Neurotransmitter abnormalities as determinants of seizure susceptibility and intensity in the genetic models of epilepsy.
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Acetylcholine↗
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Specificity of behavioral and neurochemical dysfunction in the chakragati mouse: a novel genetic model of a movement disorder.
The chakragati (ckr) mouse is a transgenic insertional mutant that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability as well as body weight deficits. The mutation is autosomal and recessive. We have previously found that ckr mice have bilateral asymmetric elevations in striatal dopamine (DA) D2-like (D2, D3 and/or D4), but not D1-like (D1 and/or D5) receptors. Predictably, these mice increase turning in response to the D2-like agonist quinpirole and spontaneously rotate contralateral to the striatal side with the higher D2-like receptors. The overall objective of the present study was to assess the neurochemical specificity of the mutation in ckr mouse, particularly since motor behaviors can be elicited by a multitude of brain regions and neurotransmitter systems within the basal ganglia. Using quantitative receptor autoradiography, we examined the regional distribution of DA uptake sites and 5-HT1A, 5-HT1B/1D, GABAA and mu opioid receptors. Also, we wanted to determine whether increased behavioral laterality as seen in rotation is evident with another test of laterality, such as lateral paw preference. The ckr mice showed greater paw preferences than normal mice; however, neither the degree nor direction of these preferences correlated with rotational behavior. The ckr mice showed moderate decreases in the density of DA uptake sites in all subregions of the striatum, but not in the nucleus accumbens or olfactory tubercle. Interestingly, these decreases in ckr mice were not accompanied by a reduction in striatal tissue DA content. 5-HT1 and mu opiate receptor populations were normal in ckr mice. However, GABAA sites in the mediodorsal thalamus and superior colliculus were bilaterally and asymmetrically elevated in ckr mice. These data are consistent with the idea that the motor phenotypes of the ckr mouse result from specific disturbances within nigro-striatal, striato-pallido-thalamic and striato-nigro-collicular circuitry. The implications of these and past findings are discussed in relation to current thinking about hyperkinetic motor syndromes in humans involving reduced basal ganglia outflow.
Animals↗
Anticonvulsant effects of antagonists of the N-methyl-D-aspartate receptor complex in a genetic model of epilepsy: the quaking mouse.
Tonic-clonic convulsions of mutant quaking mice were antagonized by the intracerebroventricular injection of N-methyl-D-aspartate receptor antagonists. The competitive antagonists, CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)-2-piperidine carboxylic acid), exerted a partial anticonvulsant action, with ED50S of 0.115 and 0.076 nmol, respectively. The non-competitive antagonists, TCP (1-(1-(2-thienyl)cyclohexyl)piperidine) and MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine), provided full protection, with ED50s of 4.49 and 2.67 nmol, respectively. The competitive antagonists elicited a marked ataxia whereas the non-competitive antagonists did not have side-effects. These results might reflect the involvement of glutamatergic neurotransmission in the convulsions of the quaking mutants.
Animals↗
A quasi-genetic model for plant virus host ranges. II. Differentiation between host ranges.
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Ecology↗
A quasi-genetic model for plant virus host ranges. IV. Cacao swollen-shoot and mottle-leaf viruses.
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Cacao↗
Is there a "genetic model" in the genesis of malignant pleural mesothelioma?
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Adult↗
Involvement of nigral glutamatergic inputs in the control of seizures in a genetic model of absence epilepsy in the rat.
The reticular part of the substantia nigra is known to be a critical site in the control of epileptic seizures. Potentiation of the direct striatonigral GABAergic projection has been shown to suppress seizures in different animal models of epilepsy. Besides this GABAergic input, the substantia nigra receives glutamatergic inputs, especially from the indirect striatonigral pathway, via the subthalamic nucleus. To investigate the involvement of the nigral excitatory amino acid transmission in the remote control of non-convulsive generalized seizures, several drugs interacting with glutamatergic receptors were first injected into the substantia nigra pars reticulata in rats with spontaneous absence seizures. Blockade of N-methyl-D-aspartate receptors suppressed spontaneous generalized non-convulsive seizures in the rat, whereas blockade of non-N-methyl-D-aspartate receptors was without effect. Second, inhibition of the subthalamic projection by bilateral injections of a GABAergic agonist in this structure similarly suppressed absence seizures. These results suggest that excitatory amino acid inputs are critical in the triggering of the nigral control of generalized epilepsies. Furthermore, they support the hypothesis of a possible involvement of the subthalamonigral pathway in the control of generalized non-convulsive seizures.
Animals↗
Is poliomyelitis a genetically-determined disease: I: A genetic model.
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Age Factors↗
Altered expression of preproenkephalin and prodynorphin mRNA in a genetic model of paroxysmal dystonia.
The dtsz mutant hamster represents a model of primary paroxysmal dystonia, in which dystonic episodes occur in response to stress. Previous examinations demonstrated striatal dysfunctions in dtsz hamsters. In the present study, in situ hybridization was used to examine preproenkephalin and prodynorphin expression as potential indices of imbalances between the striatopallidal and striatonigral pathways. Brain analyses were performed in dtsz hamsters under basal conditions, i.e., in the absence of dystonia, as well as mutant hamsters that exhibited severe stress-induced dystonic attacks immediately prior to sacrifice. In the striatum the basal expression of prodynorphin tended to be higher, while that of preproenkephalin tended to be lower in mutant hamsters in comparison to non-dystonic control hamsters. Significant basal changes were restricted to higher levels of prodynorphin in the ventrolateral striatum and lower prodynorphin and preproenkephalin mRNA expression in the hippocampus and/or in subregions of the hypothalamus. After stressful stimulation, the neuropeptides increased in several regions in both animals groups. In comparison to stimulated control hamsters, a significantly lower prodynorphin expression was found in several limbic areas of stimulated mutant hamsters during the manifestation of dystonia, while preproenkephalin mRNA was significantly lower in the anterior and dorsal striatal subregions and in nucleus accumbens. Since changes in the expression of these opioid peptides have been suggested to be related to abnormal dopaminergic activity, the present findings may reflect disturbances in striatal dopaminergic systems, and also in limbic structures in the dtsz mutant, particularly during the expression of dystonia.
Analysis of Variance↗
The kynurenine 3-hydroxylase inhibitor Ro 61-8048 improves dystonia in a genetic model of paroxysmal dyskinesia.
The effects of the novel kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro 61-8048) on severity of dystonia were examined in dt(sz) mutant hamsters, an animal model of paroxysmal dystonia, in which stress precipitates dystonic episodes. Ro 61-8048 (50, 100 and 150 mg/kg i.p.) significantly reduced the severity of dystonia in dt(sz) hamsters without leading to marked central side effects. Determinations of kynurenic acid concentrations in brain homogenates demonstrated that Ro 61-8048 (100 mg/kg i.p.) provoked a two- to threefold increase of the endogeneous broad spectrum glutamate receptor antagonist kynurenic acid in the striatum, cerebellum and brainstem of mutant hamsters. The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias.
Animals↗
Effects of calcium and of the Vitamin D system on skeletal and calcium homeostasis: lessons from genetic models.
Targeted deletion of genes encoding the 1,25-dihydroxyVitamin D [1,25(OH)(2)D]-synthesizing enzyme, 25 hydroxyVitamin D-1alpha-hydroxylase [1alpha(OH)ase or CYP27B1], and of the nuclear receptor for 1,25(OH)(2)D, the Vitamin D receptor (VDR), have provided useful mouse models of the inherited human diseases, Vitamin D-dependent rickets types I and II. We employed these models and double null mutants to examine the effects of calcium and of the 1,25(OH)(2)D/VDR system on skeletal and calcium homeostasis. Optimal dietary calcium absorption required both 1,25(OH)(2)D and the VDR. Skeletal mineralization was dependent on adequate ambient calcium but did not directly require the 1,25(OH)(2)D/VDR system. Parathyroid hormone (PTH) secretion was also modulated primarily by ambient serum calcium but the enlarged parathyroid glands which the mutants exhibited and the widened cartilaginous growth plates could only be normalized by the combination of calcium and 1,25(OH)(2)D, apparently independently of the VDR. Optimal osteoclastic bone resorption and osteoblastic bone formation both required an intact 1,25(OH)(2)D/VDR apparatus. The results indicate that calcium cannot entirely substitute for Vitamin D in skeletal and mineral homeostasis but that the two agents have discrete and overlapping functions.
Animals↗
Striatal increase of extracellular dopamine levels during dystonic episodes in a genetic model of paroxysmal dyskinesia.
In vivo microdialysis was used to examine the levels of dopamine, serotonin, and their metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of dt(sz) mutant hamsters, an animal model of paroxysmal dyskinesia, in which stress can precipitate dystonic episodes. Measurements were made under three different conditions in each animal: (1) at baseline in the absence of abnormal involuntary movements, (2) during an episode of paroxysmal dystonia precipitated by handling, and (3) during the recovery (postdystonic) period. In comparison to nondystonic control hamsters, which were treated in the same manner as dystonic animals, no changes could be detected under basal conditions, although the levels of DOPAC and HVA tended to be higher in mutant hamsters. Significantly elevated striatal levels of dopamine and DOPAC became evident during the period of stress-induced dystonic attacks in mutant hamsters. During dystonic episodes, dopamine levels were approximately 6.5-fold higher (followed by a 2.5-fold increase of DOPAC) in dt(sz) hamsters than in normal controls. Before the disappearance of dystonia, the levels of dopamine returned to basal concentrations in mutant hamsters. Consistent with previous pharmacologic findings, paroxysmal dystonia in mutant hamsters is associated with temporary increases of extracellular dopamine levels in the striatum.
Animals↗
Thiol redox state and oxidative stress in midbrain and striatum of weaver mutant mice, a genetic model of nigrostriatal dopamine deficiency.
In this study we measured thiol redox state (TRS) and the oxidative stress indicator lipid peroxidation in midbrain and striatum of adult (4 months old) male control (+/+) and weaver (wv/wv) mice in order to relate them with oxidative stress in conditions of progressive and severe (approximately 70%) nigrostriatal dopaminergic neurodegeneration. Specifically, we measured the specific TRS components glutathione (GSH), glutathione disulfide (GSSG), cysteine (CSH), and the general classes of TRS components. The latter are the protein thiols (PSH) and the disulfides between (a) protein (P) and protein thiols (PSSP), (b) protein and non-protein (NP/R) thiols (PSSR, PSSC) and (c) non-protein and non-protein thiols (NPSSR, NPSSC). In addition, the main product of lipid peroxidation malonyl dialdehyde (MDA) was estimated. In the midbrain of wv/wv, GSH and NPSSC levels are decreased (44% and 64%, respectively) and GSSG, NPSSR, CSH, PSH, PSSP, PSSR and MDA levels are increased (23%, 660%, 110%, 51%, 68%, 18% and 44%, respectively). In the striatum of male wv/wv, protein and non-protein thiol/disulfide and MDA levels do not change, possibly due to the high decrease in striatal dopamine level versus midbrain. Our data show that the high degeneration of the dopaminergic nigrostriatal neurons in male adult wv/wv mice is accompanied by significant changes in TRS and an increase in lipid peroxidation in the midbrain, suggesting involvement of oxidative stress in the degeneration of dopaminergic neurons. They also strengthen the possible use of thiol antioxidants for the development of new neuroprotective therapeutic strategies for neurodegenerative diseases, such as Parkinson's disease.
Animals↗
Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction.
Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1-/-) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (0.05, 0.1, and 0.2 mg/kg). The NR1-/- mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1+/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1-/- mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1-/- mice, but did reduce startle amplitude in the NR1+/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1+/+ and NR1-/- mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1+/+ and NR1-/- mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.
Animals↗
Accelerated loss of islet beta cells in sucrose-fed Goto-Kakizaki rats, a genetic model of non-insulin-dependent diabetes mellitus.
The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of beta cells in the pancreatic islets with fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model. Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison. The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean beta-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of beta cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet beta cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of beta cells measured by 5-bromo-2'-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group. The present study thus indicated that sucrose feeding promoted the apoptosis of beta cells in GK rats through increased oxidative stress without altering their proliferative activity.
8-Hydroxy-2'-Deoxyguanosine↗
A chronic treatment with fluoxetine decreases 5-HT(1A) receptors labeling in mice selected as a genetic model of helplessness.
Two lines of mice were bred for their opposite helpless behavior in the tail suspension test, i.e., helpless (HL) mice and non helpless (NHL) mice. The 5-HT(1A) receptor labeling was quantified by means of autoradiography with (3)H-8-OH-DPAT on brain sections from mice of these two lines. We observed a significantly higher level of (3)H-8-OH-DPAT binding sites density in HL mice comparatively to NHL mice, in the medial prefrontal, cingulate, motor and sensorial cortices, in several regions of the limbic system, such as CA3 field of hippocampus, dentate gyrus, medial and baso-medial amygdala, and in dorsal and median raphe nuclei. A chronic 21-day treatment with the antidepressant fluoxetine (10 mg/kg, i.p. daily) attenuated significantly the spontaneous helplessness in HL mice but did not alter the behavior of NHL mice. In the brain of HL mice chronically injected with fluoxetine, the elevated (3)H-8-OH-DPAT binding sites density was no longer observed after treatment in several regions, among which the raphe nuclei. Conversely, the antidepressant treatment did not modify the (3)H-8-OH-DPAT binding sites density in NHL mice. The variation of 5-HT(1A) receptors binding density in the HL mice in response to a chronic fluoxetine treatment parallels the attenuation of the spontaneous helplessness observed in the tail suspension test, and may underlie this behavior.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior.
Congenitally helpless rats have been selectively bred to display an immediate helpless response to stress in order to model hereditary brain differences that contribute to depression vulnerability. Differences in regional brain metabolism between congenitally helpless and non-helpless rats were investigated using quantitative cytochrome oxidase histochemistry. The results indicated that congenitally helpless rats had 64-71% elevated metabolism in the habenula and a 25% elevation in the related interpeduncular nucleus. In contrast, helpless rats had 28% reduced metabolism in the ventral tegmental area (VTA) and 14-16% reductions in the basal ganglia and basolateral and central amygdala. The opposite metabolic changes in the habenula and ventral tegmental area may be especially important for determining the congenitally helpless rat's global pattern of brain activity, which resembles the metabolic activity pattern produced by dopamine antagonism.
Animals↗
Effects of pharmacological manipulations of cannabinoid receptors on severity of dystonia in a genetic model of paroxysmal dyskinesia.
Previous studies have shown beneficial effects of the cannabinoid CB(1)/CB(2) receptor agonist (R)-4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo [3,2,1-ij]quinolin-6-one mesylate (WIN 55,212-2) in dt(sz) mutant hamsters, a model of idiopathic paroxysmal dystonia (dyskinesia). To examine the pathophysiological significance of the cannabinergic system in the dystonic syndrome, the effect of the cannabinoid CB(1) receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716A) on severity of dystonia was investigated in dt(sz) mutants which exhibit episodes of dystonic and choreoathetotic disturbances in response to mild stress. SR 141716A (5 and 10 mg/kg i.p.) failed to exert any effects on the severity of dystonia. While the antidystonic efficacy of WIN 55,212-2 (5 mg/kg i.p.) was confirmed, cannabidiol (which has low affinity to cannabinoid receptors) tended to delay the progression of dystonia only at a high dose (150 mg/kg i.p.). The antidystonic and cataleptic effects of WIN 55,212-2 (5 mg/kg i.p.) were completely antagonized by pretreatment with SR 141716A at doses of 2.5 mg/kg (catalepsy) and 10 mg/kg (antidystonic efficacy). These data indicate that the antidystonic efficacy of WIN 55,212-2 is selectively mediated via CB(1) receptors. The lack of prodystonic effects of SR 141716A together with only moderate antidystonic effects of WIN 55,212-2 suggests that reduced activation of cannabinoid CB(1) receptors by endocannabinoids is not critically involved in the dystonic syndrome. In view of previous pathophysiological findings in mutant hamsters, the antidystonic efficacy of WIN 55,212-2 can be explained by modulation of different neurotransmitter systems within the basal ganglia.
Animals↗