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Effect of CCK1 and CCK2 receptor blockade on amphetamine-stimulated exploratory behavior and sensitization to amphetamine.

Interactions between dopaminergic neurotransmission and cholecystokinin (CCK) in the CNS may be important in the pathogenesis of psychotic disorders and substance abuse. In this study, the effect of coadministration of the selective CCK receptor antagonists devazepide and L-365,260 (for selectively blocking CCK1 and CCK2 receptors, respectively), on the effect of amphetamine on the rat exploratory behavior, and on sensitization of locomotor response to amphetamine, were studied. Amphetamine (0.5 mg/kg) increased exploratory activity in the exploration box for 5 consecutive testing days, while devazepide (10 microg/kg) blocked and L-365,260 (10 microg/kg) enhanced amphetamine-induced stimulation of activity. Devazepide coadministration prevented the development of sensitization to amphetamine, while coadministration of L-365,260 with amphetamine potentiated the locomotor effect of a challenge dose of amphetamine. These results suggest that endogenous CCK, released during exploratory activity, shapes behavioral responses to amphetamine by acting on both receptor subtypes, and modulates the development of sensitization to amphetamine.

Amphetamine↗

Fimbria-fornix lesions disrupt the dead reckoning (homing) component of exploratory behavior in mice.

Exploration is the primary way in which rodents gather information about their spatial surroundings. Thus, spatial theories propose that damage to the hippocampus, a structure thought to play a fundamental role in spatial behavior, should disrupt exploration. Exploration in rats is organized. The animals create home bases that are central to exploratory excursions and returns, and hippocampal formation damage alters the organization of exploration by disrupting returns. Mice do not appear to readily establish home bases in novel environments, thus, for this species, it is more difficult to establish the contribution of the hippocampus to exploration. The purpose of the present study was threefold: develop a task in which mice center their exploration from a home base, determine whether the exploratory behavior is organized, and evaluate the role of fimbria-fornix lesions on exploration. Mice were given a novel exploratory task in which their nesting material was placed on a large circular table. Video records of control and fimbria-fornix mice were made in both light and dark (infrared light) conditions. Exploration patterns (outward trips, stops, and homeward trips) were reconstructed from the video records. Control mice centered their activity on their bedding, from which they made circuitous outward trips marked by many stops, and periodic direct returns. The bedding-centered behavior and outward trips of the fimbria-fornix mice were similar to those of the control mice, but significantly fewer direct return trips occurred. The direct homeward trips observed under light and dark conditions were consistent with a dead-reckoning strategy, in which an animal computes its present position and homeward trajectory from self-movement cues generated on the outward trip. Because the fimbria-fornix lesions disrupted the homeward component of exploratory trips, we conclude that the fimbria-fornix may contribute to dead reckoning in mice. The results also show that the home-bedding methodology facilitates the establishment of a home base by mice, thus providing a useful methodology for studies with mice.

Animals↗

A corticotropin-releasing factor antagonist reverses the stress-induced changes of exploratory behavior in mice.

Corticotropin-releasing factor (CRF) administered intracerebroventricularly (ICV) to rats and mice has been shown to elicit a variety of behaviors resembling those that occur in stress. In a novel multicompartment chamber, ICV CRF altered the behaviors in a manner closely resembling that observed following a period of restraint. In particular, 75 ng CRF ICV or 30-40 min restraint markedly reduced the time mice spent in contact with novel stimuli. ICV injections of a peptide antagonist of CRF, alpha-helical CRF9-41 (ahCRF), reversed the effects of restraint on this measure. This effect of ahCRF was dose dependent, with a minimal effective dose of 10 micrograms. Other behavioral measures appeared normal, and ahCRF did not significantly alter the stimulus-contact time in unrestrained mice. These results provide strong evidence to support the hypothesis that endogenous CRF may be a factor affecting stress-induced changes in exploratory behavior in mice.

Animals↗

A comparative analysis of learning and exploratory behavior of rats with varying resistance to stressor influences and the level of brain monoamines.

Experiments have demonstrated that Wistar rats resistant (R) to acoustic stimulation differed from nonresistant (NR) rats by elevated exploratory activity under the condition of moderate stress in an open field test, by heightened reactivity to sensory stimuli of varying modality (somatosensory, visual, and olfactory), and by a reduced level of exploratory behavior in a burrow chamber. The rats of the R group differ from the NR animals by a greater capacity to learn a goal-directed reaction and by a lower capacity for discrimination of emotionally distinct influences. The results of a biochemical analysis of the content of biogenic amines in particular brain structures revealed in the resistant rats an increase in the level of norepinephrine, and in the non-resistant rats, a higher level of dopamine and serotonin.

Acoustic Stimulation↗

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol.

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonist d-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 and beta-adrenergic antagonist d,l-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 micrograms/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 micrograms/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. (ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗

Action of ipsapirone and 8-OH-DPAT on exploratory behavior in hamsters (Mesocricetus auratus): effects of antagonists and p-CPA.

The effect of the serotonergic drugs 8-OH-DPAT (0.0625, 0.125, and 0.25 mg/kg) and ipsapirone (5.0 and 10.0 mg/kg) on the exploratory behavior shown by hamsters under light:dark conditions was studied. These drugs produced an increase in the number of transitions similar to that induced by diazepam (0.25, 0.5, and 1.0 mg/kg), suggesting an anxiolytic action. The antagonists, methiotepin (0.31 mg/kg), pindolol (2.0 mg/kg), and alprenolol (5.0 mg/kg), did not modify the number of transitions per se and were partially effective in reverting ipsapirone's action. Similarly, methiotepin and pindolol partially blocked 8-OH-DPAT actions, whereas alprenolol lacked an effect. Drug-induced increases in this behavior occurred despite the administration of p-CPA (400 mg/kg x 3 days). The neurochemical analysis revealed that this treatment decreased 5-HT levels (from 40% to 60%). Motor activity was assessed to control unspecific drug actions; 8-OH-DPAT produced an increase that was effectively blocked by methiotepin, but was unaffected by pindolol, alprenolol, or p-CPA. These results suggest that the increase in the number of transitions produced by 8-OH-DPAT cannot be interpreted on the basis of a reduced anxiety state. Data are discussed in terms of the similarities and differences between the actions of 5-HT1A drugs in hamsters when compared with rats and mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

[Effects of NMDA antagonist, MK-801 on spatial exploratory behavior in the rat].

Rats given an antagonist against N-methyl-D-aspartate, (+)-10, 11-dihydro-5-methyl-5H-debenzo (a, d) cycloheptene-5, 10-imine (MK-801), were compared with control rats for their activity and exploratory behavior (habituation, exploration time to the spatial change of one of 4 objects and to the new object) in a circular open field. Rats given 0.07 mg/kg dose of MK-801 displayed no significant differences with the controls. Rats given 0.1 mg/kg dose of MK-801 failed to respond to the spatial change, whereas they displayed habituation and exploration to the new object at the same degree as the control rats. Rats given 0.3 mg/kg dose of MK-801 displayed hyperactivity and did not display habituation and exploration. The result suggests that the 0.1 mg/kg dose of MK-801, which dose not affect on activity, habituation and exploration to the new object in rats, selectively affects on acquisition of spatial information and reduces their spatial exploration.

Animals↗

Cerium tissue/organ distribution and alterations in open field and exploratory behavior following acute exposure of the mouse to cerium (citrate).

Cerium chloride (1:3 complex with sodium citrate) was administered to male Swiss mice (6 to 8 weeks old) either intragastrically or subcutaneously at the 7 day LD5 or LD25 level. Open field behavior (ambulations, rearings) was quantified and tissue/organ Ce levels determined at 4 hr., 1, 3 or 7 days post administration. Via the i.g. route, Ce was poorly absorbed resulting in no observable behavioral alterations and no correlations between behavior and tissue levels. Via the s.c. route, Ce significantly (p less than 0.05) depressed ambulations and rearings, mainly at short times following administration of the LD25 dose. Analogous findings were obtained in a separate study of exploratory behavior. There was a significant (p less than 0.05) correlation between open field behavior and tissue Ce levels: thus, rearings were inversely correlated with lung, stomach, cerebrum, cerebellum and brain stem Ce levels and ambulations were inversely correlated with liver, kidney, lung, blood, stomach, intestine, muscle, cerebrum, cerebellum and brain stem levels. Spleen Ce levels and ambulations were directly correlated and it is speculated that the spleen may serve a protective function in the case of Ce intoxication.

Administration, Oral↗

Abnormal exploratory behavior in transgenic mice carrying multiple copies of the human gene for S100 beta.

S100 beta, a calcium-binding brain protein, has been implicated in brain development and hippocampal neurophysiology including long-term potentiation. Its gene maps to chromosome 21, which is duplicated in Down syndrome. S100 beta levels are elevated in both Down syndrome and Alzheimer's disease, human neurodegenerative diseases associated with mental retardation and dementia. To investigate whether or not elevated S100 beta levels can cause brain dysfunctioning in mammals, transgenic mice carrying multiple copies of the human S100 beta gene were generated. Several independent lines of transgenic mice were compared to age-matched normal control mice of identical genetic background (CD1) by measuring their exploratory behaviors in novel situations. Transgenic mice exhibited a range of defects including female specific hyperactivity, lack of habituation to novelty and reduced T-maze spontaneous alternation rate. Although the neuroanatomical or physiological substrate of these abnormalities is unknown, they are similar to the behavioral manifestations of hippocampal dysfunction. The S100 beta mouse offers one of the first opportunities to investigate the relationship between over-expression of a human chromosome 21 gene product and abnormal behavior and brain functioning.

Animals↗

Circadian effects of scopolamine on memory, exploratory behavior, and muscarinic receptors in mouse brain.

Mice were maintained at light-dark cycle with lights on from 05:00-19:00 for 10 d in laboratory. The study was performed at 07:00-09:00, 15:00-17:00, and 21:00-23:00 in June and July. Scopolamine (Scop, 0.1 and 0.4 mg.kg-1, ip) was injected 15 min prior to training or the first exploratory test. The amnesic effects of Scop showed hyperresponses at 07:00-09:00 and 15:00-17:00, and hyporesponses at 21:00-23:00 using step-through and step-down tasks. The circadian effects of Scop on exploratory behavior were consistent with the findings above mentioned. The numbers of [3H]quinuclidinyl benzilate ([3H]QNB) binding sites in the temporal cortex and hippocampus were more at 08:00 and 16:00 than those at 22:00. However, muscarinic receptor levels in the striatum were lower at 08:00 than those at 22:00. These results indicated that the effects of Scop on memory, behavior in a novel environment, and muscarinic receptors in brain regions showed circadian changes in mice.

Animals↗

Mesolimbic and mesocortical dopaminergic neurons are necessary for normal exploratory behavior in rats.

After ablation of mesolimbic and mesocortical dopaminergic neurons produced by 6-hydroxydopamine (6-OHDA) injections in the anterolateral hypothalamus, rats investigate a novel object less. Systemic administration of the dopamine (DA) agonist apomorphine increases investigatory movements in these DA-denervated rats when the object is novel, but not when the object is familiar. Pimozide pretreatment prevents the increased investigation produced by apomorphine in DA-denervated rats. These findings suggest that mesolimbic and mesocortical DA neurons are necessary for normal exploratory behavior in the rat.

Animals↗

Postnatal lead exposure affects motor skills and exploratory behavior in rats.

The present study was undertaken to investigate the behavioral effects of postnatal lead exposure. Newborn male Sprague-Dawley rats were given 1 or 8 mg/kg lead acetate intraperitoneally daily for 20 days. Control rats received 1 mg/kg sodium acetate, or 8 mg/kg sodium acetate in oversized litters. The high dose lead acetate group and the high dose, oversized sodium acetate group showed impaired weight and length increment during the end of the treatment. Rats treated with the higher dose of lead showed delayed eye opening. The time required to turn in a negative geotaxis test was transiently longer in rats treated with the higher dose of lead. A tendency of reduced forepaw grasping ability was seen in lead-treated rats during the end of the lead exposure. Ambulation and rearing in an open field were lower for the rats treated with the higher dose of lead acetate during certain periods of development. Impaired performance in a balancing rod test was also seen in the rats treated with the higher dose of lead at the adult stage, while no difference was seen in ambulation or gnawing activity during tail pinch-induced stress. Thus, lead intoxication in rats during the early postnatal period, with doses that approximate those in children, induced transient as well as persistent dysfunctions in exploratory behavior and motor skills. These observed actions of lead may be related to impaired maturation of sensitive brain regions which develop postnatally.

Animals↗

Modulation of exploratory behavior in female mice by protein-borne male urinary molecules.

Male pheromones are believed to attract females and repel male mice in open field tests but, when tested in more complex environments, they can attract male mice in usually avoided areas. Females were tested in an apparatus with one dark and one light side, in the absence or presence of male urine or the major urinary proteins (MUPs) bearing the natural ligands. Diestrous females were slower in leaving from the dark area when male urine or MUPs were present in it. Estrogen-primed females showed the opposite behavior, with an increase in the same latency. The light-avoidance behavior of prepubertal females, or females reared without males was not influenced by the presence of male chemosignals. The results show that adult female mice can react to MUP-borne volatiles as to adult male urine and use them as cues of male mice, if they were previously exposed to male cues during infancy. MUP-borne molecules are, thus, the olfactory trace of males in the environment and modulate mice exploratory behavior.

Alpha-Globulins↗

Effect of age and level of cognitive function on spontaneous and exploratory behaviors in the beagle dog.

Cognitively characterized young and aged beagle dogs were administered six different spontaneous behavior tests, which provided measures of locomotion, exploration, and social interaction. Consistent with our previous findings, we obtained no overall effect of age on locomotion. We did find, however, that for the aged dogs locomotion correlated with level of cognitive function, being lowest in age-unimpaired dogs and highest in impaired dogs. Exploratory behavior, as measured by response to novelty, varied with age, with young dogs scoring the highest. Young dogs spent more time with novel toys and a person, responded more to a silhouette of a dog, and interacted more with a model dog compared to aged dogs. Among the aged dogs, age-unimpaired dogs spent the greatest amount of time sitting or standing beside a person whereas age-impaired dogs spent the most time reacting to a reflection in a mirror. The age-impaired dogs show undirected, stereotypical types of behavioral patterns. These differences in activity patterns may be linked to underlying age-associated neuropathology.

Aging↗

Prior exposure to stress reduces the diversity of exploratory behavior of novel objects in the rat (Rattus norvegicus).

Although a large literature has documented the varied effects of stress on an organism, relatively little attention has been devoted to investigating stress effects in ecologically relevant situations. Our experiment was conducted to assess the effects of stress on rats' (Rattus norvegicus) exploration of novel objects in a seminaturalistic and familiar environment that is relatively free of the constraints that have been placed on rats in prior investigations of stress. The results show that prior exposure to stress decreased the rats' diversity of exploration but did not affect general activity in comparison with animals not exposed to stress. We propose that the effect of stress on the qualitative aspects of exploratory behavior may be due to effects on organisms' sensitivity to predation.

Animals↗

2-DG uptake patterns related to single vibrissae during exploratory behaviors in the hamster trigeminal system.

Stimulation of one or several whiskers activates discrete foci throughout the trigeminal (V) neuraxis. These foci contribute to patterns, corresponding to the patterns of vibrissae, that have been directly related to aggregates of cells and axon terminals in the "barrel" cortex. Here, we combine high-resolution, 2-deoxyglucose (2DG) mapping and cytochrome oxidase (CO) staining to determine whether the known pattern of V primary afferent projections is sufficient to deduce the functional activation of their targets during exploratory behavior. Four adult hamsters had all of their large mystacial vibrissae trimmed acutely, except for C3 on the left, and B2 and D4 on the right; in two others, the left C3 and right A1 and E4 whiskers were spared. After fasting overnight, 2DG was injected and the animals behaved freely in the dark for 45 minutes. The brainstem, thalamus, and cortices were sectioned, then processed for both CO staining and 2DG autoradiography. Image-processing microscopy was used to separate the autoradiographic silver grains from the histochemical staining. CO patches were patterned in a whisker-like fashion in the full rostrocaudal extent of V nucleus principalis and in caudal portions of spinal V subnuclei interpolaris and caudalis, but absent in subnucleus oralis. 2DG silver grains were densest above those CO patches in the pattern corresponding to the active whiskers. There were no consistent 2DG foci in subnuclei oralis or rostral caudalis. In these same cases, prominent 2DG labeling was restricted to the appropriate barrels in the contralateral cortex. Only one case, however, displayed a clear and appropriate region of heightened 2DG uptake in contralateral ventroposteromedial thalamus (VPM) and the adjacent part of the reticular thalamic nucleus. Patterns of increased glucose utilization with single whisker stimulation are well matched to the CO patterns that mirror distributions of neurons associated with a vibrissa in the V brainstem complex, thalamus, and cortex. Single whiskers are represented by relatively homogeneous longitudinal columns of 2DG labeling in the V brainstem nuclei. The columns are not continuous through the axial extent of the V brainstem complex; rather, they occur separately within principalis, interpolaris, and caudalis. While whisker columns were consistently labeled in interpolaris and caudalis in all animals, the labeling was increasingly variable in principalis, barrel cortex, and VPM, respectively. This suggests that the behaving animal can and does significantly modulate activity in this major, synaptically secure pathway.

Afferent Pathways↗