V. G. Shalyapina

The Role of Sex Steroids in Forming Anxiety States in Female Mice

Natural fluctuations in sex hormones during the ovarian cycle have enormous influences on ongoing psychological status in the female body. We report here studies of the effects of exogenous sex steroids on anxiety levels in female mice, as evaluated in the elevated cross maze test. Female NMRI mice were subjected to bilateral oophorectomy and one week later received s.c. injections of solvent (sesame oil, controls) or estradiol benzoate for 7 days, either alone or with an additional dose of progesterone on day 7. Elevated maze tests performed 6 h later showed that animals given progesterone had the highest levels of anxiety and the highest levels of grooming reactions as compared with the other groups. Immunohistochemical analysis of the distribution of progesterone receptors in different parts of the brain demonstrated significant increases in the numbers of immunopositive cells after injections of estradiol benzoate alone, with further increases after progesterone injections. Thus, the data obtained here suggest that the genomic effects of sex steroids are important, as they appear to be involved in non-sexual forms of behavior, particularly the level of anxiety.

Expression of Early Genes in the Rat Brain after Administration of Corticoliberin into the Neostriatum

In situ hybridization using oligonucleotide probes was used to study the effects of intrastriatal microinjection of corticoliberin on the expression of the early genes c-fos, jun B, c-jun, and NGFIA in the rat brain. Administration of corticoliberin (0.25 μg) into the neostriatum induced the expression of mRNA encoded by the early genes c-fos, jun B, and NGFIA in both the neostriatum itself and in its efferent structures, particularly the nucleus accumbens and various parts of the cortex. Intrastriatal microinjection of corticoliberin had no effect on the expression of mRNA for the oncogene c-jun in the brain. These results suggest that neuronal activation in the neostriatum and its projection targets manifest as the expression of early genes is one of the mechanisms underlying the adaptive effects of corticoliberin in stress.

Neuroendocrine mechanisms of the formation of adaptive behavior.

The behavioral and neuroendocrine responses of the body to external changes are determined by genetically determined programs of individual development, and are established during pre- and post-natal ontogenesis. These responses, however, can be changed by stress or administration of corticosteroid hormones in “critical periods” of the bodys development. Mineralo- and glucocorticoid receptors mediate the “inhibition” of particular neuroendocrine or neuromediator systems, promoting behavioral modification.

Involvement of the striatum in the central regulation of the hormonal functions of the gonads.

Studies reported here show that intrastriatal administration of corticoliberin to rats decreases the blood testosterone level. However, in conditions of chemical deficiency of dopaminergic transmission in the dorsal striatum induced by injection of 6-hydroxydopamine, the effect of this neurohormone did not appear. It is concluded that extrahypothalamic corticoliberin is involved in regulating the hormonal reproductive system acting via dopaminergic mechanisms.

Involvement of Dopaminergic Processes in the Striatum during the Effects of Corticoliberin on the Behavior of Active and Passive Rats

The effects of intranasal corticoliberin on behavior in the open field test were studied in rats with active and passive behavioral strategies (lines KHA and KLA); levels of dopamine and noradrenaline and their metabolites were measured in the striatum and hypothalamus. In KLA rats, administration of the neurohormone led to increases in motor and investigative activity, while decreases were seen in KHA rats. There were no interline differences in catecholamine levels in the hypothalamus, while dopamine levels in the KLA striatum nearly doubled and metabolite levels (DOPAC, HVA) were significantly lower than in KHA rats. Corticoliberin increased dopamine and noradrenaline levels in the hypothalamus of both rat lines, with significant decreases in the striatum. This decrease was more marked in KLA rats, probably due to the faster metabolism of transmitters in the presence of neurohormones, as indicated by the increase in metabolite levels in this structure.

Electrophysiological characteristics of depressive states in rats with passive strategies of adaptive behavior

The behavior of rats in a T-maze was used to select individuals with a passive strategy of adaptive behavior from a population of Wistar rats. These animals were subjected to water immersion and olfactory cortex slices were prepared from the brain 10 days later and used for recording of evoked focal potentials and the effects of tetanic stimulation. Postsynaptic potentials, of both the AMPA and NMDA types, were initially of decreased amplitude in passive rats. After unavoidable stress, the suppression of excitatory potentials increased and there was a simultaneous increase in the amplitude of inhibitory GABAB-ergic mechanisms. Addition of corticoliberin (10−10 M) to the incubation medium led to reversible blockade of synaptic transmission. Tetanic stimulation of slices from stressed rats led to the development of posttetanic depression in 84% of cases and to post-tetanic potentiation in 12%; this is evidence for profound changes in synaptic transmission. Thus, activation of corticoliberinergic mechanisms in cortical structures does not promote recovery from depressive states in rats with the passive behavioral strategy induced by unavoidable stress.

Free-Radical Lipid Oxidation in the Brains of Active and Passive Rats during the Development of Post-Stress Depression

Free-radical lipid oxidation was studied in the cerebral cortex, striatum, hippocampus, and hypothalamus of KHA and KLA rats (Koltushi High and Low Avoidance) during the development of post-stress depression. After unavoidable emotional-pain exposure, changes in the free-radical oxidation of lipids were phasic in nature and had a clear structural specificity in the early phases. During the maximum development of depression, the most marked impairments to lipid peroxidation were seen in KHA rats in the striatum and hippocampus, while the greatest changes in KLA rats were seen in the striatum and hypothalamus. These data support the important role of the initial behavioral strategy in the pathogenetic mechanisms forming post-stress psychopathology.

Functioning of hypophysial adrenocortical system in rats selected by the threshold of sensitivity to electrical current

An enhancement of stress reactivity of the hypophysial-adrenocortical system in response to emotional and physical influence was shown in rats with a low threshold of sensitivity to electrical current. This phenomenon was observed as a rise in the maximum level of blood corticosterone and acceleration of stressor hormonal response. In the high-threshold rats a decrease in sensitivity of the hypophysial adrenocortical system to the feedback signals was observed.

Correlation between protein oxidation and antioxidant system and individual typological particularities of rat behavior in norm and post-stress psychopathology

We studied the oxidative modification of proteins and the activity of components of antioxidant systems in the blood serum of rats with different types of behavioral activity in the norm and during post-stress psychopathology. After testing of behavior, animals were separated into four groups. We found that the groups in the norm have different levels of oxidative modification of proteins and activity of superoxide dismutase. To generate post-stress psychopathology, we used water-immersion stress in combination with immobilization. After the development of post-stress psychopathology, we observed changes in the indices studied. It is possible to conclude that different changes in oxidative modification of proteins and the activity of the antioxidant system occur during the development of post-stress psychopathology in rats with different individual typological particularities of behavior.

Effects of Corticoliberin on Synaptic Transmission in Rat Olfactory Cortex Slices in a Water Immersion Model of Depression

Corticoliberin (corticotrophin-releasing factor, CRF, CRH) is an active regulator of endocrine, autonomic, and immune functions in stress, as well as a mediator of anxiety, determining the behavioral stress response. The present report describes studies of its action on neuron activity evoked by microstimulation of olfactory cortex slices. Behavioral testing in a T maze was used to select individuals with a passive behavioral strategy from a population of Wistar rats, and the animals were subjected to water immersion. Olfactory cortex slices were prepared 10 days later and evoked focal potentials were recorded on perfusion with medium containing corticoliberin (0.1 μM). Among active rats, 60% of slices retained high excitability after stress, and corticoliberin produced only insignificant reductions in the amplitudes of excitatory potentials in these slices, simultaneously increasing the amplitudes of inhibitory potentials. Low excitability was found in 40% of slices from active stressed rats, and corticoliberin had a significant inhibitory effect in these slices. Addition of corticoliberin to the incubation medium used for slices from passive rats with initially low excitability led to complete blockade of synaptic transmission. These data support the involvement of corticoliberin in the development of depression.