Restoration of Parkinson's Disease-Like Deficits by Activating Autophagy through mTOR-Dependent and mTOR-Independent Mechanisms in Pharmacological and Transgenic Models of Parkinson's Disease in Mice.

We studied the possibilities of inhibition of neurodegeneration in MPTP-induced model of Parkinson's disease (PD) in C57Bl/6J mice and transgenic model of early PD stage (5-monthold B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J mice) by autophagy activation through mTOR-dependent and mTOR-independent pathways with rapamycin and trehalose, respectively. Therapy with autophagy inducers in a "postponed" mode (7 days after MPTP intoxication) restored the expression of the dopaminergic neuron marker tyrosine hydroxylase and markedly improved cognitive function in the conditioned passive avoidance response (CPAR; fear memory). The transgenic model also showed an increase in the expression of tyrosine hydroxylase in the nigrostriatal system of the brain. An enhanced therapeutic effect of the combined treatment with the drugs was revealed on the expression of tyrosine hydroxylase, but not in the CPAR test. Thus, activation of both pathways of autophagy regulation in PD models with weakened neuroinflammation can restore the dopaminergic function of neurons and cognitive activity in mice.

[GABA-Receptors in Modulation of Fear Memory Extinction].

GABA is the major inhibitory neurotransmitter in the central nervous system determining the efficacy of neuronal interaction. GABA-receptors play a key role in different aspects of fear memory--acquisition and consolidation, retention, reconsolidation and extinction. Extinction is an important behavioural phenomenon which allows organism to adapt its behavior to a changing environment. Extinction of fear memory is a form of new inhibitory learning which interferes with expression of the initial acquired fear conditioning. Resistance to extinction is symptom of depression and posttraumatic stress disorder. The aim of the present review was to summarize own and literary data about GABAergic modulation of fear extinction and pharmacological correction of extinction impairment at influences on GABA(A)- and GABA(B)- receptors.

[BEHAVIOR, MEMORY AND IMMUNOLOGICAL STATUS IN MICE MODEL OF DESYNCHRONOSIS].

Interstrain differences in behavior and parameters of the immune system of CBA and C57BL/6 mice with round the clock coverage (KO) were investigated. Open field, light/dark, acoustic startle response, forced swimming, elevated plus-maze, passive avoidance were used for measuring emotional behavior and memory. The number of lymphocyte subpopulations CD3+, CD4+8-, CD4-8+, CD4+8+, CD19+, CD3+hi spleen and thymus, the ratio of cells in different phases of the cell cycle was determined by flow cytometry. C57BL/6J mice strictly increased anxiety in response to the KO compared to CBA mice. Moreover, KO-treated C57BL/6J mice impaired the passive avoidance learning. We found that KO evoked significant changes in the cellular composition of the thymus and decrease of thymocytes proliferation in C57BL/6J mice. In opposite KO-treated CBA mice showed change of splenic cellular structure with increased % CD19+ cells and the proliferation of splenocytes. Our study demonstrated genotype-dependent reactions of the nervous and immune systems in response chronic constant light.

Characteristics of antiamnestic effects of blockade and activation of dopamine D1 receptors after stress stimulation in mice.

Changes in the effects of D1-receptor activation and blockade on the amnesia induced by delay in unsafe compartment in mice after forced swimming were studied using conditioned passive avoidance test. The most pronounced antiamnestic effects in mice with behavioral despair reaction were observed after administration of D1 receptor antagonist SCH23390, while D1 receptor antagonist SKF38393 was most effective in mice without preliminary stimulation.

[Latent inhibition and extinction of passive avoidance in mice C57BL/6J AND DBA/2J].

The study was carried out in mice C57BL/6J and DBA/2J for comparative analysis of two interference processes: latent inhibition and extinction of passive avoidance produced with an unconditioned aversive stimulus of different parameters (0.5 and 0.25 mA). With a strong training to new stimulus, impairment of extinction has been detected only in mice DBA/2J. Reduction in the strength of punishment during training was accompanied by acceleration of extinction in mice C57BL/6J and its appearance in mice DBA/2J. The learning of passive avoidance in strong and weak reinforcement was the same for both strains of mice. Interline differences were found also in the analysis of latent inhibition. With strong and weak training to conditional stimulus, lost of novelty by repeated an 8-fold pre-exposures to the experimental chamber, in DBA/2J mice, in contrast to C57BL/6J, latent inhibition was disrupted. In addition, DBA/2J mice showed impairment of extinction with weak training to non-relevant stimulus.

[Fear memory extinction accelerated by simultaneous activation of GABA(B) and NMDA receptors].

Effects of the N-methyl-D-aspartate (NMDA) agonist (D-cycloserine) and GABA(B) agonist (baclofen) on the fear memory extinction as manifested in the passive avoidance reaction in C57Bl/6J mice with "behavioral despair" (model of depression) and without previously developed stress have been studied. The positive acceleration of the fear memory extinction was observed in depressive mice upon the simultaneous administration of D-cycloserine and baclofen.

[Interaction of N-methyl-D-aspartate and Dopamine D1 receptors in modulation of passive avoidance extinction at mice with depressive-like state].

The effect of activation of N-methyl-D-aspartate (D-cycloserine) and dopamine D1 (SKF 38393) receptors on learning and extinction of the passive avoidance response in mice under normal conditions and after formation of "behavioural despair" is studied. The data on ineffectiveness of D-cycloserine and SKF 38393 on training a conditional reflex were obtained. In mice with the normal state, SKF 38393 did not alter the dynamics of extinction, and D-cycloserine facilitated a more rapid decline in retrieval of memory trace when testing without penalty. On exposure to D-cycloserine + SKF 38393 injection, dynamics of extinction was similar to that under the action of D-cycloserine. In mice with the reaction of "behavioral despair", D-cycloserine and SKF 38393 reduced the deficit of the passive avoidance extinction typical for "depressed" animals without drugs. With simultaneous activation of NMDA and D1 receptors we observed acceleration of the extinction start and development of complete extinction of the memory trace about pain impact as compared with single injections of D-cycloserine and SKF 38393.

[Extinction of fear memory in experimental models of depression].

The review contains the materials of scientific literature, research results of the author with colleagues about important cognitive symptom of depression--impairment of fear memory extinction. Experimental models of depressive-like state and behavior involved in the development of depression are reviewed. Special attention is focused on data that demonstrates genetic determination to the emergence of deficit of fear memory extinction as factor of risk to occurrence of depression.

Involvement of different types of dopamine receptors in the formation of latent inhibition of a conditioned passive avoidance reaction in rats.

The effects of systemic injections of dopaminergic agents on normal and weak latent inhibition of a conditioned passive avoidance reaction were studied in rats. Formation of normal latent inhibition was induced using 20 pre-exposures to a contextual conditioned stimulus prior to training. Weak latent inhibition was modeled using 10 pre-exposures. The effects of the D(2)/D(3) receptor agonist quinpirole (1 mg/kg) and the D(1) receptor agonist SKF 38393 (1 mg/kg) separately and in combination with haloperidol (0.5 mg/kg) were tested. Quinpirole induced the expression of normal latent inhibition but had no effect on weak latent inhibition. Activation of D(1) receptors with SKF 38393 had no effect on the formation of latent inhibition regardless of the number of pre-exposures. Haloperidol significantly strengthened weak latent inhibition but impaired normal latent inhibition. Administration of haloperidol in combination with SKF 38393 prevented this impairment. These results suggest that while D(1) receptors have no influence as an independent substrate on the formation of latent inhibition, activation of these receptors is required for the complete manifestation of D(2)-mediated modulation of this process.

Effects of activation and blockade of dopamine receptors on the extinction of a passive avoidance reaction in mice with a depressive-like state.

Learning and extinction of a conditioned passive avoidance reaction resulting from neuropharmacological actions on dopamine D(1) and D(2) receptors were demonstrated to be specific in intact mice and in mice with a depressive-like state. Learning was degraded only after administration of the D(2) receptor antagonist sulpiride and was independent of the initial functional state of the mice. In intact mice, activation of D(2) receptors with quinpirole led to a deficit of extinction, consisting of a reduction in the ability to acquire new inhibitory learning in conditions associated with the disappearance of the expected punishment. In mice with the "behavioral despair" reaction, characterized by delayed extinction, activation of D(1) receptors with SKF38393 normalized this process, while the D(2) agonist was ineffective. A positive effect consisting of accelerated extinction of the memory of fear of the dark ("dangerous") sector of the experimental chamber was also seen on blockade of both types of dopamine receptor.

[Extinction of passive avoidance response in various mouse strains].

Dependence of the passive avoidance extinction dynamics on a mouse strain was shown. Mice C57BL/6J and AKR/J extinguished more quickly relative to DBA/2J, CBA/Lac and BALB/c, and this extinction was stable. Individual instability of extinction was characteristic of C3H/HeJ mice. Extinction of the passive avoidance in mice CBA/Lac and BALB/c was slower: with a delay in the beginning and prolonged retention of memory trace of the shock exposure. In DBA/2J mice, the extinction was impaired. These data suggest that DBA/2J, CBA/Lac and BALB/c mice constitute groups of risk with high predisposition to impairment of extinction of memory of aversive events, which is thought to be a symptom of a depressive-like state.

[Flumazenil restores amnesic trace of memory in mice with depression-like state].

Experiments on C57BL/6J mice of submissive stereotype and behavioral despair response and ASC/Icg mice with high predisposition to catalepsy, which served as depression-like state models, were used to study the influence of benzodiazepine receptor antagonist flumazenil on the restoration of a passive avoidance reaction learned under conditions of the amnesic effect of animal detention in a dark compartment. It is established, that flumazenil (10 mg/kg) reactivated retrieval of the amnesic memory trace in mice of submissive stereotype with the behavioral despair response, while being ineffective in ASC mice.

Development of amnesia in different mouse strains.

We studied passive avoidance retrieval after amnestic stimulation (arrest in unsafe section of the experimental setup) in C57Bl/6J, BALB/c, CBA/Lac, AKR/J, DBA/2J, C3H/HeJ, and ASC/Icg mice. We demonstrated resistance to amnestic stimulation in mice with high predisposition to freezing reaction (ASC/Icg) and memory deficit in other mouse strains.

[Involvement of dopamine receptors of different types in formation of latent inhibition of passive avoidance reaction in Wistar rats].

The effect of the intraperitoneal injection of dopaminergic agents on normal and weak latent inhibition of step-through passive avoidance task was studied in rats. Normal latent inhibition was caused by 20-fold preexposure (four times daily) of environmental conditional stimulus before training. For modeling of the weak latent inhibition 10-fold preexposure was used. Effects of D2 agonist quinpirole (1 mg/kg) and selective D1 agonist SKF 38393 (1 mg/kg) injected individually and in combination with haloperidol (0.5 mg/kg) were tested. Quinpirole caused a significant potentiation of the normal latent inhibition (20-fold preexposures) but did not affect the weak latent inhibition. Haloperidol reinforced the weak latent inhibition but reduced the normal latent inhibition. The agent SKF 38393 was not able to affect the latent inhibition independently of the preexposure number. Injected in combination with haloperidol, SKF 38393 prevented the normal latent inhibition from being impaired by haloperidol. These findings suggest that D1 receptors do not appear to participate in the modulation of the latent inhibition as an independent substrate, but D1 receptors are essential for the full manifestation of the D2-mediated modulation of the latent inhibition.

Learning and extinction of a passive avoidance response in mice with high levels of predisposition to catalepsy.

This report presents results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in ASC mice, which were bred for a high level of predisposition to catalepsy, and in CBA and AKR mice. The following findings were obtained: 1) impairments to the extinction of the memory of fear represent an important symptom of depression in ASC mice; 2) extinction is delayed in CBA mice; and 3) new inhibitory learning occurs quickly in AKR mice. Prolonged retention of the fear memory in ASC mice appears to be related to increased anxiety on prolonged testing without a punishment. The deficit of inhibition of the fear reaction in ASC mice allows this strain to be regarded as a genetic model of depression.

[Effects of activation and blockade of dopamine receptors on extinction of passive avoidance response in mice with depressive-like state].

Selectivity of training and extinction of passive avoidance response caused by pharmacological influences on D1 and D2 dopamine receptors in intact mice and mice in depressive-like state was shown. Training was impaired only by administration of D2 receptor antagonist sulpiride and did not depend on the initial functional condition of mice. In intact mice, activation of D2 receptors by quinpirole evoked deficiency of extinction, i.e., impairment of the capability of new inhibitory training under conditions of disappearance of the expected punishment. In mice with reaction of "behavioral despair" characterized by a delay of extinction, activation of D1 receptors by SKF38393 normalized this process (as distinct from the inefficiency of D2 agonist). The positive effect of acceleration of fear memory extinction was revealed also under conditions of blockade of D1 and D2 dopamine receptors.

Contribution of GABA receptors to extinction of memory traces in normal conditions and in a depression-like state.

A relationship between the effects of activation and blockade of GABA receptors on extinction of a conditioned passive avoidance reaction on the one hand and the type of receptor and initial psychoemotional state on the other was found in mice. Activation of GABA(A) receptors with muscimol impaired extinction in normal conditions but had no effect on the delay in this process in mice with "behavioral despair" reactions. Activation of GABA(B) receptors with baclofen accelerated extinction of the memory of fear in mice with the depression-like state. Blockade of GABA(A) receptors with bicuculline had no extinction-modifying effect. Blockade of GABA(B) receptors with faclofen promoted retention of the expression of fear in intact mice and acceleration of extinction in "depressed" mice.

[Learning and extinction of passive avoidance in mice with high predisposition to catalepsy].

The passive avoidance learning and extinction in mice strain ASC with high predisposition to catalepsy as compared with mice of CBA and AKR strains were analyzed. Impairment of fear extinction as a major symptom of depression was revealed in ASC mice, whereas a delay of extinction in CBA mice and fast formation of new inhibitory learning in AKR mice were found. It is suggested that the long persistence of fear in ASC mice results from increased anxiety during the repeated presentation of a context in the absent of aversive stimulus. Defect of fear inhibition in ASC mice makes it possible to use this strain of mice as genetic model of depression.

Comparative analysis of the persistence of a conditioned passive avoidance reflex in rats with different forms of inherited hypertension.

The characteristics of anxiety behavior and reproduction of a conditioned passive avoidance reflex acquired in response to a single combination with an unconditioned aversive stimulus were studied in NISAG rats with inherited stress-sensitive arterial hypertension and spontaneously hypertensive SHR rats. SHR rats were characterized by hyperactive behavior, very low levels of anxiety, and poor reproduction of the conditioned reflex as compared with NISAG and control Wistar and WAG rats. Intermediate-anxiety NISAG rats showed no difficulties in acquiring and subsequently retaining the conditioned reflex. These differences in the ability to undergo single-combination learning in rats with different forms of hypertension suggest that memory processes are independent of elevated arterial blood pressure. The effects of the genetic characteristics of behavior and emotional status of these animals on memory are discussed.

[GABA(B) receptors and amnesia in mice withalternative stereotypes of behavior].

The influence of agonists and antagonists of GABA(B) receptors on the development of amnesia has been studied using the passive avoidance test in C57Bl/6J mice with previously generated aggressive and submissive behavioral stereotypes. It is established that baclofen in a dose of 1 mg/kg produces amnesia in aggressive mice and imparts stability with respect to the amnestic influence in submissive mice. Phaclofen in a dose of 5 mg/kg prevents the development of amnesia that is most strongly pronounced in submissive mice.