Habituation Of Locomotor Activity Research Articles

Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring

Developmental neurotoxicity of a wide variety of toxicants mediated via maternal exposure during gestation is very well established. In contrast, the impacts of paternal toxicant exposure on offspring neurobehavioral function are much less well studied. A vector for paternal toxicant exposure on development of his offspring has been identified. Sperm DNA can be imprinted by chemical exposures of the father. Most but not all of the epigenetic marks in sperm are reprogrammed after fertilization. The persisting epigenetic marks can lead to abnormal genetic expression in the offspring. We have found that paternal delta-9-tetrohydrocannabinol (THC) exposure in rats causes changes in methylation of sperm (Murphy et al., 2018). This is similar to cannabis-associated changes in sperm DNA methylation we found in human males who smoke cannabis (Murphy et al., 2018). In the current study we investigated the intergeneration effects of THC exposure of young adult male rats (0 or 2 mg/kg/day orally for 12 days) to the neurobehavioral development of their offspring. This paternal THC exposure was not found to significantly impact the clinical health of the offspring, including litter size, sex ratio, pup birth weight, survival and growth. However, it did cause a long-lasting significant impairment in attentional performance in the offspring relative to controls when they were tested in adulthood. There was also a significant increase in habituation of locomotor activity in the adult offspring of the males exposed to THC prior to mating. This study shows that premating paternal THC exposure even at a modest dose for a brief period can cause deleterious long-term behavioral effects in the offspring, notably significant impairment in an operant attention task. Further research should be conducted to determine the degree to which this type of risk is seen in humans and to investigate the mechanisms underlying these effects and possible treatments to ameliorate these long-term adverse behavioral consequences of paternal THC exposure.

Modulatory Effects of Cortexin and Cortagen on Locomotor Activity and Anxiety-Related Behavior in Mice

Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.

Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human CU/ZN superoxide dismutase (GLY 93→ALA) mutation

Apart from the extensive loss of motor neurons, degeneration of midbrain dopaminergic cells has been described in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Mice overexpressing the mutant human Cu/Zn superoxide dismutase (SOD1) show an ALS-like phenotype in that they show a progressive death of motor neurons accompanied by degeneration of dopaminergic cells. To describe the functional alterations specifically associated with this dopaminergic dysfunction, we have investigated the corticostriatal synaptic plasticity in mice overexpressing the human SOD1 (SOD1+) and the mutated (Gly 93→Ala) form (G93A+) of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generates long-term depression (LTD) in SOD1+ mice and in control (G93A−/SOD1−) animals, whereas in G93A+ mice the same stimulation generates an N-methyl-D-aspartic acid receptor-dependent long-term potentiation. No significant alterations were found in the intrinsic membrane properties of striatal medium spiny neurons and basal corticostriatal synaptic transmission of G93A+ mice. Bath perfusion of dopamine or the D 2 dopamine receptor agonist quinpirole restored LTD in G93A+ mice. Consistent with these in vitro results, habituation of locomotor activity and striatal-dependent active avoidance learning were impaired in G93A+ mice. Thus, degeneration of dopaminergic neurons in the substantia nigra of G93A+ mice causes substantial modifications in striatal synaptic plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.

Isolation rearing affects sequential organization of motor behavior in post-pubertal but not pre-pubertal Lister and Sprague–Dawley rats

Objective: Dopaminergic and serotonergic modulation potently influences the sequential organization of rat movements in a simple unconditioned motor paradigm. Rats reared in social isolation post-weaning differ profoundly from their socially reared litter mates on behavioral, neurochemical, and neuroanatomical measures. This investigation examined (1) whether social isolation significantly affects the sequential organization of rat movements, (2) whether these changes occur at different ages, and (3) whether these changes differ across strains. Method: male Lister and Sprague–Dawley rats reared in isolation post-weaning and socially reared controls were tested at 2 and 8 weeks post-weaning, in the Behavioral Pattern Monitor for 30-min sessions. The amount of activity and the spatial patterns of movements as measured by both the spatial scaling exponent and the fluctuation spectrum of local spatial scaling exponents were assessed in 10-min intervals. Results: Habituation of locomotor activity was significantly attenuated in isolation reared rats during the 30-min sessions irrespective of strain. Spatial patterns of movements were significantly affected by isolation rearing in movements in post-pubertal but not pre-pubertal Lister and Sprague–Dawley rats. The spatial scaling exponent and the fluctuation spectrum analysis revealed a shift towards straight, distance-covering, and repetitive movements rather than a complex re-organization of the behavioral repertoire. Conclusions: Isolation rearing profoundly affects the sequential organization of movements in post-pubertal rats, suggesting that emerging behavioral dysfunctions parallel developmentally those found in patients with schizophrenia.

The effect of serotonin depletion on rat adaptive behavior in high and low responders to novelty

Adaptive behavioral responses to repeated daily testing in the open field test (OFT) were studied in rats that had a different locomotor response to a novel environment (ambulatory scores above and below the median, respectively). A clear-cut progressive habituation of exploratory activity was observed over the 5 daily sessions, but was more pronounced in HR (high responders) than in LR (low responders). p-Chlorophenylalanine-induced serotonin depletion, confirmed biochemically by high-performance liquid chromatography (HPLC), attenuated the rate of behavioral habituation in the LR and HR (to a minor degree), and abolished the between group differences in motor activity in the OFT. Autoradiography revealed a significantly greater specific binding of the GABAA receptor agonist, [3H]muscimol, to the entorhinal cortex of LR than to the entorhinal cortex of HR rats, and a near-significant trend within the dentate gyrus of the hippocampus, but not within other brain structures. In conclusion, serotonin was found to contribute in a complex way to the habituation of locomotor activity, an effect that depended on the initial level of locomotor activity. The intrinsic mechanism underlying the observed effects might involve changes in central GABAA receptors.

Behavioural and histological effects of low concentrations of intraventricular AF64A

The effects of ethylcholine mustard aziridinium ion (AF64A; 0.3, 1.0 and 3.0 nmol), injected into each lateral ventricle in the rat, were determined in a range of behavioural tests, each involving a learning component. Effects were observed at 1.0 and 3.0 nmol/side and, to a lesser extent, at 0.3 nmol/side. Habituation of locomotor activity was impaired and deficits in learning were obtaining using a variety of mazes including the Morris swimming maze. Slight, non-significant impairments occurred in shock reinforced behaviours. Histologically, marginal effects were observed at 0.3 nmol/side, and slight ventricular dilatation with necrosis of the hippocampus, restricted to the site of injection at 1.0 nmol/side; at 3.0 nmol/side more widespread necrosis was apparent. Biochemical efficacy of the lesions in terms of cholinergic changes was confirmed by analysis of acetylcholinesterase (AChE) levels showing decreases in the hippocampus and the cortex; no studies were carried out with respect to other neurotransmitters. Cognitive deficits can therefore be obtained by i.c.v. injection of AF64A at doses which cause significant cholinergic changes with minimal histological disturbances.

Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats.

Awake Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 micrograms 5,7-dihydroxytryptamine (5,7-DHT) through chronically implanted cannulae. Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 5,7-DHT. In a separate set of animals, liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 80-90% and caudate 5HT by 30-42% as early as 24 h after administration of 5,7-DHT. One or 3 days after lesioning, locomotor and exploratory behavior was characterized with a Behavioral Pattern Monitor (BPM). Relative to controls, lesioned rats exhibited a decreased rate of habituation of both locomotor activity and investigatory holepokes. Although the amount of locomotor activity elicited by amphetamine (1.0 mg/kg) was unchanged by the 5HT depletion, lesioned animals exhibited highly stereotyped patterns of locomotion during the last 30-min test session, in contrast to the relatively random patterns characteristic of control animals given amphetamine. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats.

Development of cholinergic drugs for the treatment of Alzheimer's disease

AbstractAlzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long‐term habituation of locomotor activity and retention of a one‐trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long‐term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.

Spontaneous activity and apomorphine stereotypy during and after withdrawal from 3 1/2 months continuous administration of haloperidol: some methodological issues.

Rats were treated continuously with haloperidol (1.5 mg/kg/day in drinking water) for 3 1/2 months. Prior to withdrawal of neuroleptic both spontaneous activity and stereotypy responses to a low dose of apomorphine (0.15 mg/kg SC) were significantly reduced. Thus these indices of dopamine receptor blockade did not show tolerance or adaptation. When these measures were repeated shortly after haloperidol withdrawal stereotypy responses of the control group were indistinguishable from their responses on initial testing while haloperidol-withdrawn animals showed substantially more intense responsivity than on their initial assessment; the stereotypy responses of haloperidol-withdrawn animals were indistinguishable from parallel control values at 10--20 min after apomorphine challenge but were significantly above control values at 30--40 min after challenge. Control animals showed habituation of locomotor activity in the motility monitor when measures on the first and second assessments were compared while haloperidol animals showed indistinguishable activities on each assessment. Such methodological epiphenomena may influence the interpretation of studies on the functional sequelae of prolonged neuroleptic treatment and its subsequent withdrawal in the rat.

Habituation and dishabituation of rats’ exploration of a novel environment

The habituation of locomotor activity across repeated exposures to a novel maze was studied in a series of experiments using rats as subjects. Habituation, defined as a decrease in ambulation, was greater on a second trial occurring 5 min after a first trial than on one occurring 60 min after. This short-term decrement occurred only when the same maze was used on both trials, and could be dishabituated by intertriai detention in another novel environment. On a delayed test trial, habituation was, in one case, somewhat greater following initial spaced trials, and in another condition, comparable following both massed and spaced trials. The longer term habituation was maze specific, but was not affected by the presence of a dishabituator following either or both of the first two trials. The results were discussed in terms of theories of “priming” and encoding variability.

Brief periods of socialization and later behavior in the rat.

AbstractJuvenile rats were allowed short daily periods of social contact to see if this would reduce the known effects of isolation rearing upon habituation of locomotor activity and object contact in the open field. Animals totally deprived of social experience (ISOL) were slower to habituate than animals living in small social groups (SOC). Rats allowed 1 hr of social contact (partial isolates, PI), but living otherwise in isolation, were intermediate between ISOL and SOC animals. In further experiments the quality of social interactions in the daily period was altered by drugging one of the partners, either with amphetamine or with chlorpormazine. In later tests in the open field, the rats that had interacted with amphetamine‐injected or chlorpromazine‐injected partners differed from PI animals in the direction of resembling complete isolates (ISOL); this was particularly true of those paired with amphetamine animals. Observation revealed that injection of 1 of the partners considerably altered social interactions in the pair. A further test showed that 1 hr of contact a day considerably alleviated the deleterious effects of isolation rearing upon response reversal. We conclude that normal development in the rat may depend upon the flexibility of behavior encouraged by the early social situation.

The Development of Habituation in the Domestic Chick

Age-dependent changes in both within- and between-session habituation of locomotor activity were found in young Vantress x Arbor Acre chicks. In three experiments, 1- and 4-day-old chicks were given a series of either six short 10-min. habituation sessions or three long 20-min. habituation sessions in a large cylindrical drum. Individual locomotor activity was measured as the mean number of photocell beam interruptions/min. After their last activity session, the chicks were isolated for 3 hr. and then were tested for retention. Major findings were as follows: (a) the 4-day-old chicks showed significant within- and between-session decreases in activity during both the short and long habituation sessions; (b) the 1-day-old chicks did not show either within- or between-session habituation on the initial sessions when brief exposures were given, but did show significant habituation on the longer sessions; and (c) significant spontaneous recovery was observed in the chicks of both ages following the longer but not the shorter sessions. Rubel and Rosenthal (1975) have reported that 1- and 4-day-old chicks do not differ in their rate of habituation of an elicited eye-opening response. Therefore, our finding of an age-dependent change in the young chicks’ habituation of locomotor activity suggests that the precocial chick, like the altricial rat, shows an ontogenetic dissociation in habituation of elicited and emitted responses.

Habituation of open field activity during cortical spreading depression in rats

Habituation of locomotor activity in an open field was investigated in a first experiment in 6 groups of rats which received different CSD treatments on 2 successive days. Both short-term habituation and long-term habituation were investigated. During bilateral CSD short-term habituation was slower and less negatively accelerated, whereas during unilateral CSD it was not different from control. Long-term habituation within treatments was significant for the control treatment and approached significance for the bilateral CSD treatment; for the unilateral CSD treatment no significant long-term habituation was found. The latter finding which was replicated in a second experiment was ascribed to neurological imbalance during unilateral CSD, leading to greater overall reactivity. Long-term habituation after treatment change revealed state dependent learning effects which were ascribed to retrieval failure, caused by the change in the functioning of the brain.