The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats.
BACKGROUND
Ketamine or MK-801 induced sensorimotor gating deficit, but the underlying neural mechanisms are not completely known. We have previously demonstrated that the medial septum (MS) mediated the phencyclidine-induced deficit in prepulse inhibition of the acoustic startle (PPI) in rats.


OBJECTIVE
We investigated the involvement of the supramammillary area (SUM) to MS pathway in PPI impairment and behavioral hyperlocomotion induced by MK-801 or ketamine in rats and correlated the behavioral deficits with hippocampal gamma wave increase.


METHODS
Ketamine (6 mg/kg, s.c.) or MK-801 (0.5 mg/kg, i.p.) was administered after infusion of saline or the GABA(A) receptor agonist, muscimol (0.25 microg), into the MS or SUM. Locomotion, PPI, and hippocampal electroencephalogram (EEG) were recorded.


RESULTS
MK-801 or ketamine induced PPI impairment and behavioral hyperlocomotion, accompanied by an increase in hippocampal gamma waves (30-100 Hz). The changes in behavior and gamma waves induced by ketamine or MK-801 were antagonized by pre-infusion of muscimol, but not saline, into the SUM or MS. Infusion of muscimol into the SUM alone did not significantly affect PPI, but it suppressed spontaneous locomotor behavior and hippocampal EEG. Infusion of ionotropic glutamate receptor antagonists into the MS did not affect the PPI deficit or the gamma wave increase after MK-801.


CONCLUSIONS
A non-glutamatergic component of the supramammillo-septal pathway mediates the hyperlocomotion and the deficits in PPI induced by MK-801 or ketamine. Inactivation of the MS or SUM normalized both the hippocampal gamma waves and the behavioral deficits (PPI impairment and hyperlocomotion).
Ma
Jingyi
J
Department of Physiology and Pharmacology, Medical Sciences Building, The University of Western Ontario, London, ON, N6A 5C1, Canada. jma2@uwo.ca
Leung
L Stan
LS
D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D005684:Gait / Q000187:drug effects*; D020233:Gait Disorders, Neurologic / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008326:Mammillary Bodies / Q000187:drug effects / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D009118:Muscimol; C056723:FG 9041; D007649:Ketamine; D016291:Dizocilpine Maleate