Abstract
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 GABAB 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 GABAB receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 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. GABAB receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.
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Acknowledgements
This study was supported in part by a Grant-in-Aid for Scientific Research (19390062) and for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant from the Smoking Research Foundation, and JSPS and KOSEF under the Japan-Korea Basic Scientific Cooperation Program.
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Arai, S., Takuma, K., Mizoguchi, H. et al. 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. Neuropsychopharmacol 33, 3164–3175 (2008). https://doi.org/10.1038/npp.2008.41
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DOI: https://doi.org/10.1038/npp.2008.41
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