The effects of atomoxetine and methylphenidate on the prepulse inhibition of the acoustic startle response in mice.

Atomoxetine (ATM) and methylphenidate (MPD) have been used for the treatment of attention deficit hyperactivity disorder (ADHD). ATM is a selective norepinephrine reuptake inhibitor, whereas MPD is a psychostimulant and acts as a norepinephrine and dopamine reuptake inhibitor. In the present study, we investigated the effects of ATM (1, 3 or 10mg/kg) and MPD (5, 10 or 20mg/kg) on pharmacological mouse models of sensorimotor gating measured by prepulse inhibition (PPI) using the acoustic startle response test. MK-801, a non-competitive N-methyl-d-aspartate receptor antagonist, or apomorphine, a non-competitive dopamine receptor agonist, was used to induce PPI deficits. ATM (3 or 10mg/kg, s.c.) significantly attenuated the MK-801-, but not apomorphine-, induced PPI deficits. In contrast to ATM, MPD did not reverse the PPI deficits induced by either MK-801 or apomorphine. Immunostaining revealed that the number of c-Fos-immunopositive cells was increased in the nucleus accumbens following MK-801 treatment, and this was reversed by the administration of ATM (3mg/kg), but not MPD (10mg/kg). However, neither ATM nor MPD reversed the increased number of c-Fos-immunopositive cells in the nucleus accumbens following apomorphine treatment. These results suggest that the attenuating effect of ATM on the increased c-Fos immunoreactivity in the nucleus accumbens induced by MK-801 may be attributed to the PPI deficit-ameliorating effects of ATM and that ATM would be useful to treat sensorimotor gating-related disorders by improving the patient's attention span or cognitive function.

Kami-ondam-tang, a traditional herbal prescription, attenuates the prepulse inhibition deficits and cognitive impairments induced by MK-801 in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Kami-ondam-tang (KODT) has been used to treat neuropsychiatric disorders, including neurosis and insomnia, in traditional herbal medicine. However, the mechanisms of this drug have not been well characterized in the treatment of schizophrenia-like behaviors. AIM OF THE STUDY: We investigated whether schizophrenia-like behaviors induced by MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, could be attenuated by KODT. MATERIALS AND METHODS: Acute systemic administration of MK-801 was used to establish an animal model of schizophrenia. The effects of KODT on the MK-801-induced prepulse inhibition (PPI) deficits, hyperlocomotion, social withdrawal, and cognitive impairment were assessed. We also examined the changes in the expression levels of Akt and extracellular signal-regulated kinase (ERK) after the administration of KODT with MK-801 in the cortical and hippocampal tissues. RESULTS: The acoustic startle response test showed that the acoustic startle enhancement and PPI deficits induced by MK-801 were attenuated by KODT. Moreover, KODT ameliorated social and objective recognition impairments that were induced by MK-801 in the social novelty preference test and the novel object recognition test. In addition, the upregulation of phosphorylated Akt or phosphorylated ERK expression induced by MK-801 was blocked by KODT in the cortex. However, MK-801-induced hyperlocomotion was not affected by KODT in the open field test. CONCLUSION: These findings suggest that KODT attenuates MK-801-induced PPI disruption, social interaction deficits, and cognitive impairments, possibly, by regulating of cortical Akt and ERK signaling.