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Motor activity of boys (age 8-12 years) with (n=19) and without (n=18) ADHD was objectively measured with actigraphy across experimental conditions that varied with regard to demands on executive functions. Activity exhibited during two n-back (1-back, 2-back) working memory tasks was compared to activity during a choice-reaction time (CRT) task that placed relatively fewer demands on executive processes and during a simple reaction time (SRT) task that required mostly automatic processing with minimal executive demands. Results indicated that children in the ADHD group exhibited greater activity compared to children in the non-ADHD group. Further, both groups exhibited the greatest activity during conditions with high working memory demands, followed by the reaction time and control task conditions, respectively. The findings indicate that large-magnitude increases in motor activity are predominantly associated with increased demands on working memory, though demands on non-executive processes are sufficient to elicit small to moderate increases in motor activity as well., (Published by Elsevier Ltd.)

Schizophrenia is a severe neuropsychiatric disorder that is characterized by core psychiatric symptoms, including positive, negative, and cognitive symptoms. Current treatments for schizophrenia have an effect on positive symptoms but have a limited efficacy on negative or cognitive symptoms. Oleanolic acid is a plant-derived pentacyclic terpenoid that is known to exhibit anti-oxidative and anti-inflammatory activities. Here, we investigated the effects of oleanolic acid on schizophrenia-like behaviors in mice elicited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. A single administration of oleanolic acid blocked MK-801-induced hyperlocomotion in the open field test. In the acoustic startle response test, oleanolic acid itself did not have any effects on the acoustic startle response or prepulse inhibition (PPI) level, whereas the MK-801-induced PPI deficit was ameliorated by oleanolic acid. In the novel object recognition test, the attention and recognition memory impairments induced by MK-801 were reversed by a single administration of oleanolic acid. Additionally, oleanolic acid normalized the MK-801-induced alterations of signaling molecules including phosphorylation levels of Akt and GSK-3β in the frontal cortex. These results suggest that oleanolic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, and cognitive impairments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Hyperkinetic perseveration (HKP) refers to perseverative repetition of rudimentary motor output. Although HKP is known to be associated with brain injuries and certain neurodegenerative disorders (primarily those involving the frontal lobes and the basal ganglia), an increased tendency to exhibit HKP is also commonly associated with apparently normal aging (i.e., in the absence of known neuropathology). The purpose of the present study was to examine anomalies in brain functioning associated with HKP tendencies in a non-injured brain., Method: The present study examined functional MRI connectivity patterns associated with HKP in a sample of 24 "young" (ages 25-35 years) and 20 "old" (ages 65-75 years) healthy community dwelling women. Participants performed a motor learning task (the Push-Turn-Taptap task: PTT) known to elicit HKP. On a separate day, participants were scanned on a Siemens 3T Trio MR scanner with a 12-channel head coil, while performing a block-design motor sequence learning task that was designed to be a scanner analog for the PTT task. Cortico-subcortical connectivity patterns involving two subcortical regions of interest (putamen and thalamus) and three cortical regions (sensory-motor cortex, Brodmann Area 6, inferior frontal gyrus) were examined., Results: Older participants exhibited a higher rate of HKP compared to younger participants. Age-related HKP was associated with hemispheric asymmetry marked by a relatively stronger right-hemisphere cortico-subcortical connectivity involving the sensory-motor cortex and, to a lesser extent, Brodmann Area 6. These patterns were distinct from connectivity patterns associated with aging alone., Conclusions: HKP is related to anomalies involving frontal-subcortical circuits. Future research should examine specific components of the basal-ganglia circuitry., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The 5-HT₂A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT₂A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT₂A/₂C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT₂A knockout mice, indicating the effect is a consequence of 5-HT₂A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT₂A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT₂A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT₂A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT₂A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT₂A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT₂A activation and hallucinogenesis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed. Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects. In the present studies, dose-response curves for d-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism. AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming. We then tested AMPH in B6 and BTBR on the 3-chambered social approach task. One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced. This finding replicated across multiple cohorts treated with AMPH and saline vehicle. In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task. Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'., (Published by Elsevier Ltd.)

Non-competitive N-methyl-D-aspartate receptor (NMDA-R) antagonists have been extensively used in rodents to model psychotic symptoms of schizophrenia. Although the motor syndrome induced by acute and systemic administration of low doses of dizocilpine (MK-801) has been extensively characterized, its neurobiological basis is not fully understood. NMDA-R antagonists can disinhibit excitatory inputs in certain brain areas, but the precise circuitry is not fully known. We examined the involvement of the anterior thalamic nucleus (ATN) in hyperlocomotion and other related behaviors (stereotypies, ataxia signs) induced after acute systemic administration of MK-801. Since GABAergic neurons of the reticular thalamic nucleus (RTN) exert the main inhibitory control on thalamic projection neurons, we hypothesized that systemically injected MK-801 might block NMDA-R on RTN GABAergic neurons. This effect would subsequently result in disinhibition of GABAergic inputs onto ATN projections to cortical motor areas, thereby inducing behavioral effects. We evaluated the behavioral syndrome induced by the systemic administration MK-801 (0.2 mg/kg) in control rats and in rats subjected to a bilateral stereotaxic infusion of the GABA(A) agonist muscimol (0.2 μl of 2.5 and 5.0 mM; 0.5-1 nmol per application, respectively) into the ATN. As previously reported, MK-801-induced hyperlocomotion in parallel with disorganized movements (e.g. not guided by normal exploration) slight ataxia signs and stereotypies. All responses were antagonized by pre-infusion of muscimol but not saline into the ATN. According to our results we suggest that the ATN plays a role on hyperlocomotion evoked by MK-801 and could involve a thalamic GABAergic disinhibition mechanism., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Domoic acid (DA), the cause of Amnesic Shellfish Poisoning, is a naturally occurring marine biotoxin that is usually produced by the microscopic algae Pseudo-nitzschia. As is the case for other types of toxic algae, Pseudo-nitzschia outbreaks are becoming more frequent. Acute high-dose symptomology in humans includes vomiting, cramping, coma and death as well as neurological effects such as hallucinations, confusion and memory loss. Experimental studies and medical reports have collectively shown that DA exposure primarily affects the hippocampal regions of the brain and is associated with seizures and the disruption of cognitive processes. The neurobehavioral signature of DA is unique in that it includes transient and permanent changes in memory function that resemble human antegrade amnesia. Experimental studies with adult nonhuman primates have established that DA is a dose-dependent emetic that produces clinical and neuropathological changes consistent with excitotoxicity. Behavioral evaluations of treated rodents have shown that hyperactivity and stereotypical scratching are the first functional markers of toxicity. Mid-dose treatment is associated with memory impairment and behavioral hyperreactivity, suggesting changes in arousal and/or emotionality. At higher doses, DA treatment results in frank neurotoxicity that is characterized by seizures, status epilepticus and death in treated animals. The route of DA exposure is important and influences the severity of effects; intraperitoneal and intravenous treatments produce classic signs of poisoning at significantly lower doses than oral exposure. While developmental studies are few, DA readily crosses the placenta and enters the fetal brain. Domoic acid is not associated with congenital dysmorphia but is linked to persistent changes in motor behavior and cognition in exposed offspring. Comparative research suggests that functional losses associated with DA can be persistent and injuries to the CNS can be progressive. Long-term studies will be necessary to accurately track the expression of DA-related injury, in health and behavior, over the lifespan., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

The anterior cingulate cortex (ACC) is involved in the pathophysiology of a variety of mental disorders, many of which are exacerbated by stress. There are few studies, however, of stress-induced modification of synaptic function in the ACC that is relevant to emotional behavior. We investigated the effects of chronic restraint stress (CRS) on behavior and synaptic function in layers II/III of the ACC in mice. The duration of field excitatory postsynaptic potentials (fEPSPs) was longer in CRS mice than in control mice. The frequency of miniature inhibitory postsynaptic currents (mIPSCs) recorded by whole-cell patch-clamping was reduced in CRS mice, while miniature excitatory postsynaptic currents (mEPSCs) remained unchanged. Paired-pulse ratios (PPRs) of the fEPSP and evoked EPSC were larger in CRS. There was no difference in NMDA component of evoked EPSCs between the groups. Both long-term potentiation (LTP) and long-term depression of fEPSP were larger in CRS mice than in control mice. The differences between the groups in fEPSP duration, PPRs and LTP level were not observed when the GABA(A) receptor was blocked by bicuculline. Compared to control mice, CRS mice exhibited hyper-locomotive activity in an open field test, while no difference was observed between the groups in anxiety-like behavior in a light/dark choice test. CRS mice displayed decreased freezing behavior in fear conditioning tests compared to control mice. These findings suggest that CRS facilitates synaptic plasticity in the ACC via increased excitability due to disinhibition of GABA(A) receptor signalling, which may underlie induction of behavioral hyper-locomotive activity after CRS., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Maternal virus infection or maternal polyinosinic-polycytidilic acid injection confers behavioral alterations including deficit in prepulse inhibition on the offspring. We previously found delayed myelination specifically in the early postnatal hippocampus in the polyinosinic-polycytidilic acid-injection model. To test whether the transient delay in myelination in the juvenile hippocampus leads to abnormal behaviors after adolescence, we injected lysophosphatidylcholine, a potent demyelinating agent, into the ventral hippocampus of the 10-day-old rat. The lysophosphatidylcholine treatment yielded hypomyelination at postnatal day 16, but myelination reverted to normal level in the adult rat. Neuronal arrays and morphology were not disturbed in this model. We then performed a battery of behavioral tests on the lysophosphatidylcholine-treated and control PBS-injected rats. The lysophosphatidylcholine-treated rats showed deficit in prepulse inhibition, motor hyperactivity in response to methamphetamine and anxiety-related behaviors, all of which are typical behaviors observed in the maternal infection models. These findings suggest that the timing of myelination in the early postnatal hippocampus is crucial for the proper development of sensorimotor and emotional functions. The lysophosphatidylcholine-treated rat without a gross anatomical defect is useful as a model for psychotic disorders.

Developmental vitamin D (DVD) deficiency alters brain development and behaviour in the rat. The aim of this study was to vary levels of vitamin D deficiency during gestation and examine the effects on developmental milestones and behaviour in adult offspring. By manipulating the withdrawal and reintroduction of vitamin D in the diet of female Sprague-Dawley rats, their offspring were subjected to four different prenatal vitamin D conditions: (a) control (normal vitamin D throughout gestation); (b) early-DVD deficiency; (c) late-DVD deficiency; and (d) full-DVD deficiency. We show that the standard measure for vitamin D status, 25(OH)D(3), can be significantly manipulated within 7 days by dietary intervention. We also show that levels of the active form of this vitamin, 1,25(OH)(2)D(3), replete within the same time frame as 25(OH)D(3) but are slower to deplete. Developmental milestones remained normal across all four dietary groups. Concerning the adult behavioural phenotype, both full- and late-DVD deficiency were associated with MK-801-induced hyperlocomotion. Overall, these data suggest that vitamin D deficiency restricted to late gestation only is sufficient to disrupt adult brain functioning in the rat. These findings suggest there may be a therapeutic window for maternal dietary intervention in the DVD model of psychosis.

Mania is the defining feature of bipolar disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a "reverse-translational" approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multi-dimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents.

Hippocampal damage produces spatial memory impairment and hyperactivity in animals, while reductions in hippocampal size have been associated with memory deficits in humans. There are no known treatments for the behavioral changes specifically related to reduced hippocampal size. The purpose of this study was to determine if risperidone, an atypical antipsychotic drug that has shown cognitive-enhancing properties in animals and humans, could alleviate the behavioral disturbances produced by hippocampal damage in rats. Young adult male Sprague-Dawley rats received either sham stereotaxic surgery or direct stereotaxic infusions of N-methyl-d-aspartate (NMDA) into the dorsal hippocampus to produce hippocampal damage. One week later, animals in each group received daily subcutaneous injections of either saline or risperidone (0.2mg/kg) until the end of the experiment. Three weeks after surgery, locomotor activity was tested in all animals. During the fourth and fifth post-surgical weeks, animals were tested in a discrete-trial, delayed rewarded alternation memory paradigm. Risperidone reversed lesion-induced hyperactivity; however it also decreased activity in the sham control rats. In the delayed alternation task, there were significant drug and lesion effects irrespective of the day of testing, but there was no drugxlesion interaction. Hippocampal lesions impaired performance in the delayed alternation task in saline and risperidone-treated rats. However, risperidone modestly improved performance in lesioned and sham controls in comparison to saline-treated lesioned and sham controls. Risperidone also slowed choice time in the alternation task. These data indicate that risperidone does not specifically correct the neurobiological consequences of hippocampal damage, but that animals with hippocampal damage nonetheless maintain a significant degree of sensitivity to the beneficial effects of risperidone.

There is growing evidence from both uncontrolled and controlled clinical studies that lamotrigine (LTG) significantly augments clozapine (CLZ) in the treatment of refractory schizophrenia (RS) [Dursun, S.M., McIntosh, D., Milliken, H., 1999. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch. Gen. Psychiatry 56, 950; Dursun, S.M., Deakin, J.F.W., 2001. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J. Psychopharmacol. 15, 297-301; Tiihonen, J., Hallikainen, T., Ryynanen, O.P., Repo-Tiihonen, E., Kotilinen, I., Eronen, M., Toivonen, P., Wahlbeck, K., Putkonen, A., 2003. Lamotrigine in treatment-resistant schizophrenia; a randomized placebo-controlled cross over trial. Biol. Psychiatry 54, 1241-1248; Kremer, I., Vass, A., Gorelik, I., Bar, G., Blanaru, M., Javitt, D.C., Heresco-Levy, U., 2004. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol. Psychiatry. 56, 441-446]. However, the precise mechanism of action of this synergistic augmentation between clozapine and lamotrigine remains unclear. Therefore, the goal of this research is to explore the mechanism of action of this synergistic interaction between CLZ and LTG, utilizing a pharmacological animal model of schizophrenia by using phencyclidine (PCP). The effects of CLZ plus LTG were assessed by measuring PCP-induced hyper-locomotion and stereotyped behaviours in rats. Adult male rats (250-300 g) were pre-treated via intra-peritoneal (i.p.) injection with vehicle or drug 30 min before a PCP (5 mg/kg) or saline challenge. The behaviours were recorded and analysed for a 90-min period using the Etho Vision-computer based system. PCP produced hyper-locomotion, which was maximal at 30 min. LTG (10 mg/kg) significantly increased hyperlocomotion induced with PCP. However, a combination treatment of CLZ (5 mg/kg) plus LTG (10 mg/kg) significantly blocked the potentiation of PCP-induced hyper-locomotion observed with LTG (10 mg/kg) alone. Furthermore, the PCP-induced locomotion in the combination CLZ plus LTG-treated rats was significantly decreased when compared to vehicle. Therefore, LTG at doses that do not induce ataxia enhanced PCP-induced hyper-locomotion in rats, whereas the combination of LTG and CLZ significantly decreased PCP-induced hyper-locomotion consistent with clinical data.

Arsenic is an environmental contaminant found in soil, water and air in some zones of the world. It has been widely studied for its effects as a human carcinogenic agent, but few studies have dealt with neurobehavioral effects. In addition, studies of arsenic effects on development have only addressed its effects on embryotoxicity and teratogenicity after a single oral, gavage or intraperitoneal exposure. Among the behavioral alterations reported after intoxication with arsenic are both increased and decreased locomotor activity and learning deficits in a delayed alternation task [Toxicol. Lett. 54 (1990) 345; Bull. Environ. Contam. Toxicol. 50 (1993) 100; Brain Res. Bull. 55 (2001) 301]. To further characterize developmental and behavioral alterations induced by arsenic exposure, Sprague-Dawley rats were exposed to arsenite (36.70 mg arsenic/l in drinking water) from gestation day 15 (GD 15) or postnatal day 1 (PND 1), until approximately 4 months old. The pregnant or lactating dams received either the arsenic solution or regular drinking water and once pups were weaned, they continued receiving the same solution as drinking water. Animals exposed from GD 15 showed increased spontaneous locomotor activity and both exposed groups showed increased number of errors in a delayed alternation task in comparison to the control group. Total arsenic (TA) content in brain was similar for both exposed groups and significantly different from the control group. These results indicate that rats exposed to arsenic during development present deficits in spontaneous locomotor activity and alterations in a spatial learning task.

Tardive dyskinesia (TD) is a late side effect of long-term antipsychotic use in humans, and the vacuous chewing movement (VCM) model has been used routinely to study this movement disorder in rats. Recent receptor occupancy studies in humans and rats have found that antipsychotics given in doses which lead to moderate levels of D(2) receptor blockade can achieve optimal clinical response while minimizing the emergence of acute motor side effects. This suggests that clinicians may have been using inappropriately high doses of antipsychotics. A review of the existing VCM literature indicates that most animal studies have similarly employed antipsychotic doses that are high, i.e. doses that lead to near complete D(2) receptor saturation. To verify whether the incidence or severity of VCMs would decrease with lower antipsychotic doses, we conducted initial experiments with different doses of haloperidol (HAL) given either as repeated daily injections or as depot injections over the course of several weeks. Our results demonstrate that (1) the incidence of VCMs is significantly related to HAL dose, and (2) significant levels of VCMs only emerge when haloperidol is continually present. These findings are consistent with the possibility that total D(2) occupancy, as well as 'transience' of receptor occupation, may be important in the development of late-onset antipsychotic-induced dyskinetic syndromes.

Adenosine A(2A) agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A(2A) and dopamine D(2) receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic neurotransmission in the motor effects of adenosine A(2A) receptors is not yet known. Therefore in the present study the effect of GABAergic agents on adenosine A(2A) receptor agonist (NECA- or CGS 21680) induced catalepsy and inhibition of amphetamine elicited motor hyperactivity was examined. Pretreatment with GABA, the GABA(A) agonist muscimol or the GABA(B) agonist baclofen potentiated whereas the GABA(A) antagonist bicuculline attenuated NECA- or CGS 21680-induced catalepsy. However, the GABA(B) antagonists phaclophen and delta-aminovaleric acid had no effect. Administration of NECA or CGS 21680 not only reduced spontaneous locomotor activity but also antagonized amphetamine elicited motor hyperactivity. These effects of NECA and CGS 21680 were potentiated by GABA or muscimol and antagonized by bicuculline. These findings provide behavioral evidence for the role of GABA in the motor effects of adenosine A(2A) receptor agonists. Activation of adenosine A(2A) receptors increases GABA release which could reduce dopaminergic tone and induce catalepsy or inhibit amphetamine mediated motor hyperactivity.

Based on the hypothesis that drugs of abuse increase locomotor activity through mechanisms related to reinforcement, i.e. the mesolimbic dopamine (DA) system, ethanol-induced hyperactivity might provide a screening model to investigate the effect of ethanol on reward pathways. In the present study, ethanol had bidirectional effects on locomotion in mice: hyperactivity at low doses (2-3 g/kg) and sedation at high doses (4-5 g/kg). Such high doses induced a loss of righting reflex (LRR). The stimulant effect of ethanol was blocked by the D2/D3 antagonists, haloperidol (0.2 mg/kg) and tiapride (30-60 mg/kg), and by the D1 antagonist, SCH 23390 (0.03 mg/kg) whereas the non selective DA antagonist, clozapine decreased ethanol-induced hyperactivity at a dose (1 mg/kg) which also decreased activity in control animals. Unlike haloperidol and clozapine which potentiated LRR induced by ethanol, the selective DA antagonists, tiapride and SCH 23390, had no effect. Pretreatment with the D2/D3 agonist, quinpirole (0.1-0.3 mg/kg), reduced hyperactivity induced by ethanol presumably by stimulation of pre-synaptic receptors but did not change LRR. The D1 full agonist, SKF 81297 which produced hyperactivity by itself and the D1 partial agonist, SKF 38393, did not specifically affect ethanol-induced activities. The results indicate that activation of D1 and D2/D3 DA receptors is implicated in ethanol-induced hyperactivity whereas other mechanisms might mediate the sedative effects of ethanol. Tiapride and haloperidol, both used in the management of alcohol dependence, might exert beneficial effects by counteracting the reinforcing effects of ethanol. Tiapride's lack of interaction with the depressant effects of ethanol may account for its better tolerance in alcoholic patients.

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a popular recreationally used drug among young people in Europe and North America. The recent surge in use of MDMA and increasing concerns about possible toxic effects of the drug have inspired a great deal of research into the mechanisms by which the drug may affect the central nervous system. This paper reviews studies on the neurochemical, behavioral and neurophysiological effects of MDMA, with emphasis on MDMA effects in regions of the brain that have been implicated in reward. Experiments in awake, behaving laboratory animals have demonstrated that single injections of MDMA increase extracellular levels of the neurotransmitters dopamine (DA) and serotonin (5HT) in the nucleus accumbens and in several other brain regions that are important for reward. Most of the behavioral and electrophysiological changes that have been reported to date for single doses of MDMA appear to be mediated by this MDMA-induced increase in extracellular DA and 5HT. As an example, MDMA-induced hyperthermia and locomotor hyperactivity in laboratory animals can be blocked by administering drugs that prevent MDMA-induced 5HT release and can be attenuated by administering 5HT receptor antagonists, whereas effects of MDMA on delayed reinforcement tasks appear to be mediated by MDMA-induced increases in extracellular DA. Similarly, the effects of MDMA on neuronal excitability in the nucleus accumbens and in several other brain regions can be prevented by administering drugs that block MDMA-induced 5HT release and can be attenuated by depleting brain DA levels or by administering either DA D1 receptor antagonists or 5HT receptor antagonists. In addition to the acute effects of MDMA, it is now well established that repeated or high-dose administration of MDMA is neurotoxic to a subpopulation of 5HT-containing axons that project to the forebrain in laboratory animals. Recent studies have shown that this neurotoxic effect of MDMA is associated with long-duration changes in both DA and 5HT neurotransmission in the nucleus accumbens. Whether these long-duration changes in neurotransmission might be related to reports of depression and other psychopathologies by some frequent users of MDMA remains to be determined. Methylene-dioxymethamphetamine has been found to increase extracellular levels of norepinephrine and to alter brain levels of several neuropeptides as well as altering levels of DA and 5HT. Much additional research is required to understand the multiple ways in which this complex drug may alter neurotransmission in the brain, both acutely and in the long term.

We have replicated the findings of Mirmiran and colleagues that neonatal administration of the antidepressant clomipramine (CLI) to male rats results in hyperactivity in open-field tests in adulthood. We report that this effect does not reliably occur in a "Digiscan" activity device. The difference in effect between the two activity measuring devices may be due to more stress being present in the open-field test, and we propose that the CLI-treated rats may be more reactive to stress. This hypothesized enhanced reactivity to stress may be similar to the proposed vulnerability of depressed humans to stress. In addition, we have found that the open-field effect does not occur until the rats are at least 4 months old; this delayed effect may be analogous to the progressive onset of endogenous depression in humans.

Several changes of spontaneous motor and learned behaviours were obtained in the male offspring of pregnant rats that were treated on gestation day 15 with the antimitotic agent methylazoxymethanol (MAM, 25 mg/kg). MAM-treated offspring, when tested at adult ages, showed notable increases in motor activity parameters as measured by direct observation or in automated photocell test cages. This hyperactive state was accompanied by clear impairments by MAM offspring in the acquisition of instrumental learning in a radial arm maze and in a circular swim maze. In Skinner boxes, MAM offspring made fewer responses during the Fixed Ratio (FR) 1 schedule but did not differ from the saline offspring in the acquisition of the difficult differential-reinforcement-of-low-rates (DRL) 72 sec task. Neurochemical assays indicated that the MAM rats had elevated noradrenaline and dopamine levels in several brain regions. These findings are discussed with regard to possible alterations of habituation processes in MAM rats.