstrated to regulate AMPA-type glutamate receptor trafficking by recruiting endosomal pathways, suggesting a direct role in synaptic plasticity. The purpose of the present study is to examine the fidelity of Arc mRNA translation and the temporal dynamics of behaviorally induced Arc protein expression after rats explore a novel environment. These experiments reveal two waves of Arc protein expression after a single exploration session. In the initial wave, virtually all cells that express Arc mRNA in the hippocampus and parietal cortex also express Arc protein, indicating, at a cellular level, that mRNA transcription and translation are closely correlated from 30 min to 2 h in hippocampal CA and parietal neurons. A second wave of protein expression spans the interval from 8 to 24 h and is also remarkably specific to cells active in the original behavior-induced network. This second wave is detected in a subset of the original active network and displays the novel property that the proportions of Arc-positive neurons become correlated among regions at 24 h. This suggests that the second expression wave is driven by network activity, and the stabilization of circuits reflecting behavioral experience may occur in temporally discrete phases, as memories become consolidated. This is the first demonstration of network-selective translational events consequent to spatial behavior and suggests a role for immediate-early genes in circuit-specific, late-phase synaptic biology.

Animals↗

PubMed1992

Enhanced social interactions in rats following chronic, centrally infused oxytocin.

Most studies investigating the behavioral effects of centrally administered oxytocin (OT) have been confined to single acute injections followed by brief behavioral observations lasting up to 90 min. The present study examines the behavioral effects of chronic, centrally administered OT in male rats observed continuously for prolonged periods of time. Either artificial cerebrospinal fluid or OT was centrally infused (via osmotic minipump) to gonadally intact male rats. Behavioral observations were made on males paired with either ovariectomized or estrous females during a 6-h time period. Most striking was the observation that durations of physical contact were doubled in pairs containing OT-infused males, even in the absence of sexual interactions. Also, OT-infused males showed significantly higher levels of anogenital sniffing of females and autogrooming; however, sexual interactions were unaffected by chronic OT. Chronic OT had no effect on body temperature, analgesia, or exploratory behavior in an open field. These findings suggest that chronic OT in male rats has behavioral effects that may significantly enhance adult social (nonsexual) interactions, possibly through alterations in olfactory and somatosensory information processing.

Analgesia↗

PubMed2006

Genetic and immunological factors interact in a mouse model of CNS antiphospholipid syndrome.

The antiphospholipid syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and beta(2)-glycoprotein I (beta(2)-GPI). We have recently reported the induction of APS associated with behavioral and cognitive deficits in BALB/c female mice that developed 4-5 months after immunization with beta(2)-GPI. In the present study, we examined the influence of genetic factors on the ability to induce experimental APS with CNS involvement by testing several mouse strains immunized with beta(2)-GPI. Female mice from five strains were immunized once with beta(2)-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). Autoantibody levels were examined at 1 and 5 months after immunization. Neurological assessment in a staircase test was performed 4-5 months following the immunization. Induction of APS resulted in elevated levels of antibodies against negatively charged phospholipids and beta(2)-GPI in all five mouse strains. Autoantibody levels were significantly higher in Balb/c, ICR, and C57BL/6 mouse strains compared to AKR and C3H. aPL levels dropped significantly more in the C57BL/6 compared to Balb/c mice over a period of 4 months. Hyperactivity reflected by higher number of stairs climbed in 3 min, was induced by APS in the Balb/c and ICR, mouse strains. Exploratory behavior reflected by more frequent rears, was seen in the APS-Balb/c and AKR mice. Hypoactivity and less exploration were seen in the APS-C57BL/6 and C3H mice. The study supports a link between high levels of aPL and behavioral changes in a mouse APS model. Qualitative differences in behavioral patterns may be due to nervous system as well as immune genetic factors. The minimal effect of APS in C57BL/6 mice may provide a suitable background for the study of transgenes in these mice.

Analysis of Variance↗

PubMed1990

Latency to enter a mirrored chamber: a novel behavioral assay for anxiolytic agents.

Many animal species exhibit approach-avoidance responses upon the novel placement of a mirror into an individual animal's environment. With a view toward identifying new behavioral measures with qualitatively or quantitatively different responses to anxiolytic agents, we developed a mirrored chamber apparatus for which adult male BALB/cByJ mice showed an extended latency to enter. Administration of diazepam significantly reduced this latency to enter a mirrored chamber in a dosage-dependent manner. The psychomotor stimulant, methylphenidate, had no effect on latency to enter the mirrored chamber at a dose which stimulated locomotor activity to the same extent as diazepam. Thus, the decreased latency to enter the mirrored chamber brought about by diazepam seems unlikely to reflect the motor effects of this benzodiazepine. The potency of diazepam was significantly lower in the mirrored chamber assay than it was on three other measures of exploratory activity--"head-dipping" performance, plus-maze performance and locomotor activity stimulation. The findings of our study indicate that the mirrored chamber method is simple to carry out, nonpunishing, rapid and quantitative and that it possesses pharmacological attributes which distinguish its response to anxiolytics from other assays of exploratory behavior.

Animals↗

PubMed1989

A new one-trial test for neurobiological studies of memory in rats. II: Effects of piracetam and pramiracetam.

The effects of the nootropic drugs Piracetam (Pir) and Pramiracetam (Pram) were evaluated on recognition-memory of rats in a new one-trial test. This test is based on spontaneous exploratory activity and does not involve rule learning or reinforcement. Recognition is measured by the time spent by rats in exploring two different objects, one familiar (the sample), the other new. When the retention interval is 1 min, normal rats spend more time exploring the new object which demonstrates that they recognize the familiar one, but they do not discriminate between the two objects after a 24-h interval. Three doses of Pram (15, 30 and 60 mg/kg) and Pir (100, 200 and 400 mg/kg) were administered i.p. 30 min before the acquisition trial. The doses of 30 mg/kg of Pram and of 400 mg/kg of Pir produced a significant improvement in retention when the intertrial interval was 24 h. This effect was not associated with a change in overall exploratory behavior. This study shows that the new object-recognition test may be a useful tool for pharmacological studies of memory in rats.

Animals↗

PubMed2005

Central nervous system and other effects.

Amylin enhanced the uptake of certain amino acids, crossed the blood-brain barrier, and increased body temperature. The physiological significance of these responses is currently unclear. An effect of peripherally injected amylin to enhance weakly trained memory fitted with similar effects of other gastrointestinal peptide hormones. Centrally administered amylin reduced locomotor and exploratory behavior. Amylin administered alone was analgesic when administered peripherally, via a non-opiate pathway. When administered in combination with opiates, there was an opiate-sparing synergy.

Amyloid↗

PubMed1995

Anxiolytic effects of dotarizine, a possible antimigraine drug.

In experiments on rats in elevated plus-maze and in Opto Varimex apparatus, used for studying exploratory behavior, we observed that dotarizine (DOT), a drug with Ca2+ and 5-HT1/5-HT2-receptor antagonistic action, exerted effects suggesting anxiolytic action. The 5-HT uptake inhibitor fluoxetine (FLU) produced mainly anxiogenic effects. The simultaneous administration of DOT and FLU weakened the anxiolytic effect of DOT. The effects of the 5-HT1B/5-HT1C receptor agonist with promigraine action, m-chlorophenylpiperazine (m-CPP), indicated anxiogenic action, which was increased to a certain extent when it was combined with FLU. Some of the other 5-HT-receptor agonists and antagonists tested showed anxiogenic action and others anxiolytic action. In most cases, these effects were changed when they were administered simultaneously with FLU. DOT increased general locomotor activity and when combined with FLU this effect tended to decrease. In contrast, m-CPP decreased general locomotor activity and this effect was potentiated by FLU. DOT at the two doses used did not significantly change the rate of development of habituation, while m-CPP, buspirone and ondansetron increased it. The behavioral effects of DOT observed in all cases opposite to the same effects of the promigraine drug m-CPP suggest an antimigraine action of DOT.

Animals↗

PubMedDate not supplied

[Change in the level of vasoactive intestinal peptide in the cerebral cortex and hypothalamus and behavioral reactions of rats after frontal lobectomy].

The effect of a change in the level of the vasoactive intestinal peptide (VIP) on the behavior of rats in frontal lobectomy was studied. It was shown by means of the radioimmunological method that damage to the frontal cortex leads to a decrease of the VIP level in the cortex and increase of its content in the hypothalamus on the 9th postoperative day. Daily injection of VIP in small doses into the lateral ventricles of the brain is conducive to more rapid and complete restoration of the conditioned bilateral avoidance reflex and the animals' exploratory behavior under conditions of an "open field" as compared to that in control rats which received a physiological solution. The possibility of using VIP in experimental complex pathogenetic therapy of disturbed functions of the central nervous system is discussed.

Animals↗

PubMed2006

The role of the basal ganglia in exploration in a neural model based on reinforcement learning.

We present a computational model of basal ganglia as a key player in exploratory behavior. The model describes exploration of a virtual rat in a simulated water pool experiment. The virtual rat is trained using a reward-based or reinforcement learning paradigm which requires units with stochastic behavior for exploration of the system's state space. We model the Subthalamic Nucleus-Globus Pallidus externa (STN-GPe) segment of the basal ganglia as a pair of neuronal layers with oscillatory dynamics, exhibiting a variety of dynamic regimes such as chaos, traveling waves and clustering. Invoking the property of chaotic systems to explore state-space, we suggest that the complex exploratory dynamics of STN-GPe system in conjunction with dopamine-based reward signaling from the Substantia Nigra pars compacta (SNc) present the two key ingredients of a reinforcement learning system.

Animals↗

PubMed1998

Combination of open field and elevated plus-maze: a suitable test battery to assess strain as well as treatment differences in rat behavior.

1. A test battery consisting of a standard open field, an enriched open field and an elevated plus maze was used to study behavior in rats. 2. Male rats of the strains PVG/OlaHsd (PVG) and Sprague-Dawley-Hsd (SPRD) (150-200 g body wt) were used to assess interstrain differences as well as handling effects. In a subsequent experiment an other set of male PVG rats (150-200 g body wt) treated either with diazepam or zolpidem was used to evaluate the test battery for pharmacological purposes. 3. SPRD rats displayed higher motor activity levels and also higher levels of exploratory behavior than the PVG rats. In contrast plus-maze activity indicated more anxiety of SPRD than PVG rats. One week pre-test handling increased the activity of both strains but it increased explorative behavior in the enriched open field only in SPRD rats. Diazepam had a substantial anxiolytic effect. Zolpidem enhanced the explorative activity in a differently to diazepam and exerted only minor anxiolytic properties. 4. We concluded that the test battery used here enables to reveal differentially strain, and treatment effects in rats.

Analysis of Variance↗

PubMed2006

Hesr1 knockout mice exhibit behavioral alterations through the dopaminergic nervous system.

The basic helix-loop-helix (bHLH) transcriptional factor Hesr1 gene (hairy and enhancer of split-related 1, also called Hey1/HRT1/CHF2/HERP2) has been identified and characterized as a member of the subfamily of hairy/Enhancer of split, and shown to be involved in cardiovascular and neural development. We report that HESR1 binds directly to a part of the 3' non-coding region of the human dopamine transporter (DAT1) gene and represses the endogenous DAT1 gene in HEK293 cells. To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis. Several dopamine-related genes, such as DAT, dopamine receptors D1, D2, D4, and D5, were significantly upregulated. Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests. These results indicate that the HESR1 gene is related to neuropsychiatric disorders and behavioral traits through the dopaminergic nervous system.

Analysis of Variance↗

PubMed2005

Behavioral correlates of activity in identified hypocretin/orexin neurons.

Micropipette recording with juxtacellular Neurobiotin ejection, linked micropipette-microwire recording, and antidromic and orthodromic activation from the ventral tegmental area and locus coeruleus were used to identify hypocretin (Hcrt) cells in anesthetized rats and develop criteria for identification of these cells in unanesthetized, unrestrained animals. We found that Hcrt cells have broad action potentials with elongated later positive deflections that distinguish them from adjacent antidromically identified cells. They are relatively inactive in quiet waking but are transiently activated during sensory stimulation. Hcrt cells are silent in slow wave sleep and tonic periods of REM sleep, with occasional burst discharge in phasic REM. Hcrt cells discharge in active waking and have moderate and approximately equal levels of activity during grooming and eating and maximal activity during exploratory behavior. Our findings suggest that these cells are activated during emotional and sensorimotor conditions similar to those that trigger cataplexy in narcoleptic animals.

Action Potentials↗

PubMed1980

Gender and early environmental influences on activity, overresponsiveness, and exploration.

One hundred eighty-five rats reared in either an enriched or restricted environment were tested during adulthood to determine the influence of gender and rearing environment on 3 related response characteristics, activity, overresponsiveness, and exploratory behavior. Eight experiments were performed. It was found that although females are more active than males, rearing environment does not influence behavior in the running wheel or open field. When tested in a complex compartmentalized open field, females in general and restricted rats are significantly more active than enriched males. In addition, over subsequent testing, restricted animals are increasingly responsive and fail to habituate to the testing stimuli. When tested and retested for maze learning ability, males excel over females; enriched rats maintain their ability to outperform restricted rats, although both groups had previously learned the problem. Moreover, enriched rats demonstrate a greater tendency to explore and make irrelevant section entries on a maze that is problem free. Restricted rats, specifically, and females generally, have difficulty suppressing a learned repetitious pattern of rewarded responding when it is subsequently punished; restricted rats were deficient in the ability to passively avoid or escape noxious stimuli. These experiments, as well as supporting evidence in the literature, indicate that rats reared in a restricted environment develop a limited behavioral repertoire which is characterized by a generalized tendency to overrespond, a propensity towards perseverating in repetitious patterns of limited and circumscribed responding, and a failure to habituate to repeated contact with novel stimuli.

Aging↗