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Recreational abuse of solvents continues, despite cyclohexane (CHX) is used as a safe replacement in gasoline or adhesive formulations. Increasing evidence indicates that CHX inhalation affects brain functioning; however, scanty information is available about its effects on behavior and brain activity upon drug removal. In this study, we used CD1 adult mice to mimic an intoxication period of recreational drugs for 30 days. During the CHX exposure (~30,000 ppm), we analyzed exploratory and biphasic behaviors, stereotypic circling, and locomotion. After CHX removal (24 h or a month later), we assessed anxiety-like behaviors and quantified c-Fos cells in motor- and anxiety-related brain regions. Our findings indicate that the repeated inhalation of CHX produced steady hyperactivity and reduced ataxia, sedation, and seizures as the exposure to CHX progressed. Also, CHX decreased grooming and rearing behaviors. In the first week of CHX inhalation, a stereotypic circling behavior emerged, and locomotion increased gradually. One month after CHX withdrawal, mice showed low activity in the center zone of the open field and more buried marbles. Twenty-four hours after CHX removal, c-Fos expression was low in the dorsal striatum, ventral striatum, motor cortex, dorsomedial prefrontal cortex, basolateral amygdala, lateral hypothalamus, and ventral hippocampus. One month later, c-Fos expression remained low in the ventral striatum and lateral hypothalamus but increased in the dorsomedial prefrontal cortex and primary motor cortex. This study provides a comprehensive behavioral characterization and novel histological evidence of the CHX effects on the brain when is administered in a recreational-like mode., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H 3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H 3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H 1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H 1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H 2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H 4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H 3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H 3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H 3 receptors, which then bind to the post-synaptic histamine receptor H 1 (but not H 2 or H 4 ). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Observations of hyperactive (/restless, agitated) behaviour as a consequence of mild traumatic brain injuries (mTBI) in sports are inconclusive as reduced or slowed movement behaviour is also commonly described post-concussion. This might be grounded in the fact that the movement behaviour of athletes has not been systematically investigated during standardized settings and with objective methods of nonverbal movement analysis. Thus, we investigate whether symptoms after mTBI in sports are characterized by a hyper- or hypoactive movement behaviour experimentally., Methods: Three matched groups of 40 athletes were investigated: 14 symptomatic and 14 asymptomatic athletes with a mTBI; and 12 non-concussed athletes. Four certified raters analysed with a standard analysis system for nonverbal behaviour each athlete's hand movement activity, hand movement contacts, and resting positions that were displayed during a videotaped standardized anamnesis protocol., Results: Symptomatic athletes spend significantly more time with act apart hand movements and less time with closed rest positions when compared to non-concussed athletes. Post-concussion symptom (PCS) scores positively correlate with act apart hand movements. A linear regression analysis revealed that act apart hand movements significantly predict the PCS score., Conclusions: Athletes with increased symptoms after mTBI move their hands in a hyperactive and restless manner. Increased act apart hand movements, i.e., when both hands move simultaneously without touching each other, indicate a motoric destabilization in symptomatic athletes' behaviour that might be related to impaired inhibitory motor control systems. Future diagnoses should concern the systematic analysis of the nonverbal movement behaviour as a potential behavioural marker of symptoms after mTBI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1 -/- ) mice and PRG-1/LPA 2 -receptor double knockout (PRG-1 -/- /LPA 2 -/- ) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG-1 -/- mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1 -/- mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1 -/- mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1 -/- mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1 -/- /LPA 2 -/- did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA 2 -receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA 2 -R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The Bax gene is a member of the Bcl-2 gene family and its pro-apoptotic Bcl-associated X (Bax) protein is believed to be crucial in regulating apoptosis during neuronal development as well as following injury. With the advent of mouse genomics, mice lacking the pro-apoptotic Bax gene (Bax KO) have been extensively used to study how cell death helps to determine synaptic circuitry formation during neurodevelopment and disease. Surprisingly, in spite of its wide use and the association of programmed neuronal death with motor dysfunctions and depression, the effects of Bax deletion on mice spontaneous locomotor activity and depression-like traits are unknown. Here we examine the behavioral characteristics of Bax KO male mice using classical paradigms to evaluate spontaneous locomotor activity and depressive-like responses. In the open field, Bax KO animals exhibited greater locomotor activity than their control littermates. In the forced swimming test, Bax KO mice displayed greater immobility times, a behavior despair state, when compared to controls. Collectively, our findings corroborate the notion that a fine balance between cell survival and death early during development is critical for normal brain function later in life. Furthermore, it points out the importance of considering depressive-like and hyperactivity behavioral phenotypes when conducting neurodevelopmental and other studies using the Bax KO strain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Sleep deprivation in women resulting from their modern lifestyle, especially during pregnancy, is a serious concern as it can affect the health of the newborn. Anxiety disorders and cognitive deficits in the offspring are also on the rise. However, experimental studies on the effects of sleep loss during pregnancy, on emotional development and cognitive function of the newborn, are scanty in literature. In the current study, female rats were sleep-deprived for 5h by gentle handling, during the 6 days of the third trimester (days 14-19 of pregnancy). The effects of this sleep deprivation on anxiety-related behaviors of pups during their peri-adolescence age were studied using elevated plus maze (EPM). In addition to body weights of dams and offspring, the maternal behavior was also monitored. The weanlings of sleep-deprived dams showed heightened risk-taking behavior as they made increased explorations into the open arms of EPM. They also showed higher mobility in comparison to the control group. Though the body weights of sleep-deprived dams were comparable to those of the control group, their newborns had lower birth weight. Nevertheless, these pups gained weight and reached the control group values during the initial post-natal week. But after weaning, their rate of growth was lower than that of the control group. This is the first report providing evidences for the role of sleep during late pregnancy in shaping the neuropsychological development in offspring., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Several lines of evidence demonstrate that glutamatergic system plays an important role in drug addiction. The present study was designed to investigate the effects of Chicago sky blue 6B (CSB6B), a vesicular glutamate transporters (VGLUTs) inhibitor, on methamphetamine (METH)-induced behaviors in mice. Mice were induced behavioral sensitization to METH by subcutaneous injection of 1mg/kg METH once daily for 7 days and then challenged with 1mg/kg METH in 14th day. Intracerebroventricular administration of CSB6B (7.5μg) 2.5h prior to METH was to observe its effects on METH -induced behavioral sensitization. Our results showed that the expressions of behavioral sensitization were significantly attenuated by intracerebroventricular administration of CSB6B 2.5h prior to METH either during the development period or before methamphetamine challenge in mice, while CSB6B itself had no effect on locomotor activity. Meanwhile, pretreatment of CSB6B also attenuated hyperactivity caused by a single injection of METH in mice. These results demonstrated that CSB6B, a VGLUTs inhibitor, attenuated acute METH-induced hyperactivity and chronic METH-induced behavioral sensitization, which indicated that VGLUTs were involved in the effect of chronic METH-induced behavioral sensitization and may be a new target against the addiction of METH., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The analysis of behavioural hyperactivity can provide insights into how perturbations in normal activity may be linked to the altered function of the nervous system and possibly the symptoms of disease. As a small vertebrate zebrafish have numerous experimental advantages that are making them a powerful model for these types of studies. While the majority of behavioural studies have focused on adult zebrafish, it has become apparent that larvae can also display complex stereotypical patterns of behaviour. Here we have used three compounds (pentylenetetrazole (PTZ), aconitine and 4-aminopyridine) that have different neuronal targets (GABA, sodium and potassium channels), to induce distinct patterns of hyperactivity in larvae. Our studies have revealed that each compound produces a number of distinct concentration-dependent activity patterns. This work has shown for the first time that at sub-convulsive concentrations, PTZ can reverse the normal behavioural response to alternating periods of light and dark in zebrafish larvae. It also appears that both PTZ and 4-aminopyridine produce distinct changes in the normal startle response patterns immediately following light/dark transitions that may be the result of an elevation in stress/anxiety. Aconitine produces a general elevation in activity that eliminates the normal response to light and dark. In addition to differences in the patterns of behaviour each compound also produces a unique pattern of c-fos (an immediate early gene) expression in the brain. While more work is required to make direct links between region specific neuronal activity and individual behaviours, these models provide a framework with which to study and compare mechanistically different types of inducible behaviours., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

Rats and mice with bilateral vestibular loss exhibit dramatic locomotor hyperactivity and circling behaviours, which to date cannot be explained. Dysfunction of the striatal dopaminergic system is responsible for a number of known movement disorders and the D(2) dopamine receptor is known to be implicated. Therefore, it is possible that changes in striatal function are responsible for locomotor hyperactivity and circling following bilateral vestibular lesions. The aim of this study was to investigate the effects of the D(2) receptor antagonist, eticlopride (0.02, 0.04 and 0.06mg/kg; s.c.), on locomotor behaviour in rats at 5 months following bilateral vestibular deafferentation (BVD), using an open field maze. The levels of the D(2) receptor protein in the striatum were measured at 1 and 6 months post-BVD using western blotting. BVD rats exhibited locomotor hyperactivity and circling, which eticlopride did not eliminate. However, BVD rats did exhibit a decreased response to the inhibitory effect of eticlopride compared to sham controls at the 0.02 mg/kg dose. There were no changes in the amount of the D(2) receptor in the striatum at 1 or 6 months post-BVD; however, D(2) receptor levels were significantly higher on the right side than the left in both sham and BVD animals. These results suggest that locomotor hyperactivity and circling behaviours following BVD are not due simply to changes in D(2) receptor protein expression in the striatum and that other neurophysiological changes in the brain account for these behaviours following BVD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In previous studies, we reported that a single afterdischarge (AD) or repeated ADs (kindling) in the hippocampus resulted in schizophrenia-like behaviors such as hyperactivity and loss of sensorimotor gating. Given that medial prefrontal cortex (PFC) dysfunction is also found in models of schizophrenia, we hypothesized that a single AD in the PFC induces postictal hyperactivity, and PFC kindling results in loss in prepulse inhibition (PPI). An AD was induced by stimulating the PFC with a 5s stimulus train of 60 Hz frequency and 600-800 microA intensity. An initial AD evoked in the PFC was not accompanied by clear postictal behavioral change. After partial kindling (11+/-2 ADs) of the PFC, the PFC-AD propagated into the hippocampus and nucleus accumbens (NAC) and postictal hyperactivity lasted > 5 min. The postictal hyperactivity was accompanied by increased gamma EEG oscillations in both PFC and NAC. A single AD in hippocampal CA1 also induced > 5 min of postictal hyperactivity and increased gamma oscillations in the NAC and the PFC, with a transient increase in hippocampus-NAC gamma coherence occurring 2-3 min after a hippocampal AD. Electrolytic lesion or inactivation of the dorsal hippocampus abolished the behavioral hyperactivity and the NAC/PFC gamma wave increase induced by a PFC-AD. Kindling of the PFC (21 ADs) but not of the lateral frontal cortex resulted in a deficit of PPI to the acoustic startle response tested 3 days after the last AD. In summary, gamma waves in the NAC were found to accompany postictal hyperactivity induced by an AD in the PFC. Postictal gamma and hyperactivity required an intact hippocampus, perhaps through the hippocampal-NAC pathway. PFC kindling, similar to hippocampal CA1 kindling, resulted in a prolonged deficit in PPI.

Animal models are critical for the study of psychiatric disorders since they allow the use of invasive methods that cannot be used for ethical reasons in humans. Currently there are three general models of schizophrenia; (i) those produced with acute pharmacological intervention (i.e. MK-801, ketamine, PCP and amphetamine), (ii) genetic models (i.e. mutant DISC-1, D(2)-R over expression) and (iii) developmental disruption models (i.e. MAM, neonatal ventral hippocampal lesion, isolation rearing, maternal infection). Here we review evidence for the validity of gestational (day 17) MAM administration as a developmental disruption rodent model of schizophrenia. Offspring from MAM-treated dams are reported to display deficits consistent with those observed in schizophrenia patients, including anatomical changes, behavioral deficits and altered neuronal information processing. Thus gestational MAM administration has been demonstrated to induce a pathodevelopmental process leading to neuroanatomical and behavioral phenotypes consistent with that observed in schizophrenia in humans.

An important aspect of attention deficit hyperactivity disorder (ADHD) is its temporary amelioration by novelty and by stimulant medication. Extant learning-based accounts of ADHD are unable to account for the temporary amelioration effect. One possible mechanism is a drive for novelty. Computational simulations have previously shown that such a drive can result from a "dopamine appetite". Empirical demonstration of such a process requires, as a first step, the development of standard criteria for identifying drive-based, versus learning-based, changes in behaviour. Using a variable-interval reinforcement schedule, we looked over a range of timescales for behavioural changes showing putative characteristics of drives, namely: low information content, unidirectionality, saturability, spontaneous reversibility in less than a day, and cycle stability. SHR lacks normal down-regulation of responding when the schedule becomes sparser. SHR appears to be re-learning the schedule length during the days of each calendar week. SHR hyperactivity is specific to the operant and develops gradually over the first five minutes of each session. Empirical within-session results were replicated by a simple simulation containing two interacting reward systems, one for water and the other for stimulation (including novelty). To summarise, enhanced sensation-seeking (or a subtype of it, novelty-seeking) provides the best available account of changes in SHR activity within sessions, though not of changes over longer timecourses. Sensation-seeking appears to be associated with low anxiety in the SHR. SHR propensity to display multiple influences on their behaviour makes them ideal for further pharmacological, genetic, and behavioural investigation.

Several existing theoretical models of Attention Deficit Hyperactivity Disorder (ADHD) predict that a high or low learning rate contributes to some cases of ADHD; and that this is controlled by the dopamine signal. The Spontaneously Hypertensive (Hyperactive) Rat has an abnormal Dopamine Transporter (DAT), which is likely to be hypofunctional, thereby increasing the dopamine concentration and the learning rate. We therefore test the prediction that the SHR learns too fast. Using a variable interval reinforcement schedule, we looked for increased responding within each interval, at around the durations of the last three intervals. At the time predicted by the previous interval, SHR responded significantly (10%) more than their baseline rate, and control WKY rats similarly less than their baseline. At the time predicted by the second (and third) previous intervals, there were minor trends (and no change) in the same direction. In summary, at the times predicted, SHR respond more than control rats. The effect size is insufficient to account for all the differences from control rats, such as their nearly threefold greater operant responding. At the times when SHR increase responding, WKY suppress it. This demonstrates similar learning to the SHR but the opposite response, probably due to anxiety about the bang accompanying reinforcer delivery: WKY are known to have a very negative response to stress. Interval schedules with randomised interval lengths have considerable potential for assessing multiple causes of behaviour, particularly those acting over short timecourses. Alterations in learning rate are not a sufficient explanation for either SHR or ADHD difference from controls.

Variable intervals are widely believed to produce steady rates of responding. However, based on the calming effect of unpredictability in attention deficit hyperactivity disorder (ADHD) we hypothesised that an animal model of this disorder, the Spontaneously Hyperactive (or Hypertensive) Rat, would become less active following particularly variable sequences of interval-lengths in a variable interval schedule. From a large dataset of holepokes and tray-reports by rats in a variable interval reinforcement schedule, we extracted numerous short sequences of intervals on the basis of the first, second, and third derivatives of reinforcement timing (i.e. rate, acceleration, and jerk) in recent intervals. Sets of selected intervals were compared with one another to elucidate the effect of these different derivatives on behaviour in the current interval. Results show that SHR are more active after richer recent reinforcement; after decelerating reinforcers; and after predictable reinforcers. The hypothesis is supported. In conclusion, SHR behaviour largely complies with the Extended Temporal Difference model which in turn has been previously validated against published data in ADHD. The Extended TD model therefore is able to account for two species' behaviour in a wide range of experimental paradigms. SHR are similar in several respects to group averages of children with ADHD, except that SHR have reduced variability and perform actions faster than controls. Hyperactivity in the SHR is very dependent on momentary environmentally determined states, which is an important area for future investigation of ADHD.

The current study reports the impact of different illumination conditions on exploratory activity following global ischemia in rats. Exploratory activity was tested at different post-ischemic intervals under bright (450 lux) or dim (40 lux) light exposure. A 30 min testing period performed 5 days post-reperfusion examined within-session open-field habituation in ischemic and sham-operated animals. Additional animals were tested in the open-field under the two illumination conditions for shorter 10 min tests on days 3, 6, and 9 following reperfusion. Our findings demonstrated illumination-related activity profile in the open-field in ischemic animals. While ischemic rats showed increased activity when tested under bright open-field illumination, reduced activity was observed under dim illumination as compared to sham-operated controls. Further, habituation deficits were not apparent in animals subjected to global ischemia under any illumination condition. Similar behavioral profiles and habituation were observed in ischemic animals when exposed to repetitive open-field tests at days 3, 6, and 9 following reperfusion. CA1 neuronal injury (approximately 75% as compared to sham rats) was comparable in all ischemic groups at day 12 following reperfusion. The present findings suggest that differences in initial behavioral reactivity of sham and ischemic rats to bright versus dimly lighted environments may contribute to differences in open-field exploration reported between these groups. They also challenge the notion that deficits in exploration in ischemic animals are mainly attributable to processes related to habituation, or that hyperactivity represents a reliable predictor of CA1 neuronal injury. These observations may help explain discrepant ischemia-induced behavioral effects reported in the open field.

Environmental stimuli associated with amphetamine (AMPH) can elicit conditioned locomotion in rats, and the nucleus accumbens (NAcc) is known to be important in this process. This study examined the contribution of metabotropic glutamate receptors (mGluRs) in the NAcc to the expression of conditioned locomotion in an AMPH-associated environment. Rats in different groups were administered injections in five 3-day blocks: Paired, AMPH (1.0mg/kg, IP) in locomotor activity boxes on day 1 and saline in their home cages on day 2; Unpaired, saline in the activity boxes on day 1 and AMPH in their home cages on day 2; or Control, saline in both environments. No injections were administered on day 3 of each block. One week after the last conditioning block, all rats were tested for their conditioned locomotor response in the activity boxes for 1h following an IP saline injection. In Paired rats, this injection was preceded by a bilateral microinjection into the NAcc of saline, the group I mGluR antagonist, AIDA (0.5, 5.0 nmol/side), or the group II mGluR antagonist, EGLU (0.5, 5.0 nmol/side). Unpaired and Control rats received NAcc saline. As expected, Paired rats showed both increased locomotor activity and rearing compared to rats in either the Unpaired or Control groups. However, the expression of this conditioned hyper-locomotion was dose-dependently inhibited by NAcc EGLU, but not by AIDA. These results suggest that activation of group II, but not of group I, mGluRs in the NAcc contributes to the expression of conditioned locomotion in an environment associated with amphetamine.

Developmental vitamin D (DVD) deficiency has been proposed as an environmental risk factor for a number of brain disorders. The absence of this vitamin during foetal development in the rat is known to alter behaviour in the adult, and many of these alterations are informative with respect to the clinical features of schizophrenia. Here we investigated whether DVD deficiency had a similar effect on 129/SvJ and C57BL/6J mice. Female mice were fed a diet deficient in vitamin D for 6 weeks prior to conception until birth, after which dams and their offspring were fed a normal diet (i.e. containing vitamin D). Control mice were fed a normal diet throughout the experiment. The adult offspring underwent a comprehensive behavioural test battery at 10 weeks of age. We found that DVD-deficient mice of both strains exhibited significantly higher levels of exploration, as measured by the frequency of head dipping on the hole board test. In addition, DVD-deficient 129/SvJ mice, but not C57BL/6J mice, displayed spontaneous hyperlocomotion. There was no effect of maternal diet on parameters assessed by the SHIRPA primary screen, or on tests of sensorimotor gating, social behaviour, anxiety or depression. Some of these findings resemble the rat phenotype (hyperlocomotion) but there are also novel effects of DVD deficiency on mouse behaviour (increased exploration). This study confirms that the developmental absence of this vitamin affects brain function in another species (mouse), and lends further weight to the hypothesis that DVD deficiency in humans may contribute to adverse neuropsychiatric outcomes.

Rho family GTPases have been implicated as important regulators of neuronal development. Rac3 is a member of this family specifically expressed in vertebrate developing neurons, where it is coexpressed with the ubiquitous Rac1 GTPase. We have previously shown that Rac3 knockout mice are viable and fertile. The Rac3 protein shows highest expression around postnatal day 7 in brain regions relevant for cognitive behaviors. In this study we find that Rac3 knockout mice do not show defects in spatial reference memory assessed with water maze task, but they show a reduced behavioral flexibility to novel situations. Analysis of explorative behavior revealed hyperactive behavior and hyperreactivity to the presentation of new stimuli, as assessed by dark/light box, emergence and novel object tests. These defects were not due to reduced visual abilities, since visual acuity and contrast sensitivity were comparable in Rac3 knockout and wildtype littermates. Our data reinforce the notion that Rho family GTPases are important for normal cognitive development, and highlight specific functions of Rac3 that cannot be compensated by the coexpressed homologous Rac1.

Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA(-/-)), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2, 4, 6 and 8 months of age. In automated open-field test, IDUA(-/-) mice showed hypoactivity as early as 2 months of age and altered anxiety starting from 6 months of age during the initial exploratory phase, even though normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA(-/-) mice at almost all tested ages, but significantly reduced in 8-month old male IDUA(-/-) mice which coincided with the rapid death of IDUA(-/-) males starting from 7 months of age. In the Morris water maze, IDUA(-/-) mice exhibited impaired proficient learning only at 4 months of age during the acquisition phase. Spatial memory deficits were observed in IDUA(-/-) mice during both 1 and 7 days probe trials at 4 and 8 months of age. The IDUA(-/-) mice performed normally in a novel object recognition task at younger ages until 8 months old when reduced visual cognitive memory retention was noted in the IDUA(-/-) mice. In addition, 8-month-old IDUA(-/-) mice failed to habituate to repeated open-field exposure, suggesting deficits in non-aversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA(-/-) mice, but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA(-/-) mice from adolescence to maturity, indicating the impairments, with different ages of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition and short-term non-associative memory retention. This study would also provide guidelines for the experimental designs of behavioral evaluation on innovative therapies for the treatment of MPS type I.

Elevated homocysteine levels resulting from vitamin B deficiencies have been hypothesized to contribute to functional decline. To investigate the effects of elevated serum homocysteine on neurobehavioral performances, young adult Balb/c mice consumed a vitamin-B-deficient diet or a control diet under free-feeding and pair-fed conditions. The B-deficient diet decreased body weight and food intake but increased water ingestion. Relative to either control group, vitamin-B-deficient mice were more active in the open field and in enclosed arms of the elevated plus-maze. However, vitamin-B-deficient mice were not impaired on sensorimotor coordination and spatial learning tests, swimming to a visible platform even faster than either control group. The main effect of this diet restriction was hyperactivity with no change in anxiety, coordination, and memory. It remains to be determined whether severer deficits are demonstrable in older mice.

The most common behavioural disorder seen in children and adolescents born extremely prematurely is attention deficit hyperactivity disorder (ADHD). The hyperactive/impulsive sub-type of ADHD or the inattentive sub-type or the hyperactive/impulsive/inattentive sub-type can be evident. These sub-types of ADHD can persist into adulthood. The aim of this study was to investigate the relevance of a new immature rat model of repeated hypoxic exposure to these behavioural characteristics of extreme prematurity. More specifically, this study aimed to measure ADHD-like hyperactivity in response to delayed reward, and inattention, in repeated hypoxic versus repeated normoxic rats. Sprague-Dawley rats were exposed to either repeated hypoxia or repeated normoxia during postnatal days (PN) 1-3. The rat brain during PN1-3 is generally considered to be developmentally equivalent to the human brain during extreme prematurity. The rats were then behaviourally tested at 16 months-of-age on a multiple component fixed interval-extinction test. This test detects ADHD-like hyperactivity in response to delayed reward, as well as inattention. It was found that the repeated hypoxic rats exhibited ADHD-like hyperactivity in response to delayed reward, but no attention deficit, when compared to repeated normoxic rats. These findings provide a new animal model to investigate the biological mechanisms and treatment of ADHD-like hyperactivity due to repeated hypoxia during the equivalent of extreme prematurity.

Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine-N-methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic-tonic convulsions in Krushinsky-Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic-tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic-tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed.

In addition to morphological changes, global cerebral ischemia leads to functional changes that can be assessed by behavioral examination. The purpose of this study was to investigate the impact of the duration of global cerebral ischemia on the time course of a comprehensive set of motor behaviors in Mongolian gerbils. The common carotid arteries of gerbils were occluded either for 5 min, 10 min, or 15 min. Gerbil motor behavior was recorded in the open field at 24 h, 48 h, 4 days, 7 days, 14 days, 21 days, and 28 days after reperfusion. Each session lasted for 60 min and was composed of six intervals of 10 min. Our results revealed that ischemic gerbils quickly develop locomotor and stereotypic hyperactivity, with the expected decrease of resting time. The most evident effect was observed in gerbils submitted to a 15 min ischemia, whose locomotor activity returned to nearly normal values after 7 days. In contrast, the duration of global cerebral ischemia had no effects on rearing, clockwise, or counter-clockwise rotation. These findings indicate that exposure to global cerebral ischemia induces changes in locomotion, stereotypy, and resting time. The magnitude and duration of these effects depend on the duration of ischemia.

Aims and Methods: In order to elucidate the neural mechanisms of delirium, we administered the anticholinergic drug, biperiden (40 mg/kg i.p.), to 10 adult male Wistar rats and examined the resulting polygraphic recordings, including electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), for 60 min following injection. EEG data were investigated quantitatively by power spectrum analyses using fast Fourier transformation. Ten male Wistar rats receiving saline (i.p.) were used as the control group., Results: Treated rats demonstrated two types of alternating behavioral change: a hyperactive and hypoactive state. In the hyperactive state, rapid walking, excessive random sniffing, and retropulsion were observed, with EEG desynchronization (significantly increased alpha1 (8.0-10.0 Hz), alpha2 (10.0-13.0 Hz), and beta (13.0-30.0 Hz) power values), as well as EEG slowing (significantly increased delta (0.5-4.0 Hz) and theta1 (4.0-6.0 Hz) power values): significantly marked rapid eye movement, and increased EMG activity. In the hypoactive state, motor arrest and drowsiness were observed, with prominent EEG slowing (significantly increased delta and theta1 power values): significantly decreased rapid eye movement and moderately decreased EMG activity. On the other hand, the control group did not show any behavioral or polygraphic changes., Conclusions: The behavioral and polygraphic changes induced by biperiden administration in rats are similar to those of delirium in humans. Therefore, it is proposed that biperiden-treated rats are a good delirium model and the anticholinergic mechanism is one of the potent factors in the development of delirium in humans.

While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action.

Repeated cycles of chronic ethanol exposure and withdrawal result in sensitization of withdrawal-related CNS hyperexcitability that generally reflects an imbalance in activity of GABA and glutamate systems. Many pharmacological treatments for ethanol withdrawal target neuroadaptive changes in GABA and glutamate neurotransmission. The present study utilized a mouse model of repeated withdrawals to evaluate the ability of lorazepam and MK-801 treatments to antagonize behavioral and electroencephalographic (EEG) measures of sensitized withdrawal seizure activity. Adult male C3H/He mice received chronic intermittent ethanol vapor exposure in inhalation chambers (16 h/day) and during each withdrawal cycle, separate groups of mice were evaluated for handling-induced convulsions (HIC) or abnormal EEG (high-voltage "brief spindle episodes" (BSE)) activity. Lorazepam (0.5-1.0 mg/kg) or MK-801 (0.1-0.3 mg/kg) treatment at 1 h into each of three withdrawal cycles reduced behavioral (HIC) and electrographic (BSE) signs of seizure activity in a dose-related fashion compared to vehicle-treated mice. During a subsequent untreated withdrawal, mice previously treated with lorazepam or MK-801 for earlier withdrawals exhibited reduced HIC activity during the acute phase but exacerbated HIC activity during the protracted phase of this final (fourth) withdrawal cycle. Both lorazepam and MK-801 treatment conditions resulted in enhanced BSE activity during the entire fourth (untreated) withdrawal episode. Collectively, these results suggest that while treatment of repeated ethanol withdrawals with a benzodiazepine (lorazepam) or an NMDA receptor antagonist (MK-801) may have some initial benefits in ameliorating the development of sensitized withdrawal excitability, such treatment may also render subjects more vulnerable to seizure activity at later time points.

We investigated in an animal model of neonatal anoxia whether effects of oxygen deprivation on emotional reactivity can be reversed by neonatal novelty exposure, a behavioral method, involving daily 3min away from the home cage for the first 3 weeks of life. Male neonates were exposed to either 100% N2 gas (Anoxia) or room air (Control) for 25min on postnatal day 1. Within each of the two treatment conditions, one-half of the neonates were further individually exposed to relatively novel non-home cages for 3min daily during postnatal days 2-21 (Novel: NAnoxia=20; NControl=16), while the other half remained in the home cage (Home: NAnoxia=19; NControl=19). Emotional reactivity to an open field was evaluated on postnatal day 25 during four 20-s trials. Among home rats, temporal patterns of open-field activity across multiple trials and initial-trial activity significantly differed between the Anoxia and Control rats. In contrast, these differences were eliminated among the Novel rats. These results show that neonatal novelty exposure, an early-stimulation method that has recently been shown to enhance spatial and social memory, adaptive control of stress response, and hippocampal synaptic plasticity, can also eliminate neonatal anoxia-induced changes in emotional reactivity. These findings suggest that brief and repeated, but mild, changes in the postnatal environment may serve to counteract some of the aversive effects induced by neonatal trauma associated with oxygen deprivation.

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.

Lesions of basal forebrain cholinergic neurons by intracerebroventricular (i.c.v.) injections of 192 IgG-saporin increased the locomotor response to 0.5 and 1.5 mg/kg of D-amphetamine in adult rats [A. Mattsson, S.O. Ogren, L. Olson, Facilitation of dopamine_mediated locomotor activity in adult rats following cholinergic denervation, Exp Neurol. 174 (2002) 96-108.]. In the present study, adult male rats were subjected to bilateral injections of 192 IgG-saporin either into the septum (Sp), the nucleus basalis magnocellularis (Nbm), both structures (SpNbm) or i.c.v. Locomotor activity was assessed in the home cage 23 days after surgery, and, subsequently, thrice after an intraperitoneal injection of D-amphetamine (1 mg/kg) and twice after an injection of cocaine (15 mg/kg). Analysis of AChE-stained material showed that Sp lesions induced preferentially hippocampal denervation, Nbm lesions induced preferentially cortical denervation, while both SpNbm and i.c.v. lesions deprived the hippocampus and the cortex of almost all AChE-positive reaction products. The spontaneous and drug-induced locomotor activity of all lesioned rats did not differ significantly from that of control rats, except in rats subjected to i.c.v. injections, in which the locomotor response was significantly increased after the second administration of cocaine. In addition, in Nbm and SpNbm rats, the locomotor reaction to cocaine was weaker right after the second injection. The present results do not confirm the report by Mattsson et al. on the potentiation of amphetamine-induced locomotion by i.c.v. injections of 192 IgG-saporin, but suggest that cocaine-induced locomotion can be increased by such lesions and, to some respect, attenuated by cholinergic damage in the Nbm.

The involvement of metabotropic glutamate receptor (mGluR) subtypes in the generation of hippocampal EEG (30-100 Hz) and behaviors induced by a hippocampal afterdischarge (AD) was examined in freely behaving rats. A hippocampal AD induced an increase in gamma waves (30-100 Hz) for 20 min, accompanied by behavioral hyperactivity. Bilateral intracerebroventricular (i.c.v.) infusion of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a group I and II mGluR antagonist, 30 min before a hippocampal AD, significantly suppressed both the increase in gamma waves and the behavioral hyperactivity. The hippocampal theta rhythm, the spontaneous hippocampal gamma waves, and evoked field potential oscillations of approximately 40 Hz were not affected by MCPG. Pre-infusion (i.c.v.) of (2S)-alpha-ethylglutamic acid (EGLU; a group II mGluR antagonist), but not (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; a group I mGluR antagonist), suppressed the postictal increase of both hippocampal gamma waves and behaviors. MCPG was infused locally into different brain structures in order to specify its target sites. Intra-hippocampal infusion of MCPG, or EGLU, blocked the increase in both gamma waves and behaviors. Infusion of MCPG into the nucleus accumbens suppressed the postictal behavioral hyperactivity without affecting the increase in hippocampal gamma waves. MCPG injected into the medial septum blocked neither postictal gamma activity nor behavioral hyperactivity. It is suggested that the group II mGluRs in the hippocampus are involved in generation of the postictal hippocampal gamma waves, while behavioral hyperactivity is partly mediated by mGluRs in the nucleus accumbens. However, spontaneous gamma and theta waves in the normal hippocampus are not mediated by mGluRs.

Nicotine's neurotoxic properties in rats were investigated by administering (-)-nicotine tartrate for 5 days either continuously in doses of 5.01, 5.72, 6.44, 7.13, 20.41 and 43.1 mg/kg/day via osmotic minipump or intermittently at 11.32 mg/kg/day via one daily subcutaneous injection. As assessed by silver staining, neurotoxicity was seen almost exclusively in the axons of the medial habenula and its output tract, the fasciculus retroflexus, in all treatment groups except the lowest dose. Within the habenula, the damage was noted in the ventral-medial-most portion of the nucleus which is thought to be dense with the alpha 4 beta 2 and/or alpha 3 beta 4 receptor subtypes. Past research has shown the medial habenula to be highly sensitive to the effects of nicotine, and these findings, in conjunction with related research using dopaminergic stimulants, indicate that the habenula may be a weak link in the neurotoxicity seen following stimulant drugs of abuse.

Lesions of the hippocampus or the fimbria-fornix produce a pronounced hyperactivity in rats. This effect is thought to be due to the loss of glutamatergic hippocampal inputs to the nucleus accumbens, although the mechanisms involved remain unclear. It has been suggested that the hyperactivity is due to changes in accumbens dopamine receptors, possibly involving the gradual development of denervation supersensitivity. Consistent with this possibility, the present study found that fimbria-fornix transection produced hyperactivity which, although undetectable immediately after surgery, gradually became apparent and then continued to increase over the course of several days. This does not, however, preclude the possibility that there is an immediate increase in activity which is masked by the after effects of surgery. To address this issue, local anaesthetic was infused into the fimbria-fornix via chronic indwelling cannulae, in order to silence the hippocampal inputs to the nucleus accumbens. This procedure impaired spatial working memory on the elevated T-maze and resulted in immediate hyperactivity, suggesting that there may be at least two components to fornix lesion-induced hyperactivity, and that the immediate effects of mechanical fornix lesions on activity levels may be masked by the after effects of surgery per se.

Effects of microinjections of a single 2 or 10 nmol dose of N-methyl-D-aspartate (NMDA) into the unilateral mesencephalic reticular formation (MRF) on behavior and electroencephalogram were examined in rats (n=18) during a 15 min period (Exp. 1), and subsequent effects of sound stimulation with key jingling applied at 15, 30, and 45 min after the injections were observed (Exp. 2). The microinjections of 2 nmol dose of NMDA (n=10) induced hyperactivity (9 of 10 rats) and running/circling (8 of 10 rats) in Exp. 1, and hyperactivity (3 of 10 rats) in Exp. 2. Moreover, the microinjections of 10 nmol dose of NMDA (n=8) induced not only hyperactivity (8 of 8 rats) and running/circling (7 of 8 rats) but also generalized tonic-clonic seizures (GTCS) (5 of 8 rats) in Exp. 1; these seizure patterns were also elicited by sound stimulation in Exp. 2. The seizure patterns were accompanied by electroencephalographic seizure discharges in the MRF and the motor cortex. In contrast, the control group rats (n=10) which received a single dose of saline microinjection into the unilateral MRF showed no behavioral or electroencephalographic changes in both Exp. 1 and 2. These findings suggest that the MRF has an important role in the development of GTCS, which follows hyperactivity and running/circling, and that potentiation of excitatory neurotransmission in the MRF participates in the development of audiogenic seizures as well as GTCS.

The purpose of this study was to identify sites where striatopallidal lesions produce two distinct sensory-triggered hyperkinetic syndromes: (1) exaggerated forelimb treading alone to oral taste infusions and (2) sensorimotor exaggerated treading plus enhanced aversive reactions to taste infusions. The behavioral characteristics of these syndromes have been described previously (Berridge, K.C. and Cromwell, H.C., Behav. Neurosci., 104 (1990) 778-795). Bilateral excitotoxin lesions were made using quinolinic acid (10 micrograms in 1 microliter) in the caudate/putamen, nucleus accumbens, globus pallidus or ventral pallidum/substantia innominata. In order to identify the precise center, borders, severity and size of lesion sites that caused these hyperkinetic treading syndromes, neuron counts (modified fractionator technique) and glial fibrillary acidic protein immunoreactivity (GFAP-IR) densitometry were used in a stereological mapping analysis. The site of lesions that produced the hyperkinetic treading syndrome without enhanced aversion was found to be restricted to the globus pallidus (GP). Damage exceeding 60% neuron loss bilaterally within a 0.8 x 1.0 x 1.0 mm subregion of the ventromedial GP produced this syndrome. The site of lesions that produced the combined syndrome of hyperkinetic treading and aversive enhancement was ventral to the globus pallidus, within the ventral pallidum/substantia innominata (VP/SI). Damage exceeding 70% neuron loss bilaterally within a 1.0 x 0.5 x 1.0 mm diameter subregion of the ventromedial ventral pallidum/substantia innominata produced this syndrome. This subterritory was located immediately lateral to the border of the lateral hypothalamus. Bilateral lesions to the caudate/putamen or nucleus accumbens did not produce either hyperkinetic treading syndrome. These results are discussed in terms of the connectivity of the ventral pallidal/substantia innominata and globus pallidus regions and in terms of neuropathological models of hyperkinetic disorders.

Following right middle cerebral artery ligation in rats, there is a 2-3 week period of spontaneous hyperactivity. Concomitant with this hyperactivity catecholamine concentrations decrease in several areas of the brain including both cortical and subcortical regions. In marked contrast, there are no demonstrable effects of left hemispheric infarction on either spontaneous activity or brain catecholamine concentrations. This asymmetry of behavioral and biochemical response to cerebral infarction cannot be attributed to differences in the lesion size produced in either hemisphere. Feeding and drinking are not affected but the asymmetrical effect on activity can be demonstrated in either a home cage running wheel or an open field environment. It is uncertain whether these findings are the result of hemispheric asymmetries in either catecholaminergic or non-catecholaminergic neurons.

In a previous study, we reported that a specific size cortical suction lesion of the right posterior cortex in rats produced hyperactivity and increased concentrations of dopamine in the nigrostriatal pathway. The present study extended those findings by addressing whether this phenomenon is lateralized to the right posterior cortex and whether the increases in nigrostriatal dopamine are necessary for the behavioral changes produced by the lesion. Right posterior cortical lesions of 1.8 mm diameter produced spontaneous hyperactivity over a 30-day postoperative period while identically placed 1.3 mm or 2.4 mm diameter lesions did not. Left hemisphere lesions of 1.3 mm, 1.8 mm or 2.4 mm diameter also failed to produce hyperactivity. The hyperactivity response to 1.8 mm diameter lesions of the right posterior cortex was not blocked by 70% depletions in nigrostriatal dopamine produced by bilateral nigral injections of 6-hydroxydopamine two weeks prior to cortical lesions. These findings suggest that hyperactivity following right posterior cortical lesions is lateralized and is not dependent upon changes in the nigrostriatal dopaminergic pathway.

From their event related potentials (ERPs) to tones of four intensity levels, a sample of attention disordered and/or reading disabled children, recommended for a trial on methylphenidate, were classified as auditory augmenters or reducers. The augmenters were blindly titrated at significantly lower dosage levels than the reducers. Moreover, the ameliorative effects of the drug, as assessed by teacher ratings, were more evident in hyperactive augmenters. The children diagnosed either as hyperactive or hyperactive and reading disabled had steeper (or more augmenting) gradients than the nonhyperactive reading disabled and attention disordered subjects. The ERP (N1-P2) gradients were not consistently related to reaction time (RT) gradients to the tones or to an RT measure of nervous system sensitivity. It is suggested that ERPs index registration but not response strength, the first being largely automatic and the second purposive.

This study test the effects on autonomic nervous system (ANS) activity of two doses (0.25 mg/kg and 0.50 mg/kg) of dextroamphetamine in normal men. Skin conductance and heart rate were recorded during rest, tone presentation, and a reaction time task. Compared to placebo, dextroamphetamine increased both skin conductance and heart rate indices of arousal, slowed habituation, and reduced ANS responsivity selectively to more important vs. less important stimuli. The last result differs from previous findings on hyperactive and normal boys. The pattern of ANS effects closely resembles findings on drug-free schizophrenics, suggesting that it may be a matter for biologic changes occurring in amphetamine psychosis and spontaneous psychotic episodes.

The involuntary movements resembling the serotonin (5-HT) syndrome induced by 5-HT agonist, which is composed with symptoms such as head twitch, hind leg abduction and so on, are neurochemically evaluated in the new mutant mouse, Wriggle Mouse Sagami (WMS). Ritanserin (5-HT2 antagonist) and prazosin (alpha 1-adrenergic antagonist) both inhibited the symptoms, had a decrease in the number of times they fell down and prolonged the duration of sitting up, while SCH 23390 (dopamine1 antagonist) and YM-0911-2 (dopamine2 antagonist) did not affect them. Metergoline (5-HT1 and 5-HT2 antagonist) suppressed the locomotor activity, making it difficult to determine if it ameliorated the symptoms. The concentration of a metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) was higher than control values diffusely in the CNS except in the cerebral cortex. The accumulation of 5-HTP after the administration of amino acid decarboxylase inhibitor NSD 1015 was significantly enhanced in the hypothalamus, median raphe, cerebellum and pons. An increase in 5-HT and NA was also noted in the cerebellum. GABA was increased in the striatum. In the binding assay, the number of [3H]ketanserin binding sites was increased and that of [3H]prazosin binding sites was decreased in the striata. Meanwhile, no significant difference was observed either in the number of binding sites (Bmax) or the affinity (KD) in the [3H]5-HT binding study. The number of [3H]muscimol binding sites in the cerebellum was reduced with the dissociation constant (KD) unchanged. These results suggest the involvement of 'hyperserotonergic' neural systems, possibly due to the enhanced 5-HT synthesis, in the manifestation of the involuntary movements of WMS, with noradrenergic and GABAergic modification. WMS can be a useful model to study the function of the serotonergic system in the CNS.

Nocturnal hyperactivity, as measured by photocell counts of locomotion in a residential maze, was produced in rats by 3 different kinds of brain damage, X-irradiation at gestational day 14 or 15, exposure to carbon monoxide on the fifth day of postnatal life, or bilateral stereotaxic lesions of the globus pallidus in adult rats. These brain-damaged rats and their controls were photographed at 1 frame/sec during their first exploratory experience in a simple cage. Frequency of 15 motor acts, duration of each occurrence and associations of pairs of acts were calculated. The 15 motor acts were divided into 3 clusters of acts labeled grooming, exploratory and attention behaviors. Hyperactivity was associated with shortened durations and increases in frequency of exploratory acts, while grooming and attention behaviors tended to decrease in duration and frequency. Sequences of behavior acts were less structured in hyperactive animals than in controls. In spite of the marked differences known to be produced on brain structures by the 3 different kinds of damage, no changes in behavior structure were found which were uniquely associated with one kind of brain damage. Hyperactivity appeared to be a continuum in that the intensity of effects produced on behavior as measured by the photographic technique correlated well with the amount of increase in photocell activity.

These experiments provide a direct test of the hypothesis that median raphe lesion- or PCPA-induced hyperactivity in the rat is mediated specifically by the hippocampus. Previous studies had shown that a marked depletion of hippocampal serotonin accompanied median lesion-induced hyperactivity. In the present studies, aspiration of the anterodorsal hippocampus of adult male rats prior to median raphe lesions or PCPA administration abolished the ability of both of these treatments to produce locomotor hyperactivity in animals chronically housed in tilt cages. Control lesions of the overlying dorsal cortex and corpus callosum were ineffective in blocking the hyperactivity produced by these two treatments. The possibility that serotonin depletion-induced hyperactivity was dependent on the pituitary was excluded by the fact that PCPA effectively elevated the activity of hypophysectomized rats. These data indicate that serotonin depletion-induced hyperactivity in the rat is mediated by the hippocampus.

Locomotor activity in the rat was studied after infusion of GABAergic and enkephalinergic agonists into the nucleus basalis magnocellularis (NBM) of the forebrain. The experiments were designed to find out whether pharmacological blockade of cholinergic neurons in the NBM had similar behavioral effects to those observed after lesion of the same structure. Three experiments were carried out. In the first experiment, infusion of the GABAergic agonist muscimol (50 ng) into the NBM led to a marked locomotor hyperactivity. In the second experiment, it was shown that muscimol-induced locomotor response was reduced by pretreatment with the GABAergic antagonist picrotoxin (3 mg/kg). Further, locomotor hyperactivity was also observed after injection of the indirect GABA agonist, ethanolamine-o-sulfate (50 micrograms) into the NBM. The third experiment was designed to investigate the relationship between the blockade of NBM cholinergic neurons and the development of locomotor hyperactivity. The locomotor hyperactivity produced by the cholinergic antagonist scopolamine (0.4 mg/kg) was increased two-fold after infusion of 10 ng muscimol into the NBM. This dose of muscimol on its own had no effect on locomotor behavior. Similar enhancement of the locomotor response to that found with GABAergic agonists was observed after infusion of [D-Ala2]Met-enkephalinamide (2.5 micrograms) into the NBM. This enkephalin mediated locomotor response was blocked by the opiate antagonist naloxone (2 mg/kg). Pharmacological manipulations of the afferent inputs to the NBM could therefore be of value in studies on the behavioral role of cholinergic neurons in the NBM.