dizocilpine-maleate and Attention-Deficit-Disorder-with-Hyperactivity

Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

Topics: Animals; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Humans; Mecamylamine; Nootropic Agents; Rats; Rats, Inbred SHR; Scopolamine

Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.

Topics: Adrenergic Uptake Inhibitors; Animals; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Fluoxetine; Growth and Development; Methylphenidate; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Open Field Test; Proto-Oncogene Proteins c-akt; Selective Serotonin Reuptake Inhibitors; Sleep

Exposure of NMDA receptor antagonists during developmental stages leads to behavioral consequences like attention deficit hyperactivity disorder (ADHD). However, the underlying molecular mechanisms have remained poorly understood. Herein, we studied the phosphorylated Akt (pAkt) and caspase-3, the key regulators of neuronal cell survival/death, as the probable downstream targets of MK-801 often used to engender ADHD-like condition. Swiss albino mice at postnatal days (PND) 7, 14 or 21 were injected with a single dose of MK-801 and evaluated for hyperactivity (open field test) and memory deficit at adolescence (PND 30) and adult stages (PND 60). PND 7 or 14 treatment groups (but not PND 21) consistently showed hyperactivity at the adolescence stage. A significant increase in working and reference memory errors in radial arm maze was noted at the adolescence age. PND 7 group continued to display the symptoms even in adulthood. All the treatment groups showed a significant decrease in the percent alterations (Y-maze) and discrimination index (novel object recognition test) at adolescence age. A significant increase in caspase-3 expression was noted in the prefrontal cortex (PFC) and hippocampus, whereas increased pAkt was noticed only in the hippocampus, following a single injection of MK-801 at PND 7. Concurrently, PND 7 treatment group showed significantly decreased neuronal nuclei (NeuN) expression (a marker for mature neurons) in the dentate gyrus, cornu ammonis-3 and PFC, but not in cornu ammonis-1, at adolescence age. We suggest that the observed symptoms of ADHD at adolescence and adulthood stages may be linked to alteration in pAkt and caspase-3 followed MK-801 treatment at PND 7.

Topics: Age Factors; Animals; Attention Deficit Disorder with Hyperactivity; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Intracellular Fluid; Locomotion; Male; Maze Learning; Mice; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology

Nicotinic agonists have been shown in a variety of studies to improve cognitive function. Since nicotinic receptors are easily desensitized by agonists, it is not completely clear to what degree receptor desensitization or receptor activation are responsible for nicotinic agonist-induced cognitive improvement. In the current study, the effect of the neuronal nicotinic cholinergic α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) and the α7 nicotinic receptor antagonist methyllycaconitine (MLA) on attentional function was determined. Adult female Sprague-Dawley rats were trained on the visual signal detection task. They were required to discriminate whether or not a light signal occurred on a trial and respond with a lever press on one side after a signal and the opposite side after the absence of a signal in order to receive a food pellet reinforcer. Acute administration of the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801). Acute administration of MLA also significantly attenuated the dizocilpine-induced attentional impairment. In previous research we have shown that the α4β2 nicotinic desensitizing agent and partial agonist sazetidine-A also was effective in reversing dizocilpine-induced attentional impairments on the signal detection task and that low doses of the general nicotinic antagonist mecamylamine improved learning and memory. The current studies indicate that blockade of nicotinic receptors can effectively attenuate attentional impairments. Development of drugs that provide a net decrease in nicotinic receptor activity either through antagonism or desensitization could be worth exploring for beneficial effects for treating cognitive impairments.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Dihydro-beta-Erythroidine; Dizocilpine Maleate; Female; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic

Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.

Topics: Animals; Antipsychotic Agents; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Motor Activity; Psychomotor Agitation; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Behavior; Social Behavior Disorders

Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).. Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.. Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment.. AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Molecular Structure; Neurons; Nicotinic Agonists; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Signal Detection, Psychological

If the pregnant and lactating female rats are exposed to environmental levels of bisphenol-A (BPA), their male offspring will display hyperactivity and attention-deficit. In patients with attention-deficit/hyperactivity disorder (ADHD), the size of the amygdala is reported to be reduced. This study examined functional alterations in the basolateral amygdala (BLA) of the postnatal 28-day-old male offspring exposed perinatally to BPA (BPA-rats). We specifically focused on the synaptic properties of GABAergic/dopaminergic systems in the BLA. A single electrical stimulation of the capsule fibers evoked multispike responses with an enhanced primary population spikes (1st-PS) in the BPA-rats. A single train of high-frequency stimulation of the fibers induced NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in BPA-rats, but not in control rats. Also, paired-pulse inhibition (PPI, GABA-dependent) in control rats was reversed to paired-pulse facilitation (PPF) in BPA-rats. Perfusion of slices obtained from BPA-rats with the GABA(A) receptor (GABA(A)R) agonist muscimol blocked the multispike responses and LTP, and recovered PPI. By contrast, the dopamine D1 receptor antagonist SCH23390 abolished LTP and attenuated the increased amplitude of 1st-PS in BPA-rats. Conversely, blockade of GABA(A)R by bicuculline could produce the multispike responses and PPF in BLA in control rats. Furthermore, in BLA the infusion of SCH23390, muscimol or the NMDAR blocker MK801 ameliorated the hyperactivity and improved the deficits in attention. These findings suggest that the perinatal exposure to BPA causes GABAergic disinhibition and dopaminergic enhancement, leading to an abnormal cortical-BLA synaptic transmission and plasticity, which may be responsible for the hyperactivity and attention-deficit in BPA-rats. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

Topics: Air Pollutants, Occupational; Amygdala; Animals; Attention Deficit Disorder with Hyperactivity; Benzazepines; Benzhydryl Compounds; Bicuculline; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Female; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Glutamate Decarboxylase; Long-Term Potentiation; Male; Muscimol; Neuronal Plasticity; Phenols; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1delta (CK1delta OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels. Under basal conditions, CK1delta OE mice exhibited horizontal and vertical hyperactivity, reduced anxiety, and nesting behavior deficiencies. The CK1delta OE mice also presented paradoxical responses to dopamine receptor stimulation, showing hypoactivity following injection of d-amphetamine or methylphenidate, indicating that CK1 activity has a profound effect on dopamine signaling in vivo. Interestingly, CK1delta overexpression led to significantly reduced D1R and D2R dopamine receptor levels. All together, under basal conditions and in response to drug stimulation, the behavioral phenotype of CK1delta OE mice is reminiscent of the symptoms and drug responses observed in attention-deficit/hyperactivity disorder and therefore the CK1delta OE mice appear to be a model for this disorder.

Topics: Amphetamine; Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Casein Kinase Idelta; Dizocilpine Maleate; Down-Regulation; Excitatory Amino Acid Antagonists; Locomotion; Methylphenidate; Mice; Prosencephalon; Receptors, Dopamine D1; Receptors, Dopamine D2

Several studies involving postnatal administration of the N-methyl-D-aspartate (NMDA) antagonists, dizocilpine (MK-801; 3 x 0.5 mg/kg, at 08.00, 16.00 and 24.00 h) on Postnatal day 11, or Ketamine (1 x 50 mg/kg) or Ethanol (1 x 2.5 g/kg, Ethanol-Low, or 2 x 2.5 g/kg, 2-h interval, Ethanol-High) on Postnatal day 10, are described. Some mice from each treatment/vehicle group were sacrificed 24 h after NMDA antagonist treatment and brain regions were taken for fluoro-jade staining analysis. Functional analysis was initiated at 60 days of age. All three treatments inducing an antagonistic action at NMDA receptors, MK-801, Ketamine and Ethanol-High induced a similar pattern of initial hypoactivity followed by marked and lasting hyperactivity in the motor activity test chambers. In each case, the basal hyperactivity level was abolished by acute treatment with a low dose of D-amphetamine (0.25 mg/kg). All three treatments, MK-801, Ketamine and Ethanol-High, induced a deficit in acquisitive performance in the radial arm maze test of instrumental learning. The deficit induced by postnatal MK-801 was abolished by acute treatment with the low dose of D-amphetamine. All three treatments, MK-801, Ketamine and Ethanol-High, resulted in normal acquisitive performance during the first three test days in the circular swim with the submerged platform maintained in a constant position, but on the fourth test day, with the platform position shifted to a different "quadrant", induced marked deficits. Fluoro-jade staining analyses indicated a devastating cell degeneration in several brain regions of mice administered NMDA antagonists postnatally, including the hippocampus, frontal cortex, parietal cortex, and cerebellum. Severe cell degeneration in the laterodorsal thalamus due to Ethanol or diazepam (5 mg/kg) appeared not to affect the different aspects of function. The pattern of dysfunctional outcome and apoptotic cell loss following postnatal NMDA antagonist treatment offers a plausible similarity to the major aspects of 'syndromatic continuity' in ADHD, hyperactivity, inattention and impulsivity, thereby providing an interesting animal model of the disorder.

Topics: Animals; Animals, Newborn; Apoptosis; Attention Deficit Disorder with Hyperactivity; Central Nervous System Depressants; Central Nervous System Stimulants; Dextroamphetamine; Diazepam; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Female; Fluoresceins; Fluorescent Dyes; Hypnotics and Sedatives; Ketamine; Maze Learning; Mental Disorders; Mice; Motor Activity; Nerve Degeneration; Nervous System Diseases; Organic Chemicals; Pregnancy; Receptors, N-Methyl-D-Aspartate; Swimming; Weight Gain

Spontaneously hypertensive rats (SHR) have behavioral characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to the behavioral disturbances of children with attention-deficit hyperactivity disorder (ADHD). We have previously shown that dopaminergic and noradrenergic systems are disturbed in the prefrontal cortex of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. It was of interest to determine whether the underlying neural circuits that use glutamate as a neurotransmitter function normally in the prefrontal cortex of SHR. An in vitro superfusion technique was used to demonstrate that glutamate caused a concentration-dependent stimulation of [3H]norepinephrine release from rat prefrontal cortex slices. Glutamate (100 microM and 1 mM) caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from control slices. The effect of glutamate was not mediated by NMDA receptors, since NMDA (10 and 100 microM) did not exert any effect on norepinephrine release and MK-801 (10 microM) did not antagonize the effect of 100 microM glutamate. These results demonstrate that glutamate stimulates norepinephrine release from rat prefrontal cortex slices and that this increase is enhanced in SHR. The results are consistent with the suggestion that the noradrenergic system is overactive in prefrontal cortex of SHR, the animal model for ADHD.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Impulsive Behavior; Male; Norepinephrine; Organ Culture Techniques; Prefrontal Cortex; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tritium

Topics: Adult; Anticonvulsants; Attention Deficit Disorder with Hyperactivity; Dibenzocycloheptenes; Dizocilpine Maleate; Humans; Psychiatric Status Rating Scales