Characteristics of behavioral abnormalities in α1d-adrenoceptors deficient mice

Mishima, Kenichi; Tanoue, Akito; Tsuda, Masakazu; Hasebe, Nobuyoshi; Fukue, Yoshihiko; Egashira, Nobuaki; Takáno, Yukio; Kamiya, Hiro O.; Tsujimoto, Gozoh; Iwasaki, Katsunori; Fujiwara, Michihiro

doi:10.1016/j.bbr.2003.10.038

Cited by 39 publications

(22 citation statements)

References 34 publications

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“…1c). There were no differences between non-TG and S284L-TG in general behaviors and sensorimotor functions when assessed by rotarod test for motor coordination, open-field test for analysis of locomotor activity and circadian rhythm, hot-plate test for analysis of sensory function, and traction meter test for muscle tone (data not shown) (Mishima et al, 2004).…”

Section: Generation and Characterization Of S284l-tgmentioning

confidence: 89%

“…The rotarod performance was modified for non-TG and S284L-TG as described previously (Mishima et al, 2004). Both littermates were placed on the rotating rod (7 cm diameter; Neuroscience Inc.) with a nonskid surface, and the latency to fall was measured for up to 2 min.…”

Section: Behaviormentioning

confidence: 99%

“…Each rat was placed on the 2 ϫ 2 cm stainless grids of the apparatus, and the experimenter slowly pulled the tail in parallel at a constant speed. The forepaw resistance was measured by the detector as muscle tone (Mishima et al, 2004).…”

Section: Behaviormentioning

confidence: 99%

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Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

et al. 2008

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Mutations of genes encoding ␣4, ␤2, or ␣2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

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Section: Generation and Characterization Of S284l-tgmentioning

confidence: 89%

Section: Behaviormentioning

confidence: 99%

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Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

et al. 2008

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“…A few studies using transgenic mice have shown that mice lacking the a2C receptor have disrupted PPI (Sallinen et al, 1998) while mice lacking the a1D receptor or the a2A receptor do not show the same magnitude of disruption in PPI after psychotomimetic drug administration as wild-type mice (Lahdesmaki et al, 2004;Mishima et al, 2004). It must be pointed out though, that a recent study examined the effects of the a2 antagonist yohimbine on PPI and found that while yohimbine disrupts PPI, this effect may in part be due to its actions at serotonin-1A receptors (Powell et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Alsene

Carasso²,

Connors

et al. 2006

Neuropsychopharmacol

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Prepulse inhibition (PPI) refers to the attenuation of startle when a weak prestimulus precedes the startling stimulus. PPI is deficient in several psychiatric illnesses involving poor sensorimotor gating. Previous studies indicate that a1 adrenergic receptors regulate PPI, yet the extent to which these effects are mediated by central vs peripheral receptors is unclear. The present studies compared the effects of intracerebroventricular (ICV) vs intraperitoneal (IP) delivery of several a1 receptor agonists on PPI. Male Sprague-Dawley rats received either cirazoline (0, 10, 25, 50 mg/5 ml), methoxamine (0, 30, 100 mg/5 ml), or phenylephrine (0, 3, 10, 30 mg/5 ml) ICV immediately before testing. Separate groups received either cirazoline (0, 0.25, 0.50, 0.75 mg/kg), methoxamine (0, 2, 5, 10 mg/kg), or phenylephrine (0, 0.1, 2.0 mg/kg) IP 5 min before testing. PPI, baseline startle responses, and piloerection, an index of autonomic arousal, were measured. Cirazoline disrupted PPI; effective ICV doses were approximately six times lower than effective IP doses. Methoxamine disrupted PPI after ICV infusion but failed to affect PPI with IP doses that were up to 30-fold higher than the effective ICV dose. Phenylephrine disrupted PPI with ICV administration, but did not alter PPI after IP injection of even a 20-fold higher dose. None of the ICV treatments altered baseline startle magnitude, but phenylephrine and methoxamine lowered startle after administration of high systemic doses. Piloerection was induced by cirazoline via either route of administration, and by IP methoxamine and phenylephrine, but not by ICV infusion of methoxamine or phenylephrine. These findings indicate that a1 receptor-mediated PPI disruption occurs exclusively through stimulation of central receptors and is dissociable from alterations in baseline startle or autonomic effects.

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“…Recent studies indicate that systemic manipulations of NE modulate PPI; a1 receptor agonists disrupt PPI in rats and, in mice, deletion of a2 receptors, which can function as presynaptic autoreceptors, reduces PPI and potentiates the PPI-disruptive effects of amphetamine via presumed augmentation of NE release (Alsene et al, 2006;Carasso et al, 1998;Kamath et al, 2008;Lahdesmaki et al, 2004;Mishima et al, 2004;Sallinen et al, 1998;Swerdlow et al, 2006). Nevertheless, the specific anatomical substrates of NE regulation of PPI are unknown.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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Surprisingly little is known about the modulation of core endophenotypes of psychiatric disease by discrete noradrenergic (NE) circuits. Prepulse inhibition (PPI), the diminution of startle responses when weak prestimuli precede the startling event, is a widely validated translational paradigm for information-processing deficits observed in several mental disorders including schizophrenia, Tourette's syndrome, and post-traumatic stress disorder (PTSD). Despite putative NE disturbances in these illnesses, NE regulation of PPI remains poorly understood. In these studies, regulation of PPI by the locus coeruleus (LC), the primary source of NE to forebrain, was evaluated in rats using well-established protocols to pharmacologically activate/inactivate this nucleus. The ability of drugs that treat deficient PPI in these illnesses to reverse LC-mediated PPI deficits was also tested. Stimulation of LC receptors produced an anatomically and behaviorally specific deficit in PPI that was blocked by clonidine (Cataprese, an a2 receptor agonist that reduces LC neuronal firing after peri-LC delivery), a postsynaptic a1 NE receptor antagonist (prazosin), and second-generation antipsychotics (olanzapine, seroquel), but not by drugs that antagonized dopamine-1 (SCH23390), dopamine-2 (the first-generation antipsychotic Haloperidol), or serotonin-2 receptors (ritanserin). These results indicate a novel substrate in the regulation of PPI and reveal a novel functional role for the LC. Hence, a hyperactive LC-NE system might underlie a deficient sensorimotor gating endophenotype in a subset of patients suffering from psychiatric illnesses including schizophrenia, Tourette's syndrome, and PTSD, and the ability to normalize LC-NE transmission could contribute to the clinical efficacy of certain drugs (Cataprese, prazosin, and second-generation antipsychotics) in these conditions.

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Characteristics of behavioral abnormalities in α1d-adrenoceptors deficient mice

Cited by 39 publications

References 34 publications

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

Rats Harboring S284LChrna4Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

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