ABSTRACT
Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.
Subject(s)
Central Nervous System Stimulants/pharmacology , Cognition/drug effects , Indoles/pharmacology , Alzheimer Disease/chemically induced , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Animals , Aziridines , Biological Clocks/drug effects , Choline/analogs & derivatives , Cognition/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Pattern Recognition, Physiological/drug effects , Rats , Rats, WistarABSTRACT
α-Synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Considerable amount of α-synuclein is found in axons and presynaptic terminals of neurons located in brain areas responsible for emotions and memory. In the present study we have carried out behavioral evaluation of spatial and working long-term memory of α-synuclein knockout mice. Our data shows that α-synuclein knockout mice have reduced learning ability in tests requiring both working and spatial memory. For the first time we have demonstrated that α-synuclein is necessary for these types of learning.
Subject(s)
Avoidance Learning/physiology , Brain/physiology , Cognition/physiology , Maze Learning/physiology , alpha-Synuclein/metabolism , Animals , Mice , Mice, Knockout , Neurons/physiology , alpha-Synuclein/geneticsABSTRACT
Gamma(gamma)-synuclein is a member of synuclein family of cytoplasmic and predominantly neuronal proteins found only in vertebrates. Gamma-synuclein is abundant in axons and presynaptic terminals of neurons localized in brain regions involved in emotions, learning and memory. However, the role of gamma-synuclein in these brain functions was not previously assessed. We have demonstrated for the first time that the loss of gamma-synuclein results in a significant increase in the level of orientation response in novel environment and decrease in the level of state anxiety.
Subject(s)
Anxiety/psychology , Exploratory Behavior , gamma-Synuclein/physiology , Animals , Anxiety/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , gamma-Synuclein/geneticsSubject(s)
Aging/physiology , Maze Learning , Memory, Short-Term , alpha-Synuclein/metabolism , Animals , Mice , Mice, Inbred C57BL , Mice, Knockout , alpha-Synuclein/geneticsABSTRACT
Chronic decreases in brain cholinergic functions due to intraventricular administration of the neurotoxin AF64A were accompanied by increases in the latent period of locating an invisible platform during training of rats in a Morris water test, as compared with control sham-operated animals. Recordings of the animals' movement trajectories using a video camera along with an original computer program (Behavioral Vision) showed that administration of 17beta-estradiol and its synthetic analog J-861 (0.2 mg/kg p.o. daily for seven days before and 10 days after single intraventricular injections of AF64A) improved learning. The directivity of platform search trajectories was assessed quantitatively using a new parameter--trajectory straightness. Introduction of the "passive swimming" parameter allowed periods of immobility in water to be identified within the total latent period in animals after administration of AF64A; 17beta-estradiol but not J-861 "eliminated" these periods. The new parameters (especially trajectory straightness) allowed the ability to learn to be discriminated from decreases in mobility, including mobility losses due to study agents, in the Morris water test.
Subject(s)
Choline/analogs & derivatives , Estradiol Congeners/pharmacology , Estradiol/pharmacology , Free Radical Scavengers/pharmacology , Maze Learning/drug effects , Memory/drug effects , Adrenal Glands/pathology , Animals , Aziridines , Brain/drug effects , Brain/metabolism , Castration , Cholinergic Antagonists , Injections, Intraventricular , Male , Maze Learning/physiology , Memory/physiology , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Organ Size/drug effects , Prostate/pathology , Rats , Rats, Wistar , Reaction Time/drug effects , Receptors, Cholinergic/drug effects , Seminal Vesicles/pathology , Swimming , Thymus Gland/pathologyABSTRACT
A chronic deprivation of brain cholinergic functions in rats caused by intracerebroventricular injection of neurotoxin AF64A increases the escape latency in Morris water maze test as compared to control sham-operated animals. Measurements and analysis of rat movement tracks using an original computerized "Behavioral Vision" system revealed the ability of 17 beta-Estradiol and its synthetic isomer J-861 (both administered daily in per os dose 0.2 mg/kg during 7 days before and 10 days after a single intracerebroventricular injection of AF64A) to improve learning of the animals. Directivity of search trajectories was estimated by a novel index of track straightness. The introduction of an index of "passive swimming" made it possible to reveal episodes of immobility in water-maze behavior of AF64A-injected animals. Unlike J-861, 17 beta-Estradiol almost completely eliminated these episodes. The newly developed indices (especially straightness) seem to be very useful in differentiating learning ability of rats from a decrease in their mobility in the Morris water-maze test, in particular, in case of the estrogens under study.
Subject(s)
Brain/drug effects , Brain/metabolism , Choline/analogs & derivatives , Estradiol/pharmacology , Learning/drug effects , Memory/drug effects , Receptors, Cholinergic/deficiency , Swimming , Animals , Aziridines/pharmacology , Behavior, Animal/drug effects , Choline/pharmacology , Disease Models, Animal , Male , Neuromuscular Blocking Agents/pharmacology , Rats , Rats, Wistar , Receptors, Cholinergic/drug effectsABSTRACT
Systemic oral administration of NT-0409, a new synthetic agonist of AMPA subtype glutamate receptor, to rats with chronic partial AF64A-induced deprivation of cholinergic functions improved their learning in a Morris water maze. NT-0409 is close to memantine by the effect on learning and, in contrast to cholinomimetic arisept, ensures longer retention of the developed habit.
Subject(s)
Alzheimer Disease/physiopathology , Choline/analogs & derivatives , Excitatory Amino Acid Agonists/pharmacology , Maze Learning/drug effects , Memory/drug effects , Receptors, AMPA/agonists , Alzheimer Disease/chemically induced , Alzheimer Disease/metabolism , Animals , Aziridines/toxicity , Brain/drug effects , Brain/pathology , Choline/toxicity , Male , Memantine/pharmacology , Rats , Rats, WistarABSTRACT
It was shown for the first time that estrogens 17 beta- and 17 alpha-estradiols compensate impaired cognitive functions in rats with partial chronic deprivation of cholinergic functions in the central nervous system induced by intracerebral administration of selective cholinergic neurotoxin AF64A. 17 beta-Estradiol produced strong dose-dependent changes in the weights of hormone-sensitive endocrine glands, while 17 alpha-estradiol did not affect the weight of the gonads and slightly influenced (in high concentration) the weights of the adrenal glands and thymus. The positive effects of exogenous 17 beta- and 17 alpha-estradiols on cognitive functions are due to their antioxidant properties, rather than due to specific action on hormone-sensitive endocrine glands.
