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PubMed1984

[Body movements during sleep in Lennox syndrome].

In Lennox syndrome the brainstem which plays important roles in regulating sleep and its parameters is thought to be disturbed. In order to clarify the importance of the dysfunction of the brainstem in Lennox syndrome, polygraphic examination were studied and their findings were assessed with prognosis. 8 patients aged from 6 to 17 years were subjected to this study. They were divided into two groups according to their prognosis. Group 1 showed good prognosis. Seizures were easily controllable and have not occurred for more than 24 months. In group 2 seizures were intractable and were uncontrollable by medication. In 4 normal children ranging in age from 4 to 10 years, the same studies were performed. Recordings were performed on two consecutive nights and the second night recordings were used for analysis. Polygraph consisted of EEG from C4 and P4, bipolar EOG from electrode attached to outer canthus, surface EMG from submental muscle and 5 or 6 other muscles including trunk and limbs. Sleep stages were determined in each minute according to the standard of APSS. Body movements were classified into two types on the basis of their distribution over body parts and on duration of movements. Gross movements (GM) involved the body trunk and lasted for more than two seconds. Twitch movements (TM) were localized in one muscle on surface EMG recordings lasting less than 0.5 seconds. In normal children, the rate of GM in sleep stage 1 and REM are significantly higher than slow wave sleep. And this is the same in TM of all muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2004

Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum.

Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-d-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease.

Animals↗

PubMed2004

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury.

Dysfunction and death of spinal cord neurons are critical determinants of neurological deficits in various pathological conditions, including multiple sclerosis (MS) and spinal cord injury. Yet, the molecular mechanisms underlying neuronal/axonal damage remain undefined. Our previous studies raised the possibility that a decrease in the levels of plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump extruding calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma. However, the causal relationship between alterations in PMCA2 levels and neuronal injury was not well established. We now report that inhibition of PMCA activity in purified spinal cord neuronal cultures delays calcium clearance, increases the number of nonphosphorylated neurofilament H (SMI-32) immunoreactive cells, and induces swelling and beading of SMI-32-positive neurites. These changes are followed by activation of caspase-3 and neuronal loss. Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler(2J), a mouse with a functionally null mutation in the PMCA2 gene. Our findings suggest that a reduction in PMCA2 level or activity leading to delays in calcium clearance may cause neuronal damage and loss in the spinal cord.

Animals↗

PubMed2005

Pharmacological challenge with a serotonin 1D agonist in alcohol dependence.

BACKGROUND: Both animal and clinical studies have implicated serotonergic dysfunction in the pathogenesis of alcohol abuse and dependence. However the exact mechanisms involved remain unknown. Theoretically, low serotonin promotes alcohol seeking behavior. Sumatriptan is a serotonin1D agonist. It is postulated that sumatriptan's agonism at this terminal autoreceptor increases negative feedback, creating a net effect of decreased serotonergic neurotransmission. Administration of sumatriptan should therefore produce a craving for alcohol and the desire to drink. METHODS: Fifteen patients with alcohol dependence who had undergone detoxification were recruited. Sumatriptan (100 mg) and placebo was administered in cross-over fashion on 2 separate days 72 hours apart. Both patients and raters were blind to all treatments. Patients were assessed on the following scales at -30, 0, 30, 90, 150 and 210 minutes: A 6-item scale designed to rate the patient's intention to drink; The Sensation Scale; a 13-item affect analog scale designed to rate the pattern and extent of emotional changes; and an 8-item scale designed to rate the patient's craving for alcohol. RESULTS: No significant differences were found between the placebo and sumatriptan groups and no significant cross over effects were found. CONCLUSION: The general lack of efficacy of sumatriptan in producing alcohol-like symptoms or a desire to drink alcohol may suggest that the 5HT1D receptor plays little role in the pathophysiology of alcoholism.

Alcohol Drinking↗

PubMed2006

The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice: involvement of dopaminergic systems.

Galantamine, a drug for Alzheimer's disease, is a novel cholinergic agent with a dual mode of action, which inhibits acetylcholinesterase and allosterically modulates nicotinic acetylcholine receptors (nAChRs), as a result stimulates catecholamine neurotransmission. In the present study, we investigated whether galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular beta amyloid (Abeta)(25-35)-injected animal model of Alzheimer's disease. Galantamine (3 mg/kg p.o.) significantly increased the extracellular dopamine release in the hippocampus of saline- and Abeta(25-35)-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Abeta(25-35)-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Abeta(25-35) induced cognitive impairment. Galantamine improved the Abeta(25-35)-induced cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of galantamine were blocked by the treatment with mecamylamine, SCH-23390, a dopamine-D1 receptor antagonist, and sulpiride, a dopamine-D2 receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Abeta(25-35)-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.

Amyloid beta-Peptides↗

PubMed2003

Aging alters dendritic morphology, input resistance, and inhibitory signaling in dentate granule cells of the rhesus monkey.

The neural substrates of age-related hippocampal dysfunction in primates are poorly understood. This issue was addressed with combined intracellular biocytin filling and whole-cell patch clamp recordings of intrinsic membrane properties and inhibitory postsynaptic currents (IPSCs) in dentate granule cells in in vitro slices prepared from behaviorally characterized young (<11 years old) and aged (>24 years old) rhesus monkeys. Six of nine aged monkeys were significantly impaired in performance on the hippocampally mediated delayed nonmatch to sample (DNMS) task at a 2-minute delay. Morphometric analyses showed that cells from aged monkeys had significantly reduced vertical dendritic extents and distal dendritic branching but increased proximal dendritic branching. Intrinsic membrane and action potential properties did not differ between cells from young and aged monkeys with the exception of a small but significant increase in input resistance with age. The frequency, amplitude, and rise time of gamma-aminobutyric acid (GABA)(A) receptor-mediated miniature IPSCs were not significantly different in cells from young vs. aged monkeys. However, the miniature IPSC decay time constant and the benzodiazepine potentiation of this decay time constant were both significantly increased in cells from aged monkeys. These differences in the properties of dentate granule cells correlated positively with age but not specifically with impairment on the DNMS 2-minute delay task. Nevertheless, these changes in dendritic morphology, input resistance, and inhibitory signaling properties may be part of a constellation of subtle functional changes contributing to age-associated cognitive impairment.

Action Potentials↗

PubMed2006

The role of dopamine receptors in the neurobehavioral syndrome provoked by activation of L-type calcium channels in rodents.

In rodents, activation of L-type calcium channels with +/-BayK 8644 causes an unusual behavioral syndrome that includes dystonia and self-biting. Prior studies have linked both of these behaviors to dysfunction of dopaminergic transmission in the striatum. The current studies were designed to further elucidate the relationship between +/-BayK 8644 and dopaminergic transmission in the expression of the behavioral syndrome. The drug does not appear to release presynaptic dopamine stores, since microdialysis of the striatum revealed dopamine release was unaltered by +/-BayK 8644. In addition, the behaviors were preserved or even exaggerated in mice or rats with virtually complete dopamine depletion. On the other hand, pretreatment of mice with D(3) or D(1/5) dopamine receptor antagonists attenuated the behavioral effects of +/-BayK 8644, while pretreatment with D(2) or D(4) antagonists had no effect. In D(3) receptor knockout mice, +/-BayK 8644 elicited both dystonia and self-biting, but these behaviors were less severe than in matched controls. In D(1) receptor knockout mice, behavioral responses to +/-BayK 8644 appeared exaggerated. These results argue that the behavioral effects of +/-BayK 8644 are not mediated by a presynaptic influence. Instead, the behaviors appear to result from a postsynaptic activation of the drug, which does not require but can be modified by D(3) or D(1/5) receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2005

Impairment of pain inhibition in chronic tension-type headache.

Evidence has been accumulated suggesting that a dysfunction in pain inhibitory systems, i.e. in 'diffuse noxious inhibitory controls' (DNIC)-like mechanisms, might be-amongst other factors-responsible for the development of anatomically generalized chronic pain like fibromyalgia. The aim of the present study was to look for similar impairments in chronic tension-type headache (CTTH) as a regionally specific pain syndrome. Twenty-nine CTTH patients and 25 age- and sex-matched healthy control subjects participated in the study. After baseline assessment of electrical detection and pain thresholds, tonic heat stimuli were concurrently applied by a thermode to the thigh to induce DNIC-like pain inhibition. Tonic heat stimuli were applied either slightly above ('pain' condition) or slightly below ('heat' condition) pain threshold. For determination of electrical detection and pain thresholds, electrocutaneous stimuli were administered either to the forearm (extra-cranial site) or to the temple (cranial site), using a multiple staircase procedure. The increase in the electrical detection and pain thresholds induced by concurrent tonic heat stimulation was significantly smaller in the CTTH patients than in the control subjects. This group difference was present during the 'pain' as well as the 'heat' condition. Furthermore, the electrical detection and pain thresholds were affected in this group-specific manner both at the forearm and at the temple. These findings suggest that patients with CTTH suffer from deficient DNIC-like pain inhibitory mechanisms in a similar manner, as do patients with anatomically generalized chronic pain like fibromyalgia.

Adult↗

PubMed1992

The coordination of posture and voluntary movement in patients with cerebellar dysfunction.

Postural adjustments associated with the task of rising on tiptoes were investigated in a reaction time paradigm in 10 normal subjects and 18 patients with cerebellar disorders. Cerebellar dysfunction was due to either degenerative cerebellar disease, tumor, or ischemia. Displacements of the center of foot pressure (CFP) were recorded. The task, accomplished by the triceps surae muscle (executional activity, mean latency of 411 ms), is mechanically effective only if the center of gravity has been shifted forward in advance. To this effect, a phasic burst of preparatory EMG activity in the tibialis anterior normally occurs at a mean latency of 163 ms, shifting the center of gravity forward. Shortly thereafter, activity of the quadriceps femoris (175 ms) extends the knee and aids the forward shift of the center of gravity. Different aspects of this motor sequence were disturbed in individual patients: Latencies of preparatory and executional activity were uncorrelated in 15 of the 18 patients. Executional (n = 16) or preparatory (n = 13) EMG activity was tonic instead of phasic. Latencies of either preparatory or executional EMG activities or both were prolonged (n = 10). The time interval between motor preparation and execution was increased (n = 9). The trial-to-trial variability of biomechanical parameters and EMG latency was increased. Preparatory EMG activity in the quadriceps was entirely missing (n = 9), resulting in knee bending at the unsuccessful attempt to rise on tiptoes. Patients who were most severely affected had no preparatory activity at all (n = 2), and therefore were unable to perform the task.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2006

Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of serotonin 5-HT2 receptors to the ERK 1/2 map kinase pathway.

Dysfunction within the striatal direct and indirect projecting systems arises after 6-hydroxydopamine (6-OHDA)-induced dopamine depletion, highlighting the central regulatory function of dopamine in motor systems. However, the striatal 5-hydroxytryptamine (5-HT) innervation remains intact after 6-OHDA lesions, suggesting that the 5-HT system may contribute to the lesion-induced dysfunction, or alternatively, it may adapt and compensate for the dopamine deficit. Neonatal 6-OHDA lesions actually give rise to a 5-HT axonal hyperinnervation within the dorsal striatum, further reinforcing the idea that the 5-HT system plays a central role in striatal function after dopamine depletion. Here we show that neonatal but not adult 6-OHDA lesions result in a novel coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase pathway, a signaling cascade known to regulate neuronal plasticity. Chloroamphetamine-induced 5-HT release or direct stimulation of striatal 5-HT2 receptors via the 5-HT2 agonist DOI, produced robust ERK1/2 phosphorylation throughout the dorsal striatum of neonatal lesioned animals, a response not observed within the intact striatum. Pretreatment with the select 5-HT2 receptor antagonist Ketanserin blocked DOI-induced ERK1/2 phosphorylation. This drug-induced ERK1/2 phosphorylation was subsequently shown to be restricted to direct pathway striatal neurons. Our data show that adaptation of direct pathway neurons after neonatal 6-OHDA lesions involves coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase cascade, a pathway not typically active in these neurons. Because dopamine-mediated signaling is redundant after 6-OHDA lesions, 5-HT-mediated stimulation of the ERK1/2/MAP Kinase pathway may provide an alternative signaling route allowing the regulation of neuronal gene expression and neuronal plasticity in the absence of dopamine.

Animals↗

PubMed2002

Dendritic calcium encodes striatal neuron output during up-states.

Striatal spiny projection neurons control basal ganglia outputs via action potential bursts conveyed to the globus pallidus and substantia nigra. Accordingly, burst activity in these neurons contributes importantly to basal ganglia function and dysfunction. These bursts are driven by multiple corticostriatal inputs that depolarize spiny projection neurons from their resting potential of approximately -85 mV, which is the down-state, to a subthreshold up-state of -55 mV. To understand dendritic processing of bursts during up-states, changes in intracellular calcium concentration ([Ca2+]i) were measured in striatal spiny projection neurons from cortex-striatum-substantia nigra organotypic cultures grown for 5-6 weeks using somatic whole-cell patch recording and Fura-2. During up-states, [Ca2+]i transients at soma and primary, secondary, and tertiary dendrites were highly correlated with burst strength (i.e., the number of spontaneous action potentials). During down-states, the action potentials evoked by somatic current pulses elicited [Ca2+]i transients in higher-order dendrites that were also correlated with burst strength. Evoked bursts during up-states increased dendritic [Ca2+]i transients supralinearly by >200% compared with the down-state. In the presence of tetrodotoxin, burst-like voltage commands failed to elicit [Ca2+]i transients at higher-order dendrites. Thus, dendritic [Ca2+]i transients in spiny projection neurons encode somatic bursts supralinearly during up-states through active propagation of action potentials along dendrites. We suggest that this conveys information about the contribution of a spiny projection neuron to a basal ganglia output specifically back to the corticostriatal synapses involved in generating these outputs.

Action Potentials↗

PubMed2000

Serotonergic dysfunction across the eating disorders: relationship to eating behaviour, purging behaviour, nutritional status and general psychopathology.

BACKGROUND: Several recent studies have pointed to a dysfunction of serotonin transmission in patients with eating disorders. Notwithstanding, it is not known whether serotonergic abnormalities are related primarily to eating and/or purging behaviour, nutritional status or general psychopathological dimensions. Therefore, by using a validated neuroendocrine strategy, we investigated central serotonergic function in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder who differ on the above parameters. METHODS: Plasma prolactin response to D-fenfluramine (30 mg p.o.) or placebo was measured in 58 drug-free female volunteers, comprising 15 underweight anorexic women, 18 bulimic women, 10 women with binge-eating disorder and 15 female healthy controls. Behavioural assessment included ratings of eating disorder symptoms, depression, aggression and food-related obsessions and compulsions. RESULTS: A significantly decreased prolactin response to D-fenfluramine was found in underweight anorexic women and in bulimics with high frequency bingeing ( > 2 binge episodes/day), but not in patients with binge-eating disorder or in bulimics with low frequency bingeing (< I binge episode/day). In the whole bulimic group, a negative correlation emerged between frequency of bingeing and prolactin response. No significant correlation was found between physical or psychopathological measures and the hormonal response in any group. CONCLUSIONS: These results confirm our previous findings of an impaired serotonergic transmission in underweight anorexics and in bulimics with high frequency bingeing, but not in patients with less severe bulimia nervosa. Moreover, they show, for the first time, that the hypothalamic serotonergic system is not altered in women with binge-eating disorder.

Adult↗

PubMed1983

Arguments in favour of endocytosis of glycoprotein components of the membranes of parallel fibers by Purkinje cells during the development of the rat cerebellum.

Chloroquine (a drug known to induce a dysfunction of lysosomes) was used to study the behavior of Concanavalin A binding glycoproteins located on the axolemma of parallel fibers in young rat cerebella, and abundant on these membranes at a period preceding synaptogenesis with the dendrites of Purkinje cells. Chloroquine induces in Purkinje cells a large accumulation of grains consisting of membrane whorls in lysosomes. These grains stain for Concanavalin A, and do not stain either for a mitochondrial marker (aspartate aminotransferase mitochondrial isoenzyme) or for a marker of the Purkinje cell internal membrane (PSG). It is suggested that the material accumulating in the Purkinje cells under the effect of chloroquine comes from the parallel fibers. Together with the observation that alpha-D-mannosidase (involved in the degradation of these glycoproteins) is exclusively located inside Purkinje cells, these results provide a firm indication that this material enters the Purkinje cells through pinocytosis. The absence of ATPase activity (ATPase is a glycoprotein plasma membrane marker highly concentrated on parallel fibers) within these grains suggested that not all the components of these membranes are pinocytosed, but that the process is specific for certain molecules. These results are compatible with the ultrastructural observations of others, and support the arguments in favour of the pinocytosis phenomenon being one of the first steps of synapse formation. The observed specificity of pinocytosis for certain molecules suggests that a receptor-mediated recognition of some glycans of glycoproteins is the preliminary event in the establishment of synapses.

Adenosine Triphosphatases↗

PubMedDate not supplied

Bladder instability: a re-appraisal of classical experimental approaches and development of new therapeutic strategies.

1 Despite the growing social interest in human urinary tract disorders, the aetiology of detrusor instability remains poorly understood. Myogenic and neural impairment of detrusor activity caused by CNS or autonomic injuries can results in dysfunctions of normal voiding of the bladder such as urinary incontinence. 2 The contractility of human detrusor smooth muscle is critically dependent on acetylcholine-induced muscarinic receptor activation. Biochemical and functional in vivo and in vitro studies suggest the presence of an heterogeneous population of muscarinic receptor subtypes (M1-M4) localized at muscular and neutral sites. There is increasing evidence on the prejunctional auto- and hetero-regulation of acetylcholine release from parasympathetic nerve endings in modulating detrusor muscle contraction during micturition. 3 Activation of P2X purinoreceptors closely associated with the parasympathetic varicosities seems to be implicated to varying extent in the contractility in normal or instable human detrusor. Interestingly, P2X(1) subtype expression on smooth muscle increases considerably in the symptomatically obstructed bladder. A striking absence of P2X(3) and P2X(5) subtypes was observed in the cholinergic innervation of detrusor from patients with urgent incontinence. Thus, it is likely that alteration of the neural acetylcholine control can play a critical role in pathological states. 4 If the failures in storage and voiding can be recognized urodynamically, considerable difficulties remain in investigating the underlying functional changes especially because the study of the pathophysiology requires techniques that can be justified in animals but not in humans. 5 Recently, to solve this problem an alternative technique using human smooth muscle cells in culture has been developed. Human cell lines may be relevant in investigating the molecular pathways in physiological and pathological conditions. 6 The potential development of novel molecular therapeutic strategies such as gene therapy and tissue engineering is also discussed.

Acetylcholine↗

PubMed2001

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Acoustic Stimulation↗

PubMed2001

Potentially epileptogenic dysfunction of cortical NMDA- and GABA-mediated neurotransmission in Otx1-/- mice.

Knockout Otx1 mice present a microcephalic phenotype mainly due to reduced deep neocortical layers and spontaneous recurrent seizures. We investigated the excitable properties of layer V pyramidal neurons in neocortical slices prepared from Otx1-/- mice and age-matched controls. The qualitative firing properties of the neurons of Otx1-/- mice were identical to those found in wild-type controls, but the proportion of intrinsically bursting (IB) neurons was significantly smaller. This is in line with the lack of the Otx1 gene contribution to the generation and differentiation of neurons destined for the deep neocortical layers, in which IB neurons are located selectively in wild-type rodents. The pyramidal neurons recorded in Otx1-/- mice responded to near-threshold electrical stimulation of the underlying white matter, with aberrant polysynaptic excitatory potentials often leading to late action potential generation. When the strength of the stimulus was increased, the great majority of the Otx1-/- neurons (78%) responded with a prominent biphasic inhibitory postsynaptic potential that was significantly larger than that observed in the wild-type mice, and was often followed by complex postinhibitory depolarizing events. Both late excitatory postsynaptic potentials and postinhibitory excitation were selectively suppressed by NMDA receptor antagonists, but not by AMPA antagonists. We conclude that the cortical abnormalities of Otx1-/- neocortex due to a selective loss of large projecting neurons lead to a complex rearrangement of local circuitry, which is characterized by an excess of N-methyl-d-aspartate-mediated polysynaptic excitation that is counteracted by GABA-mediated inhibition in only a limited range of stimulus intensity. Prominent postsynaptic inhibitory potentials may also act as a further pro-epileptogenic event by synchronizing abnormal excitatory potentials.

2-Amino-5-phosphonovalerate↗

PubMed1995

Modulation of N-methyl-D-aspartate (NMDA) antagonist-induced darting behaviour by the peptidomimetic PAMTA.

The N-Methyl-D-Aspartate (NMDA) receptor has attracted much attention in recent years due to its involvement in both the functions and dysfunctions of CNS neurotransmission. The existence of multiple sites by which NMDA receptor channel function can be pharmacologically modified and the interaction between glutamate and other neurotransmitter systems such as dopamine, provide exciting therapeutic avenues for related CNS disorders. In the present study, a novel synthetic analogue of the endogenous brain peptide L-prolyl-L-leucyl glycinamide (PLG) has demonstrated a significant modulatory action on the NMDA receptor. On the basis of radioligand binding studies, the novel synthetic peptide 5-[1(S)-(2(S)-pyrrolidinylcarbonyl)amino-3-methylbutyl]-2- tetrazolylacetamide (PAMTA) has been suggested to act at a polyamine site on the NMDA receptor complex. Scatchard analysis of [3H]MK-801 binding revealed that in the presence of 100 microM PAMTA, a single binding site was obtained with the Kd being increased from 2.5 +/- 0.2 nM to 6.2 +/- 0.1 nM. The ability of PAMTA to inhibit the binding of [3H]MK-801 was sensitive to the presence of both spermidine (polyamine agonist) and arcaine (polyamine antagonist). Analyses of the binding profiles of various NMDA receptor antagonists support PAMTA's interaction with the polyamine site on this receptor complex. Furthermore, we have investigated the behavioural profile of the peptidomimetic PAMTA, by studying its effect on stereotypic behaviours induced by the NMDA receptor antagonist, CPP (3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid). Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with PAMTA, CPP, a CPP/PAMTA combination, or a saline control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat.

Evidence supports dysfunction of dopaminergic and noradrenergic systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect functionally distinct cortical areas with separate striatal regions and remain segregated in parallel striato-pallidal-thalamic and striato-substantia nigra pars reticulata-thalamic pathways. Prefrontal cortex performance is maximal at moderate stimulation of postsynaptic dopaminergic and noradrenergic receptors, and is reduced by either higher or lower levels of receptor stimulation. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity, poor stability of performance, impaired ability to withhold responses and poorly sustained attention, when compared with their normotensive Wistar-Kyoto (WKY) control rats. Evidence suggests that terminals of mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of SHR release less dopamine in response to electrical stimulation and/or depolarization as a result of exposure to high extracellular K+ concentrations, than WKY. Vesicular storage of dopamine was suggested to be impaired in SHR, causing leakage of dopamine into the cytoplasm and increased d-amphetamine-induced transporter-mediated release. While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine release appears to be impaired in SHR, suggesting that noradrenergic function may be poorly regulated in the prefrontal cortex of the SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls.

Animals↗