Suppression Of Exploratory Behavior Research Articles

Nanoparticles and nanomaterials as inevitable modern toxic agents. Review. Part 3. Influence of nanoparticles on brain and behavior. Conclusions and unsolved problems

The final part of the review focuses on the existing methods and results of studying the effects of nanoparticles (NPs) on the brain and behavior. The types of behavioral tests used to assess changes in the behavior of NP-treated animals are described. The data accumulated in the literature on the negative influence of NPs on animal brains exposed to NPs in adulthood are considered. The signs of different cellular and tissue damage are presented, such as development of oxidative stress in the brain, inflammation and swelling, disturbances in the structure of cells, and an increase in the permeability of the bloodbrain barrier. Disturbances in spatial memory, working, and long-term reference memory, decreased propensity for social interactions, inhibition of exploratory behavior, depression and anxiety, and impaired motor coordination, were found after various types and duration of contact of animals with NPs. The accumulated information about the negative consequences of prenatal and early postnatal, during lactation, for example, contact with NPs for mature offspring, is also described. Various cellular and tissue damage is found in the brain of young animals, such as the inhibition of cell proliferation, an increase in the number of cells undergoing apoptosis, edema and vascular degeneration, a decrease in the expression of genes associated with neurogenesis, and numerous signs of the development of oxidative stress. Behavioral disturbances in adult animals that had contact with NPs in early ontogenesis are considered, such as manifestations of depressive behavior or increased anxiety and suppression of spatial and short-term memory. Contradictory results of studies about contact with NPs in both adulthood and early ontogenesis are also presented. In conclusion, unresolved issues are highlighted, and general conclusions on the review are given.

Effects of Chronic Administration of Low-Dose Interleukin-1β on Exploratory Behavior and Spatial Memory in Rats

The actions of chronic i.p. administration of the proinflammatory cytokine interleukin-1β (IL-1β) on exploratory behavior and spatial memory were studied in rats. IL-1β was given at the weakly pyrogenic dose of 0.5 μg/kg daily for 14 days (starting seven days before and continuing through seven days of behavioral testing). Behavior was analyzed 23.5 h after sequential injections of cytokine. A battery of tests was used, including the open field test (on three sequential days), exploration of novel objects, and the Morris water maze. Experimental animals showed a significant decrease in motor activity, a minor increase in anxiety, and suppression of exploratory behavior. Impairments to spatial memory were not seen.

Dopamine-NO Interactions in the Nucleus Accumbens during Stress-Induced Inhibition of Exploratory Behavior

Experiments on Sprague–Dawley rats using vital intracerebral microdialysis showed that stress accompanied by the acquisition of a conditioned reflex fear reaction leads, at one day, to inhibition of exploratory activity and reductions in exploratory activity-induced increases in extracellular citrulline level (citrulline is a coproduct of NO synthesis) in the nucleus accumbens). Administration of the D2 dopamine receptor antagonist raclopride (10 μM) after acquisition of the conditioned reflex fear reaction led, one day after administration, to recovery of the parameters of exploratory behavior and reversal o the increase in the extracellular citrulline level in the nucleus accumbens accompanying this behavior. These data provide the first evidence that inhibition of exploratory behavior by previously experienced stress may be mediated by a stress-induced decrease the activity of the nitrergic system of the nucleus accumbens formed with the involvement of dopamine D2 receptors in this structure.

GABA-Nitrergic Interactions in the Nucleus Accumbens during Inhibition of Exploratory Behavior by Danger Signals

Vital intracerebral microdialysis experiments in Sprague–Dawley rats with high-performance liquid chromatography (HPLC) showed that presentation during exploratory behavior of a tone previously combined with pain stimulation decreased exploratory activity and inhibited the exploratory behavior-induced increase in the extracellular citrulline (a co-product of NO synthesis) level in the medial sector of the nucleus accumbens. Administration of the GABAA receptor antagonist bicuculline (20 μM) into the medial sector of the nucleus accumbens firstly produced partial recovery of the increase in the extracellular citrulline level in this structure induced by exploratory behavior and suppressed by a tone previously combined with pain stimulation and, secondly, prevented inhibition of exploratory behavior by this danger sound signal. The data obtained here provide the first evidence that inhibition of exploratory behavior by danger signals and the exploration-associated activation of the nitrergic system of the medial sector of the nucleus accumbens are mediated by GABAA receptor mechanisms.

Ginger (zingiber officinale roscoe) prevents morphine-induced addictive behaviors in conditioned place preference test in rats.

Consumption of chronic morphine induces neuro-inflammation and addictive seeking behavior. Ginger (Zingiber Officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments. It has been shown that ginger has anti-inflammatory, anti-oxidative and antinociceptive properties. However, its influences on morphine-induced addictive behaviors have not yet been clarified. The aim of the present study was the inhibition of exploratory behavior of morphine addiction in the conditioned place preference test in male desert rats through ginger. For conditioning to the morphine, the male Wistar rats received morphine (12 mg/kg intraperitoneally or i.p.) for 6 consecutive days and treatment groups were given different doses of ginger (25, 50 and 100 mg/kg intragastrically or i.g.) 30 min before morphine injection. For investigating addictive seeking behavior, conditioned place preference test (CPP) was used. Our result demonstrated that injection of morphine for 6 days induces dependency to morphine and creates addictive seeking behavior and ginger (100 mg/kg) could decrease time spend in conditioning box (addictive seeking behavior). The data indicated that ginger extract has a potential anti-addictive property against chronic usage of morphine.

A new animal model of headache: Ongoing pain vs stimulus-evoked hypersensitivity

The field of basic pain research has had an ongoing need to develop better ways of assessing pain in animals, especially ‘‘spontaneous’’ or ongoing pain as opposed to tactile or thermal hypersensitivity (1–7). It has been argued that the lack of adequate behavioral assays for spontaneous pain is a key factor in the failure to develop new drugs for pain treatment, in spite of enormous advances in the understanding of basic mechanisms and the identification of molecular targets. The headache field in particular for many years suffered from the severe limitation of having no behavioral assay whatsoever. One exception was the finding of Malick et al. of a moderate decrease in feeding behavior over a six-hour period following chemical stimulation of the dura in awake rats (8). However, this finding was not pursued further as a behavioral assay, in part because of the relatively long observation time required. A major breakthrough for basic headache research came when Oshinsky and Gomonchareonsiri showed that chemical stimulation of the dura induced facial allodynia in awake rats, providing for the first time an acutely measureable behavioral correlate, albeit indirect, of ‘‘headache’’ in animals (9). However, the problem still remained of finding a behavioral correlate of ongoing or ‘‘spontaneous’’ headache pain, as opposed to the allodynia that can sometimes be an accompaniment to headache (10). This issue of Cephalalgia reports a finding that represents a further breakthrough for the study of headache: a new observation of a change in ‘‘spontaneous’’/ ongoing behavior following chemical stimulation of the dura in chronically prepared awake rats (11). This observation was made possible by exceptionally careful surgical implantation of the extradural cannula and acclimation of the rats to the observation environment, and second-by-second video analysis of ongoing behavior over a 45-minute observation period, made during the awake period of the animal’s circadian cycle. The core finding is a suppression of the exploratory behavior that normally occurs in control animals when placed into the observation chamber, and a concomitant increase in the amount of ‘‘resting’ behavior or quiet wakefulness. This observation might not in itself sound very remarkable. However, it is potentially of great significance as an example of the more general phenomenon of the suppression of an innate behavior/locomotor activity by pain. Such suppression is now being recognized as a new, powerful approach for assessing ‘‘spontaneous’’/ongoing pain, which has been put forth by Andrews and others who are at the forefront of developing new methods for the study of pain behavior in animals (6,7,12–15). This observation of a suppression of exploratory behavior has further significance in view of the long-standing idea that visceral pain is associated with a distinct response pattern, consisting of behavioral as well as autonomic quiescence and withdrawal, in contrast to the arousal and escape behavior evoked by superficial pain (16–19). Future studies could test the hypothesis that this suppression of exploratory behavior or other innate behaviors is greater following stimulation of deep rather than superficial tissues. This finding of Melo-Carillo and Lopez-Avila is in a sense more direct than that of Oshinsky and Gomonchareonsiri in that it is potentially a behavioral correlate of the headache itself, not merely the allodynia that can sometimes accompany headache. It may also prove to be a more sensitive assay, in that allodynia is present only in a subset of migraine attacks, whereas headache pain is (by definition) present in all attacks. The dural stimulus also induced a brief initial period of ipsilateral facial ‘‘grooming’’ or rubbing that

GABA-NO Interaction in theN. Accumbensduring Danger-Induced Inhibition of Exploratory Behavior

In Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, it was shown that presentation to rats during exploratory activity of a tone previously pared with footshock inhibited the exploration and prevented the exploration-induced increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. Intra-accumbal infusions of 20 μM bicuculline, a GABA(A)-receptor antagonist, firstly, partially restored the exploration-induced increase of extracellular citrulline levels in this brain area, which was inhibited by presentation of the tone, previously paired with foot-shock and, secondly, prevented the inhibition of exploratory behavior produced by this sound signal of danger. The data obtained indicate for the first time that signals of danger inhibit exploratory behavior and exploration-induced activation of the accumbal nitrergic system via GABA(A)-receptor mechanisms.

Behavioural Effects of Thieno and Pyrazolo[2,1] benzothiazepine Derivatives in Mice

Behavioural studies were conducted in mice with a number of hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Previously published studies in mice have shown that some of these compounds were effective in the tetrabenazine and Porsolt tests. In the present study, four of the 15 compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50 mg/kg i.p.), but no significant antagonism of the apomorphine (16 mg/kg s.c.)-induced hypothermia and potentiation of the amphetamine actions was found. Moreover, some of them inhibited the stereotyped behaviour and/or climbing behaviour of low doses of apomorphine and compound 2 was effective in the plus-maze test. These compounds also produced a slight inhibition of exploratory behaviour in the holeboard test. On the other hand, no significant muscle relaxant and anticonvulsant activities were observed at any dose employed. Together, these data suggest that some of the compounds under study combine the antidepressant effects with additional neuroleptic or anxiolytic activities in mice.

CNS Depressant and Antiepileptic Activities of the Methanol Extract of the Leaves ofIpomoea AquaticaForsk

The central nervous system (CNS) depressant and antiepileptic activities of the methanol extract of the leaves ofIpomoea aquaticaForsk (IAF) were investigated on various animal models including pentobarbitone sleeping time and hole-board exploratory behavior for sedation tests and strychnine, picrotoxin and pentylenetetrazole-induced convulsions in mice. IAF (200 and 400 mg/kg, p.o.), like chlorpromazine HCl (1 mg/kg, i.m.), produced a dose-dependent prolongation of pentobarbitone sleeping time and suppression of exploratory behavior. IAF (200 and 400 mg/kg) produced dose-dependent and significant increases in onset to clonic and tonic convulsions and at 400 mg/kg, showed complete protection against seizures induced by strychnine and picrotoxin but not with pentylenetetrazole. Acute oral toxicity test, up to 14 days, did not produce any visible signs of toxicity. These results suggest that potentially antiepileptic compounds are present in leaf extract of IAF that deserve the study of their identity and mechanism of action.

Ghrelin alters postnatal endocrine secretion and behavior in mouse offspring

Maternal bioactive substances, such as hormones and neuropeptides, are thought to be essential for fetal development. Recently, ghrelin, a gastrointestinal peptide, has been shown to pass through the rat placenta. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), has been shown to be expressed in the rat fetal central nervous system, and plasma ghrelin levels are related to birth weight in the rodent and human. In the present study, we report a role of maternal ghrelin in mouse fetal brain development. When ghrelin was administrated to pregnant mice, pups exhibited suppression of exploratory behavior in an open-field (OF) test. Control pups, however, remained for longer periods of time in the center area, correlating with exploratory behavior. Basal corticotropin-releasing hormone (CRH) plasma levels were greater in pups from ghrelin-treated dams, and did not change in response to acute restraint stress. Moreover, reduced growth hormone secretagogue receptor and neuropeptide Y mRNA expression was observed in the hypothalamus at postnatal day 3 and remained until 16 weeks of age. In addition, under physiological condition, increased maternal ghrelin plasma levels following repeated restraint stress to the dam had effect on the increase in fetal plasma acyl ghrelin levels. These results suggest that maternal ghrelin affect fetal plasma ghrelin levels and alters endocrine systems and behaviors of offspring.

Sedative and anticonvulsant activities of the aqueous root extract of Sanseviera liberica Gerome & Labroy (Agavaceae)

The central nervous system (CNS) depressant and anticonvulsant activities of the aqueous root extract of Sanseviera liberica (ASL) were investigated on various animal models including pentobarbitone sleeping time and hole-board exploratory behaviour for sedation tests, and strychnine, picrotoxin, bicuculline and pentylenetetrazole-induced convulsions in mice. ASL (100–400 mg/kg, p.o.), like chlorpromazine HCl (1 mg/kg, i.m.), produced a dose-dependent prolongation of pentobarbitone sleeping time and suppression of exploratory behaviour. ASL (100 and 200 mg/kg) produced dose-dependent and significant ( P < 0.05) increases in onset to clonic and tonic convulsions, and at 400 mg/kg, showed complete protection against seizures induced by strychnine, picrotoxin and bicuculline, but not with pentylenetetrazole. ASL up to 10 g/kg, p.o. did not produce death, but i.p. treatment produced mortalities with LD 50 of 668.3 ± 47.6 mg/kg. Preliminary phytochemical investigations of ASL revealed the presence of carbohydrates, alkaloids, saponins, reducing sugars and oils. The results indicate that ASL has sedative and anticonvulsant activities, therefore, justifying its use in traditional African medicine.

TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat

Working memory has been proposed to require the proper functioning of the medial prefrontal cortex and its dopaminergic innervation. The dopaminergic input to the medial prefrontal cortex has been demonstrated to be sensitive to physical and psychological stress. In this report, we demonstrate that a brief exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), an odor derived from a predator of the rat, the fox, resulted in elevated dopamine metabolism in the medial prefrontal cortex and elevated serum corticosterone. We tested the effects of this olfactory stress on working memory using a spontaneous, delayed, non-matching-to-sample task using object recognition methods. Rats were exposed to one set of objects and, after a delay of 1, 15 or 60 min, later demonstrated a robust working memory of the familiar object compared to a novel object. When rats were exposed to TMT during the 15-min delay, working memory was disrupted without altering exploratory behavior. We conclude from these studies that (1) TMT selectively activates mesoprefrontal dopamine neurons, (2) TMT exposure can disrupt working memory and (3) this disruption in working memory is not due to an overall suppression of exploratory behavior but may involve altered mesoprefrontal dopaminergic activity.

PHARMACOLOGICAL EVALUATION OF ALCOHOL WITHDRAWAL-INDUCED INHIBITION OF EXPLORATORY BEHAVIOUR AND SUPERSENSITIVITY TO HARMINE-INDUCED TREMOR

Rats given a liquid diet containing 10% (v/v) alcohol consume high quantities of alcohol. Within 8 hr after cessation of the alcohol intake, the animals will show alcohol-withdrawal reactions including a supersensitivity to harmine-induced tremor and an inhibition of exploratory behaviour in a neutral environment. Several drugs can overcome one or more of these alcohol-withdrawal reactions. A reduction of the alcohol withdrawal-induced inhibition of exploration, in terms of both the number of transits into the open field and the time spent in the open field, was obtained with chlordiazepoxide, ritanserin, mianserin and propranolol. Of these four compounds, propranolol and mianserin were also active against the supersensitivity to both 5.00 and 10.00 mg/kg harmine-induced tremor. Chlordiazepoxide and ritanserin were only active against 5.00 mg/kg harmine. Other compounds that reversed the supersensitivity to harmine-induced tremor during alcohol withdrawal included buspirone, fluoxetine, haloperidol, clonidine, flunarizine and baclofen. Very limited effects on both alcohol-withdrawal reactions were observed with ondansetron, nimodipine and MK-801. Risperidone and SCH 23390 were inactive. These results demonstrate that some alcohol withdrawal reactions can be studied in a systematic way and that various pharmacological agents can differentially interact with these alcohol withdrawal reactions.

Quantification of tremor sensitivity and inhibition of exploratory behaviour during alcohol withdrawal in rats

Rats given a 10% (v/v) alcohol liquid diet over two weeks reached high blood alcohol levels of around 200mg/dl. Discontinuation of the alcohol intake resulted within 6h in several withdrawal reactions including a tremorogenic activity and a reduction in exploratory behaviour in novel environments. The tremorogenic activity of the alcohol withdrawal could be quantified, using a piezo-film technique, in terms of a supersensitivity to both an inactive and a moderately active dose of the tremorogenic compound harmine. As compared to controls, the rats in alcohol withdrawal revealed more frequent tremor after both 5 and 10mg/kg harmine. The supersensitivity to harmine-induced tremor started within 6h after alcohol withdrawal and remained present with 10mg/kg harmine for up to 48h. The supersensitivity was independent of the length of the tremor bursts used to quantify harmine-induced tremor. Alcohol withdrawal also resulted in an inhibition of exploratory behaviour in a neutral two-chamber box. Both in terms of the number of transits into the open field as well as the time spent in the open area, rats in alcohol withdrawal were significantly less active than control animals. The reduced exploration started within 6h after withdrawal and remained present for up to 24h after the last alcohol intake. These results indicate that both alcohol withdrawal-induced sensitivity to tremorogenic agents and inhibition of exploratory behaviour can be quantified over time, allowing the pharmacological mechanisms involved to be studied.

Effects of the 5-HT3 antagonist ICS 205-930 on benzodiazepine withdrawal signs in rats.

Effects of the 5-HT3 antagonist ICS 205-930 on chlordiazepoxide (CDP) withdrawal were assessed in rats treated for 21 days with doses of CDP up to 40mg/kg/day (b.i.d.). Withdrawal signs recorded were body weight and 24h food intake, which both fell during withdrawal and then recovered. ICS 205-930 (0.001-1.0mg/kg) was administered b.i.d. during withdrawal. At no dose over the wide range tested did ICS 205-930 reduce withdrawal signs. These data contrast with published findings with the 5-HT3 antagonist ondanestron, some of which indicated that ondansetron completely alleviated the "anxiogenic" suppression of exploratory behaviour observed during benzodiazepine (BZ) withdrawal. Possible reasons for these differing findings are discussed. Collectively, these findings suggest that 5-HT3 antagonists may have limited utility in the clinical treatment of BZ withdrawal.

Evidence for the involvement of the 5-HT1A receptor in the anxiolytic action of indorenate and ipsapirone

The systemic injection of diazepam (0.5 and 1.0 mg/kg), indorenate (5 and 10 mg/kg) and ipsapirone (2.5 and 5.0 mg/kg) reduced anxiety as tested in an exploratory avoidance model in mice. The injection of pindolol (2.0 mg/kg), alprenolol (5.0 mg/kg) or methiotepin (0.25 mg/kg) effectively prevented the anxiolytic action of indorenate and ipsapirone. The combined treatment of the antagonists with indorenate or ipsapirone did not reduce the motor activity, therefore suggesting that the inhibition of exploratory behaviour, after such combinations, was not mediated through a general motor impairment. Neither diazepam nor indorenate alone modified the motor activity; ipsapirone (5 and 2.5 mg/kg), however, reduced ambulation. This reduction was also prevented by administering pindolol, alprenolol or methiotepin. These observations suggest that the anxiolytic actions of indorenate and ipsapirone are mediated via stimulation of the 5-HT1A like receptor subtype.

Inhibition of exploratory behavior in the rat by handling

The effect of tail-handling on exploratory behavior of the rat, measured as step-through latency in a well-lighted, two-box apparatus, was investigated. Male adult Wistar rats, aged 60 days, were employed in all three experiments. Experiment 1, in which the subjects were handled at different times after entering the goal chamber (0, 10, 30, 60, 300, and 600 sec), showed that immediate handling, relative to detention in the goal chamber (delay of handling) had an inhibitory effect on exploration. Experiment 2 showed that groups handled immediately after entering the goal chamber but then detained there for different durations all showed the same progressive inhibition of exploration. Experiment 3 showed that the inhibition of exploration (very long step-through latencies) due to tail-handling immediately after entering the goal chamber could be significantly decreased by further trials in which handling was delayed for a sufficient duration (30 sec or more). Handling is discussed as a stimulus that is aversive enough to elicit conditioned passive-avoidance responses (inhibition of exploratory behavior), although it is subject to rapid extinction.

5HT-2 mediation of acute behavioral effects of hallucinogens in rats

In rats tested during their first exposure to a Behavioral Pattern Monitor chamber, acute injections of the 5HT-2 agonists mescaline, quipazine, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), or 2,5-dimethoxy-4-ethylamphetamine (DOET) produced an inhibition of locomotor and investigatory behavior during the first 30 min of the test session. This suppression of exploratory behavior was attenuated when rats were familiarized with the testing chamber prior to the administration of DOI. Hence, as previously observed with both LSD and DOM, 5HT-2 agonists appear to potentiate the normal neophobic reaction to a novel environment. The mixed 5HT-1 and 5HT-2 agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also produced a decrease in activity when animals were tested in the novel environment. However, as previously found with 5HT-1A agonists, this effect was unchanged when animals were tested in the familiar environment and may therefore reflect a generalized sedation. The receptor specificity of these differential effects of 5HT-1 and 5HT-2 agonists in this paradigm was tested by assessing the ability of selective 5HT-2 antagonists to block the effects of the agonists. A dose of the 5HT-2 antagonist ketanserin which had no effect by itself significantly reduced the behavioral effects of mescaline, DOM, and quipazine. Similarly, the selective 5HT-2 antagonist ritanserin blocked the effect of quipazine. In contrast, ketanserin had no significant effect on the suppression of activity produced by the 5HT-1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8OHDPAT).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of extracellular dopamine levels can be dissociated from suppression of exploratory behaviour in rats.

Reduction of extracellular dopamine levels can be dissociated from suppression of exploratory behaviour in rats.

On the mode of action of six putative dopamine receptor agonists on suppression of exploratory behaviour in rats.

The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereo-typed behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.