Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice

Bortolato, Marco; Frau, Roberto; Orrù, Marco; Piras, Antonio; Fà, Mauro; Tuveri, A; Puligheddu, Monica; Gessa, Gian Luigi; Castelli, Paola; Mereu, Giampaolo; Marrosu, Francesco

doi:10.1007/s00213-007-0845-5

Cited by 48 publications

(42 citation statements)

References 68 publications

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“…Consistent with our findings, it was reported that baclofen reversed the reduction in PPI induced by MK-801, but not by apomorphine (a direct dopamine receptor agonist), in rats (Bortolato et al, 2004), and that baclofen and clozapine, but not haloperidol, improved spontaneous PPI deficit in mice (Bortolato et al, 2007). In addition, a recent study (Wolf et al, 2007) demonstrated that acute and subchronic treatment with clozapine failed to ameliorate PPI deficits in mice.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, a marked reduction of GABA B receptors was reported in the hippocampus and prefrontal cortex (Mizukami et al, 2000;Ishikawa et al, 2005). Although the role of GABA B receptors in schizophrenia and related disorders is still poorly understood, recent pharmacologic studies have demonstrated that baclofen, a GABA B receptor agonist, prevents PPI deficits in rodents (Bortolato et al, 2004(Bortolato et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

Arai

Takuma

Mizoguchi

et al. 2008

Neuropsychopharmacol

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We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA B receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA B receptor agonist, on METH-and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (40.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH-and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA B receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

Arai

Takuma

Mizoguchi

et al. 2008

Neuropsychopharmacol

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“…Unlike the results of most studies in C57BL/6 mice (McCaughran et al 1997;Ouagazzal et al 2001), haloperidol did not increase PPI in one study on C57BL/6 mice (Bortolato et al 2007). Additionally, in the latter study, haloperidol only produced a non-significant trend towards increasing PPI in DBA/2 mice.…”

Section: Discussioncontrasting

confidence: 71%

“…PPI in CD-1 and C57BL/6 mice was insensitive to clozapine treatment (Curzon and Decker 1998;Bortolato et al 2007), although clozapine has typically increased PPI in the latter mouse strain (McCaughran et al 1997;Olivier et al 2001;Ouagazzal et al 2001;Lipina et al 2005;Singer et al 2009). While clozapine has increased PPI in several other strains (Geyer et al 2002), PPI did not increase after clozapine treatment in NMRI and 129/SvEv mice (Olivier et al 2001;Ouagazzal et al 2001;Fejgin et al 2007).…”

Section: Discussionmentioning

confidence: 97%

Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse

Flood¹,

Zuvich²,

Marino

et al. 2011

Psychopharmacology

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CF-1 mice with naturally low PPI may be useful for testing typical and atypical antipsychotics while Black Swiss mice only responded to a typical antipsychotic. DBA/2 mice remain the only strain with naturally low PPI that responds to marketed antipsychotics, as well as to compounds with novel mechanisms of action. Thus, DBA/2 mice may be the strain of choice for screening novel chemical entities for their ability to increase PPI.

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“…As the volume of the prepulse increased, the effect of THIP was lost. One possible explanation for this partial restoration is that it is known that PPI is regulated by many neurotransmitter systems, including the GABAergic system [52,53], making highly complex a complete restoration of PPI targeting only one of the systems involved. Furthermore, one study in Fmr1 KO mice has shown decreased PPI of startle eyelid responses with the magnetic distance measurement [23].…”

Section: Discussionmentioning

confidence: 99%

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

2011

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Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA_A receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.

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Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice

Abstract: Our data highlight GABA(B) receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA(B) receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances.

Cited by 48 publications

References 68 publications

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse

The GABA<sub>A</sub> Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

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