The change dynamics of the influence of daily oral exposure to silver citrate at the period of its administration growth on the behavioral and cognitive functions of laboratory mice have been investigated. An analogous study on the silver nanoparticle’s influence was held earlier and is described in [23]. The present research is important to identify the impact of nanoscale to the neurotoxic properties of silver as well as for the optimization of the choice of silver compound for antibacterial, antiviral and fungicidal therapy and prevention.

The previous research [23] was due to the recently determined phenomena such as silver accumulation in brain as well as low clearance of it from the brain [7–10, 12]. The following 3-staged change dynamics of the influence of silver nanoparticles exposure on the behavioral and cognitive functions of the C57BL/6 male mice was observed. An anxiety increase was followed by an exploration behavior increase against the background of the increased anxiety, long-term contextual memory impairment besides the absence of behavioral changes was detected at the final stage. Thus, a rather pessimistic picture was observed. Despite the exploration behavior increase, which can be regarded as adaptation and hormesis [29] manifestation, at the background of increased anxiety, the growth of the exposure period until 180 days led to a significant long-term contextual memory impairment in the mice exposed to silver nanoparticles.

We reproduced the experiment conditions from [23], however in the present study we used silver citrate as a potential xenobiotic. Some studies demonstrate silver accumulation in the brain of laboratory rodents after exposure to silver salts [7, 8, 14], even superior to that for silver nanoparticles. However, the influence of silver salts onto behavioral and cognitive functions of laboratory rodents have been insufficiently investigated before.

Within the present study we defined anxiety increase in the mice after 30 days of the exposure to silver citrate. The analogous effect was identified at the silver nanoparticle daily exposure of mice during the same period [23]. We observed the indicator of sensitivity (perceptivity) increase in 60 days of the exposure. The assessment by the parameter is our supposition. This criterion may also be the manifestation of the adaptation processes observed later, and the marker of the positive outcome of the pathological process caused by stress. An anxiety decrease and a tendency of long-term contextual memory improvement were observed in 120 days of the silver citrate exposure. The locomotor activity increase was observed in 180 days of the exposure. Thus, a rather optimistic picture of the change dynamics of behavioral and cognitive functions, reflecting the organism adaptation to the chronic exposure to the xenobiotic, was detected in the present study. A hormetic effect and the reverse of the behavior change vector from a pronounced negative to a positive one were observed. Anxiety increase likely connected to an increased sensitivity (perceptivity) is replaced by the anxiety decrease, locomotor activity growth and a tendency to cognitive function improvement. An increase of locomotor activity is regarded as the compensatory to increased anxiety in [24]. The locomotor activity increase as well as the tendency to the long-term memory improvement can be considered as the compensatory to the anxiety increase in the present case. From the other point of view, as the changes of behavioral and cognitive functions of the mice exposed to silver citrate are compared to the controls, the imaginary improvement of their behavior might be considered as tigmotaxis impairment [30], the typical rodent behavior. However, from the other point of view, the improvement can also be considered as manifestation of aging neutralization [31] by the perturbance in the form of silver citrate exposure such as stimulator.

Silver nanoparticles can have both a neurotoxic inhibitory effect on the functions of higher nervous activity and the stimulating effect. However, most well-known scientific works indicate a negative effect of silver nanoparticles on the behavioral and/or cognitive functions of mammals.

For example, a memory impairment, learning and motor function as well as social behavior change were observed after intravenous exposure of mice to silver nanoparticles in [20]. Significant decreases of long-term and short-term memory were found in rats orally exposed to 20 nm bovine serum albumin coated silver nanoparticles during 28 days, while behavior functions remained the same [21]. Along this, a selective accumulation of silver in the brain departments responsible for the spacial memory was observed. A decrease of spacial memory associated with changes in dopamine and serotonin ratios in rats exposed to 20 nm sized silver nanoparticles were observed [22]. Herewith, the result was coating-dependent. Positive restorative effects at the exposure to silver nanoparticles were observed as well. For example, an influence of silver nanoparticles synthesized using typical green synthesis approach with the application of a green tea extraction on behavioral functions of mice with induced inflammation as well as the inflammation itself were studied in [25]. The authors observed reduction of temperature hypersensitivity and edema, anxiety decrease and locomotor activity increase in the mice exposed to silver nanoparticles, so called “green tea silver nanoparticles.” Dose dependent anti-inflammatory effects of silver nanoparticles were also detected.

We suppose that the authors of [25] as well as us observed a typical hormetic effect. Hormesis may be viewed as something of a biological corollary of the words of German philosopher Friedrich Wilhelm Nietzsche (1844–1900): “That which does not kill us makes us stronger.” The key role of hormesis should be taken into the account at the consideration of the mechanism of therapeutic action of various medicine.

Thus, from the one point of view, silver citrate can be regarded as less toxic compound compared to silver nanoparticles, from the other it may be considered as an effective trigger activating the own resources of an organism. Apparently, nanosize impacts into the toxicity of a compound. The experimental research shows neurotoxicity decrease of a salt form compared to nanoparticles at the example of silver compounds [23]. Nonetheless, the other, not regarded in the present research, toxic effects should be taken into the account as well to receive the overall toxicity assessment of silver citrate. Anyway, the obtained result demonstrates higher biocompatibility of silver citrate compared to silver nanoparticles, which is proven by a more pronounced ability of mice to adapt to silver citrate than to the silver nanoparticles.

It is rather intriguing that granules of silver are observed in the tissues of laboratory animals after oral exposure to both forms of silver, nanoparticle and salt [7, 8]. It should also be noted that after the exposure of pregnant dams to silver nanoparticles and AgNO3 the levels of penetrability of the placental barrier seemed to be close to each other despite the higher level of silver accumulation in the maternal tissues within the AgNO3 exposure [14]. Thus, the silver nanoparticles may dissociate and associate during the transportation via the organism as well as the silver ions may associate in it forming granules and even nanoparticles in the close size range. Such processes are mediated, in general, by the properties of medium such as pH. In this case, it is appropriate to remind the technology of green synthesis when using plants, bacteria, yeast and algae silver nanoparticles are produced from its salts applied as precursor [32, 33]. Various active substances in the plants, bacteria, yeast and algae act as reducing and capping agents then. Taking into the account the results of [7, 8, 14] it might be suggested that an animal organism serves as a reactor to synthesize particles from salts.

There is no doubts that biological effects are sensitive to various conditions. When considering effects of medicine and xenobiotics, nanosized as well, it is usually not fully taken into the account that an organism being a synergetic complex object itself is sensitive to changes of exogenous and endogenous factors. For example, meal may cause pH change that may influence the nanoparticle introduced into the organism size [34, 35], in its turn and the following may determine their absorption, elimination and biodistribution of them. Due to the complexity of such a synergetic system as a living organism and the presence of a great number of cause-and-effect relationships the result of a biological experiment can be unpredictable. It also may contribute to the significant difference on the toxicity and toxicokinetics of silver nanoparticles received by different researchers as mentioned in [17].