The effects of adulthood nicotine treatment on D2-mediated behavior and neurotrophins of rats neonatally treated with quinpirole

This study was designed to analyze the effects of nicotine on yawning behavior and neurotrophin content in the hippocampus and frontal cortex of D2-receptor primed female adult Sprague-Dawley rats. Animals were neonatally treated with quinpirole, a dopamine (DA) D2/D3 agonist, from postnatal day 1-21 (P1-21) and raised to P60 and administered nicotine tartarate (0.3 mg/kg free base) or saline twice daily for 14 days. One day after nicotine treatment had ceased, the number of yawns was recorded for 1 h in response to an acute injection of quinpirole (i.p., 100 microg/kg). Yawning is a D2-receptor mediated event. D2-primed rats demonstrated a significant increase in yawning in response to acute quinpirole compared with that of controls, but nicotine did not alleviate this effect. Neonatal quinpirole treatment produced a significant decrease of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the hippocampus that was alleviated by adulthood nicotine treatment. Interestingly, nicotine treatment to controls produced a significant increase of NGF in the frontal cortex, but a significant decrease of both NGF and BDNF in the hippocampus and BDNF in the frontal cortex. The decreases shown in NGF and BDNF is contrary to past findings that have shown nicotine to produce significant increases of hippocampal NGF and BDNF, but these past studies utilized male rats or mice or were performed in vitro. This study shows that nicotine has complex interactions with NGF and BDNF in D2-primed and control animals, and emphasizes the importance of gender differences when analyzing nicotine's effects on neurotrophins.     

Repeated episodic exposure to ethanol affects neurotrophin content in the forebrain of the mature rat

Chronic exposure to ethanol can cause deficits in learning and memory. It has been suggested that withdrawal is potentially more damaging than the ethanol exposure per se. Therefore, we explored the effect of repeated episodic exposure to ethanol on key regulators of cortical activity, the neurotrophins. Rats were exposed to ethanol via a liquid diet for 3 days per week for 6-24 weeks. Control rats were pair-fed an isocaloric liquid diet or ad libitum fed chow and water. The concentrations of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were determined using enzyme-linked immunosorbant assays (ELISAs). Five telencephalic structures were examined: parietal cortex, entorhinal cortex, hippocampus, the basal nucleus, and the septal nuclei. All five areas expressed each of the three neurotrophins; BDNF was most abundant and NGF the least. The parietal cortex was susceptible to ethanol exposure, NGF and BDNF content increased, and NT-3 content fell, whereas no changes were detectable in the entorhinal cortex. In the hippocampus, the amount all three neurotrophins increased following episodic ethanol exposure. Neurotrophin content in the two segments of the basal forebrain was affected; NGF and NT-3 content in the basal forebrain was reduced and NGF and BDNF content in the septal nuclei was increased by ethanol exposure. In many cases where ethanol had an effect, the change was transient so that by 24 weeks of episodic exposure, no significant changes were evident. Thus, the effects of ethanol are site- and time-dependent. This pattern differs from changes caused by chronic ethanol exposure, hence, neurotrophins must be vulnerable to the effects of withdrawal. Furthermore, the ethanol-induced changes do not appear to fit a model consistent with retrograde regulation, rather they suggest that neurotrophins act through autocrine/paracrine systems.     

GM1 and ERK signaling in the aged brain

We investigated the ability of GM1 to induce phosphorylation/activation of the extracellular-regulated protein kinases (ERKs) in the striatum, hippocampus and frontal cortex of aged male Sprague-Dawley rats. Three different treatment paradigms were used: a single application of GM1 to brain slices in situ, a single intracerebroventricular (icv) administration of GM1 in vivo, and chronic administration of GM1 in vivo. In situ, GM1 induced a rapid and transient activation of ERK1 and ERK 2 in both young and aged rats, and a similar effect was observed after stimulation with the neurotrophins NGF and BDNF. The aged brain appeared to respond more robustly to neurotrophic stimulation with the pERK2 response being significantly greater in the hippocampus and frontal cortex. Acute icv administration of GM1 resulted in short-lasting phosphorylation of ERKs in both aged groups, while chronic administration of GM1 induced a protracted phosphorylation of ERKs. Following chronic GM1 treatment, pERK2 levels in the aged hippocampus were elevated over young control animals. In agreement with reports that GM1 phosphorylates TrkA in vitro or in situ, treatment with GM1 increased the phosphorylation of TrkA in hippocampus of both young and aged animals. These observations indicate that the aged brain maintains the ability to respond to neurotrophic stimuli and put forward the proposition that the ERK cascade is associated with the action(s) of GM1 ganglioside in vivo.     

Prenatal choline supplementation increases NGF levels in the hippocampus and frontal cortex of young and adult rats

Female Sprague-Dawley rats received approximately 300 mg/kg per day of choline chloride through their drinking water on days 11 of pregnancy through birth and the level of nerve growth factor (NGF) in the hippocampus and frontal cortex of their male offspring was measured at 20 and 90 days of age. Prenatal choline supplementation caused significant increases in hippocampal NGF levels at 20 and 90 days of age, while levels of NGF in the frontal cortex were elevated in choline-supplemented rats at 20 days of age, but not 90 days of age. These results suggest that increases in NGF levels during development or adulthood may be one mechanism underlying improvements in spatial and temporal memory of adult rats exposed to elevated levels of choline chloride perinatally.     

Ethanol-induced alterations in the expression of neurotrophic factors in the developing rat central nervous system

Neonatal rats were exposed to ethanol throughout gestation, or during the early postnatal period (postnatal days 4-10 (P4-10)), and enzyme-linked immunoabsorbent assays were subsequently conducted in order to assess nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein content in hippocampus, septum, cortex/striatum and cerebellum. These determinations revealed that following prenatal ethanol treatment, there were significant ethanol-induced increases in NGF in P1 cortex/striatum, but no changes in any of the three neurotrophic factors (NTFs) in the other brain regions. Cortex/striatal NGF protein returned to control levels by P10. Following early postnatal exposure, BDNF was elevated in hippocampus and cortex/striatum (assessed on P10), and NGF was also enhanced in cortex/striatum at this age. Hippocampal and cortex/striatal BDNF returned to control levels by P21, but cortex/striatal NGF levels remained enhanced at this age. This NTF did not differ in ethanol and control animals by P60, however. The possible significance of elevated levels of NTFs as a function of ethanol exposure is discussed, and it is speculated that while such alterations could play a protective role, increases in these substances during critical developmental periods could also prove to be deleterious, and could even contribute to certain of the neuropathologies which have been observed following developmental ethanol exposure.     

Chronic treatment with scopolamine and physostigmine changes nerve growth factor (NGF) receptor density and NGF content in rat brain

Nerve growth factor (NGF) and NGF receptors were measured in cortex and hippocampus of rats treated with drugs affecting cholinergic neurotransmission. High (K_d= 0.045nM) and low (K_d= 21nM) affinity¹²⁵I-NGF binding sites were present in both cortical and hippocampal membranes with hippocampus containing higher numbers of both sites than cortex. Chronic treatment of rats with the muscarinic receptor antagonist scopolamine (5 mg/kg, twice daily) decreased the density of high- and low-affinity sites by 50–90% in cortical and hippocampal membranes. These changes were seen after 7 days, but not 3 days, of scopolamine treatment. Chronic infusion of physostigmine (1 mg/kg/day) using minipumps increased the number of high- and low-affinity sites in cortex 3- and 6-fold, respectively. The changes in receptor-binding parameters induced by physostigmine were transient as they were evident after 3 days of treatment, but returned to control levels after 7 days. NGF content in cortex and hippocampus was reduced by about 50% following 7, but not 3, days of chronic physostigmine infusion. In contrast, scopolamine treatment failed to change NGF levels in the cholinergic neuronal target regions but it decreased NGF content in the septal area. The content of NGF mRNA in the cortex measured by Northern blot analysis failed to change following either scopolamine or physostigmine treatment. The results suggest that levels of NGF and NGF receptors in the target regions of cholinergic neurons are regulated by the extent of cholinergic neurotransmitter activity.     

Effect of the novel sigma1 receptor ligand and putative atypical antipsychotic E-5842 on BDNF mRNA expression in the rat brain

Changes in the expression of brain-derived neurotrophic factor (BDNF) have been implicated in some neuropsychiatric disorders. Several antipsychotic drugs affect the expression of BDNF mRNA in different areas of the rat brain. We examined the effect of single or repeated administration of 4-[4-fluorophenyl]-1,2,3,6-tetra-hydo-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842), a sigma1 receptor ligand and putative atypical antipsychotic drug on the expression of BDNF mRNA in rats. Acute treatment with E-5842 induced a down-regulation of BDNF mRNA levels in the frontal cortex and hippocampus, while a chronic treatment had no effect. Levels of another neurotrophin, nerve growth factor (NGF), remained unaltered after either acute or chronic treatment. The effects suggest that any therapeutic properties of E-5842 are not mediated by stimulation of BDNF or NGF, whereas the regulation of these trophic factors may be part of the mechanism of action of sigma1 receptor ligands.     

Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain

The effects of lithium treatment on serotonin (5-HT) receptors in rat frontal cortex and hippocampus were investigated. Long-term lithium treatment strongly blocked 5-hydroxytryptophan-induced head twitches, while acute lithium administration by itself induced head twitches in rats, and ketanserin blocked this acute lithium action. Long-term administration of lithium decreased the number of not only 5-HT2 receptors in the frontal cortex but also 5-HT1 and 5-HT2 receptors in the hippocampus in rats. Decreases in 3H-5-HT binding to hippocampal 5-HT1 receptors and 3H-spiperone binding to frontal cortical 5-HT2 receptors, caused by chronic lithium treatment, were abolished by co-administration of p-chlorophenylalanine, and were enhanced by co-administration with methiothepin. The turnover of 5-HT in either frontal cortex or hippocampus was facilitated by lithium, and co-administered methiothepin enhanced this facilitation. These results suggest that long-term lithium treatment causes the down-regulation of postsynaptic 5-HT1 and 5-HT2 receptors, in part probably through its action on presynaptic nerve terminals.     

Neuroprotective effect of chronic lithium treatment against hypoxia in specific brain regions with upregulation of cAMP response element binding protein and brain-derived neurotrophic factor but not nerve growth factor: comparison with acute lithium treatment

Objectives:  We evaluated the neuroprotective effect of chronically or acutely administered lithium against hypoxia in several brain regions. Furthermore, we investigated the contribution of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and cAMP response element binding protein (CREB) to the neuroprotective effect of lithium.
Methods:  Brain slices were prepared from rats that had been treated chronically or acutely with lithium. The cerebral glucose metabolic rate (CMRglc) before and after hypoxia loading to brain slices was measured using the dynamic positron autoradiography technique with [¹⁸F]2-fluoro-2-deoxy- d -glucose. The changes of expression of proteins were investigated using Western blot analysis.
Results:  Before hypoxia loading, the CMRglc did not differ between the lithium-treated and untreated groups. After hypoxia loading, the CMRglc of the untreated group was significantly lower than that before hypoxia loading. However, the CMRglc of the chronic lithium treatment group recovered in the frontal cortex, caudate putamen, hippocampus and cerebellum, but not in the thalamus. In contrast, the CMRglc of the acute lithium treatment group did not recover in any analyzed brain regions. After chronic lithium treatment, the levels of expression of BDNF and phospho-CREB were higher than those of untreated rats in the frontal cortex, but not in the thalamus. However, the expression of NGF did not change in the frontal cortex and thalamus.
Conclusions:  These results demonstrated that lithium was neuroprotective against hypoxia only after chronic treatment and only in specific brain regions, and that CREB and BDNF might contribute to this effect.     

Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness

Stress-induced helplessness in rodents constitutes a well-defined model to investigate neurobiological mechanisms of depression. Neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have both been shown to be involved in neurobiological changes of physiological and pathological reactions to stress. In this study we investigated NGF and BDNF protein levels in the frontal cortex and hippocampus in mice treated with an established model of inducible helplessness via electric footshocks compared to untreated controls at various times (0 h up to 14 days after treatment). NGF levels were transiently decreased by one forth in the frontal cortex of shocked mice at 6 h after the stress treatment, whereas BDNF levels remained unchanged in the brain areas investigated throughout the time course. In addition, frontal cortex BDNF levels showed a significantly higher concentration in the right compared to the left hemisphere (up to 3-fold). This effect was detectable independently of treatment, namely in shocked and control mice at any time point measured. In conclusion, a transient decrease of frontal NGF constitutes the most striking correlate of neurobiological changes in this animal model of stress-induced change of behaviour. Interhemispherical differences of BDNF content in the frontal cortex are a new finding that might reflect intracerebral side dominance. Thus, subsequent studies of frontal cortex BDNF expression should carefully consider an interhemispherical variance to avoid misinterpretation.     

Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of a rat model of depression

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Moreover, it has been hypothesized that these molecules play a role in the pathophysiology as well as treatment of depression. Using an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL), we investigated the effects of electroconvulsive stimuli (ECS) on brain NGF and BDNF. ECS or SHAM ECS were administered eight times, with a 48-h interval between each treatment. NGF and BDNF were measured with enzyme-linked immunosorbent assay (ELISA). In the hippocampus ECS increased NGF concentration in FSL but not FRL rats. ECS decreased NGF concentration in the frontal cortex of FSL rats. In both FSL and FRL rats ECS increased NGF levels in the striatum. In contrast, ECS did not change BDNF concentration in hippocampus, frontal cortex and striatum of FSL and FRL rats. Our data support the notion that neurotrophin concentrations may be altered by ECS.     

Expression of the mRNA of neurotrophins in brain regions of rats after spontaneous morphine withdrawal

The expression of specific genes is an important factor of neuroplastic changes during the formation of opiate dependence. Neurotrophic factors participate in structural-functional modifications in CNS regions after opiate intoxication. Here, we studied the levels of mRNAs of the brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) in the frontal cortex, striatum, hippocampus, and midbrain after spontaneous morphine withdrawal in dependent rats. To induce physical dependence, morphine was injected intraperitoneally twice a day with increasing doses of 10–100 mg/kg for 6 days. The expression of mRNAs of BDNF, NGF, and IGF1 in the brain areas was estimated 40 hours after spontaneous morphine withdrawal using the real-time PCR method. We found that spontaneous morphine withdrawal induced an elevation of BDNF and IGF1 mRNAs in the frontal cortex. In the hippocampus and the midbrain only BDNF mRNA increased. The content of NGF mRNA did not change in all regions studied. We believe that changes in the expression of BDNF and IGF1 are involved in the mechanisms of neuroplastic modification during the formation of opiate dependence.     

Effects of different kinds of acute stress on nerve growth factor content in rat brain

Nerve growth factor (NGF) has several effects on the central nervous system; on the one hand NGF fosters survival and function of cholinergic neurons of the basal forebrain, on the other hand this protein is implicated in the stress response of the hypothalamic-pituitary-adrenocortical axis (HPAA). In this study we tested the influence of threatening and painful stress treatments in three different intensities as well as forced motoric activity on NGF content in different brain areas in adult rats. We found that threatening treatment with or without painful stimuli was followed by a significant decrease of NGF concentration in the amygdala (44.5%; P=0.03) and the frontal cortex (-45.5%; P=0.02). We also observed that after stress of forced motoric activity NGF content in the frontal cortex (-32%; P=0.01) and the hippocampus (-32%; P=0.006) was significantly reduced. Thus, NGF content in distinct brain regions is decreased, following different forms of acute stress. This might be relevant for the pathophysiological understanding of psychiatric diseases, such as depression, which are associated with stress.     

125I-beta-nerve growth factor binding is reduced in rat brain after stress exposure

In the central nervous system (CNS), the presence of nerve growth factor (NGF) and its receptor, NGFR, in cholinergic neurons has been demonstrated. In this study we report that, after exposure to stress, there was a reduction in total binding of NGF in the hippocampus and basal forebrain of 3.5-month-old rats without significant changes in the frontal cortex or cerebellum. Chronic treatment with acetyl-l-carnitine (ALCAR), that prevents some age-related impairments of CNS, for 1.5 months, decreased NGF binding in hippocampus and basal forebrain but abolished the stress-related reduction of NGF binding observed in the hippocampus of untreated rats.     

The proline-rich hypothalamic peptide is a modulator of functions of neurotrophins and neuronal activity in amyloid-induced neurodegeneration

On a model of neurodegeneration induced by neurotoxic peptide fragment (25–35) of β-amyloid (Aβ), we studied changes in the content of neurotrophins: insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF) in different brain areas, as well as the thymus, liver, and blood serum of rats under the influence of hypothalamic proline-rich peptide-1 (PRP-1). The effect of PRP-1 on the structural-functional state of the neurons was also studied. We showed that intramuscular injections of synthetic PRP-1 at a dose of 10 μg per 100 g of body weight for the first 9 days after intracerebroventricular administration of Aβ into the lateral brain ventricles of rats resulted in a considerable increase in the concentration of IGF-1 in all investigated brain structures, mainly, in the neocortex, hippocampus, and hypothalamus at 12 week of developing the neurodegeneration. This effect was maintained also after intramuscular administration of PRP-1 at 30 days after Aβ injection (a later date). However, as a result of PRP-1 action at early stages of the process, the tendency to decrease NGF content in the cortex, hippocampus and hypothalamus was observed. Electrophysiological and morphological studies of hippocampal neurons show, that by the 18th week after the beginning of neuro-degeneration, treatment with PRP-1 results in survival and further maintenance of cells, which indicates that PRP-1 has neuroprotective characteristics. We concluded that treatment with PRP-1 at Aβ-induced neuro-degeneration may provide normal functioning of neurons during a relatively long period of time by modulation the levels of neurotrophins both in brain and peripheria.     

Cortico-hippocampal APP and NGF levels are dynamically altered by cholinergic muscarinic antagonist or M1 agonist treatment in normal mice

To determine whether altered cholinergic neurotransmission can modify the long-term secretion of amyloid precursor protein (APP), endogenous levels of APP and nerve growth factor (NGF), we administered a selective M1 muscarinic receptor agonist (RS86) or the muscarinic antagonist, atropine, for 7 days in vivo into young adult mice (C57BL/6j). The levels of NGF and total APP in the hippocampus, frontal cortex, striatum, parietal cortex and cerebrospinal fluid (CSF) were examined by ELISA and Western blot. We found that this repeated i.m. administration of M1 receptor agonist resulted in decreased total APP levels in the hippocampus, frontal cortex and parietal cortex, and increased secreted alpha-APPs levels in the CSF. M1 agonist treatment also resulted in decreased NGF levels in the hippocampus and CSF. These effects of the M1 muscarinic agonist could be blocked by atropine, which by itself elevated tissue levels of total APP. Interestingly, we found that the decrease of total APP in the hippocampus and striatum after M1 agonist treatment inversely correlated with the change in NGF levels. These data suggest that a sustained increased cholinergic, M1-mediated neurotransmission will enhance secretion of alpha-APPs in CSF and adaptively reduce the levels of total APP and NGF in the corticohippocampal regions of normal mice. The dynamic and adaptive regulation linking total APP and NGF levels in normal adult mice is relevant for understanding the pathophysiology of conditions with cholinergic and APP related pathologies, like Alzheimer's disease and Down's syndrome.     

Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions

Summary. Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons. In this study NGF-protein levels were determined in areas of the basal forebrain cholinergic system, its projection areas as well as the striatum and the cerebellum after long-term exposure (6 and 9 months) to ethanol and a phase of withdrawal in male Sprague-Dawley rats. 6-month alcohol treatment led to an increase of NGF to 650–850% of controls in the basal forebrain and the septum and to a 210–485% increase in the cholinergic projection areas (anterior cortex, hippocampus and olfactory bulb). After 9 months exposure to ethanol, a decrease of NGF by 16% in the frontal cortex was observed compared to controls. In the other brain regions no differences in NGF expression were detectable at this time-point. These results support the idea of an endogenous neuroprotective mechanism acting through a transient NGF induction followed by a decrease in NGF-levels during the course of further neuronal degeneration. Authors contributed equally to this study     

Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats

Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, induces neuronal death, decreases neurogenesis, and impairs synaptic plasticity and memory, but the mechanisms for these effects are not well understood. We hypothesize that neurotrophin levels in the brain are influenced by LPS. To test this hypothesis, we determined effects of LPS on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and NT-3 levels in the brain after intraperitoneal injection of saline or LPS (0.1, 0.3 or 1.0mg/kg) in rats. LPS significantly decreased BDNF in the hippocampus (-20%), frontal cortex (-19%), parietal cortex (-63%), temporal cortex (-29%), and occipital cortex (-41%). LPS also significantly decreased NGF levels by 10-20% in the hippocampus and different cortical regions, except in the occipital cortex. Finally, LPS decreased NT-3 by 15-25% in the frontal cortex. These observations indicate that the neuroprotection mediated by neurotrophins in the brain are compromised by systemic immune activation induced by LPS.     

Long-term administration of mouse nerve growth factor to adult rats with partial lesions of the cholinergic septohippocampal pathway

Nerve growth factor (NGF), a neurotrophic factor acting on cholinergic neurons of the basal forebrain, has been proposed as a treatment for Alzheimer's disease. Experimental support for its pharmacological use is derived from short-term studies showing that intraventricular administration of NGF during 2-4 weeks protects cholinergic cell bodies from lesion-induced degeneration, stimulates synthesis of choline acetyltransferase, and improves various behavioral impairments. To investigate the consequences of long-term NGF administration, we tested whether cholinergic cell bodies are protected from lesion-induced degeneration and whether cholinergic axons are stimulated to regrow into the denervated hippocampus following fimbrial transections. We found that intraventricular injections of NGF twice a week for 5 months to adult rats resulted in extended protection of cholinergic cell bodies from lesion-induced degeneration and did not produce obvious detrimental effects on the animals. NGF treatment mildly stimulated growth of cholinergic neurites within the 2-mm area directly adjacent to the fimbrial lesion but it failed to induce significant homotypic growth of cholinergic neurites into the deafferented hippocampus.     

Long-Term Changes in Behavior and the Content of BDNF in the Rat Brain Caused by Neonatal Isolation: The Effects of an Analog of ACTH(4-10) Semax

Exposure to stress during early postnatal development can cause neurological disorders in adulthood. The aim of this study was to evaluate changes in behavior, learning ability, and the content of the neurotrophic factor BDNF in rats that underwent neonatal stress. In addition, we studied the possibility of correction of the effects of neonatal stress by subsequent administration of an analog of the ACTH(4-10) fragment Semax. Neonatal isolation (NI) was used as a stress stimulus. Rat pups were separated from their mother and littermates for 5 h per day each day during the period from the 1st to the 14th day of life. The control animals were left in their nest in the first 2 weeks of life. From the 15th to 28th day of life, half of the rats subjected to NI were intranasally treated with Semax daily at a dose of 0.05 mg/kg. The remaining animals received intranasal injection of solvent at the same time. It has been shown that NI leads to an increase in the level of anxiety, a slight increase in depression, and impaired retention of the passive avoidance task in rats during the second month of life. At the age of 1 month, we observed an increase in the content of BDNF in the frontal cortex in the rats with NI; at the age of 2 months, a decrease occurred in the neurotrophin level in the hippocampus. Administration of Semax to rats subjected to NI decreased anxiety and depression, improved learning ability, and normalized the BDNF content in brain structures of animals. Therefore, chronic intranasal Semax administration after NI weakens the negative effects of neonatal stress.