Suppression of memory acquisition following co-administration of lithium and atorvastatin through nitric oxide pathway in mice.
OBJECTIVE
The aim of this study was to investigate the interactive effect of lithium and atorvastatin on cognitive performance and the role of NO as a potential mechanism involved in this interaction.


METHODS
Memory performance was evaluated in a two-trial recognition Y-maze test and a step-through passive avoidance task in mice. Lithium (5, 10, 20 or 40 mg/kg, i.p.) and atorvastatin (1 mg/kg, p.o.) were administered 1 h before each trial, L-NAME, a non-specific NO synthase inhibitor (3, 10 mg/kg, i.p.); aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor (100 mg/kg); and L-arginine, a NO precursor (750 mg/kg) were administered 30 min before training sessions. The level of plasma NO end-products (NOx) was determined using Griess reagent protocol.


RESULTS
1) Lithium (40 mg/kg) impaired the acquisition of spatial recognition memory; 2) lithium did not affect the retrieval phase of spatial memory; 3) atorvastatin (1 mg/kg) significantly impaired the memory performance, when co-administered with the sub-effective dose of lithium (10 mg/kg), but did not affect the status when administered with lithium (5 mg/kg); 4) L-NAME (10 mg/kg) and aminoguanidine (100 mg/kg) dramatically decreased memory performance in mice received sub-effective doses of both lithium (5 mg/kg) and atorvastatin (1 mg/kg); 5) L-arginine (750 mg/kg) improved the memory acquisition in mice administered lithium (10 mg/kg) and atorvastatin (1 mg/kg); 6) lithium did not affect the cognitive performance in the passive avoidance test. All results were compatible and confirmed with in vitro determination of plasma NOx levels.


CONCLUSIONS
Lithium, dose dependently, impaired acquisition phase of spatial recognition memory. Lithium and atorvastatin co-administration impaired spatial recognition memory mediating by nitrergic pathway. In addition to L-arginine, our data from L-NAME and aminoguanidine also support the involvement of NO pathway in this interaction.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran; Brain and Spinal Cord Injury Repair Research Center, Tehran University of Medical Sciences, Iran.
Amir Reza
AR
Honarmand
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran; Brain and Spinal Cord Injury Repair Research Center, Tehran University of Medical Sciences, Iran.
Nasim
N
Pourtabatabaei
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Nastaran
N
Rahimi
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Ahmad Reza
AR
Dehpour
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran; Brain and Spinal Cord Injury Repair Research Center, Tehran University of Medical Sciences, Iran. Electronic address: javadip@sina.tums.ac.ir.
Mehrak
M
Javadi-Paydar
D000818:Animals; D000069059:Atorvastatin; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000633:toxicity; D008094:Lithium / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D011758:Pyrroles / Q000008:administration & dosage* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D006538:Heptanoic Acids; D011758:Pyrroles; D009569:Nitric Oxide; D008094:Lithium; D000069059:Atorvastatin
Atorvastatin; Lithium; Memory; Mice; Nitric oxide