The brain serotonin system in autism.

Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases. These disorders are characterized by lack of social interaction, by repetitive behavior, and often anxiety and learning disabilities. The brain serotonin (5-HT) system is known to be crucially implicated in a wide range of physiological functions and in the control of different kinds of normal and pathological behavior. A growing number of studies indicate the involvement of the brain 5-HT system in the mechanisms underlying both ASD development and ASD-related behavioral disorders. There are some review papers describing the role of separate key players of the 5-HT system in an ASD and/or autistic-like behavior. In this review, we summarize existing data on the participation of all members of the brain 5-HT system, namely, 5-HT transporter, tryptophan hydroxylase 2, MAOA, and 5-HT receptors, in autism in human and various animal models. Additionally, we describe the most recent studies involving modern techniques for in vivo regulation of gene expression that are aimed at identifying exact roles of 5-HT receptors, MAOA, and 5-HT transporter in the mechanisms underlying autistic-like behavior. Altogether, results of multiple research articles show that the brain 5-HT system intimately partakes in the control of some types of ASD-related behavior, and that specific changes in a function of a certain 5-HT receptor, transporter, and/or enzyme may normalize this aberrant behavior. These data give hope that some of clinically used 5-HT-related drugs have potential for ASD treatment.

On the role of serotonin 5-HT1A receptor in autistic-like behavior: сross talk of 5-HT and BDNF systems.

Autism spectrum disorders (ASDs) are some of the most common neurodevelopmental disorders; however, the mechanisms underlying ASDs are still poorly understood. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known as key players in brain and behavioral plasticity and interact with each other. 5-HT1A receptor is a principal regulator of the brain 5-HT system, which modulates normal and pathological behavior. Here we investigated effects of adeno-associated-virus-based 5-HT1A receptor overexpression in the hippocampus of BTBR mice (which are a model of autism) on various types of behavior and on the expression of 5-HT7 receptor, proBDNF, mature BDNF, and BDNF receptors (TrkB and p75NTR). The 5-HT1A receptor overexpression in BTBR mice reduced stereotyped behavior in the marble-burying test and extended the time spent in the center in the open field test. Meanwhile, this overexpression failed to affect social behavior in the three-chambered test, immobility time in the tail suspension test, locomotor activity in the open field test, and associative learning within the "operant wall" paradigm. The 5-HT1A receptor overexpression in the hippocampus raised hippocampal 5-HT7 receptor mRNA and protein levels. Additionally, the 5-HT1A receptor overexpression lowered both mRNA and protein levels of TrkB receptor but failed to affect proBDNF, mature BDNF, and p75NTR receptor expression in the hippocampus of BTBR mice. Thus, obtained results suggest the involvement of the 5-HT and BDNF systems' interaction mediated by 5-HT1A and TrkB receptors in the mechanisms underlying autistic-like behavior in BTBR mice.

Effects of the Cc2d1a/Freud-1 Knockdown in the Hippocampus of BTBR Mice on the Autistic-Like Behavior, Expression of Serotonin 5-HT1A and D2 Dopamine Receptors, and CREB and NF-kB Intracellular Signaling.

The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 (encoded by the Cc2d1a gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT1A serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the Cc2d1a/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the Cc2d1a/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT1A serotonin and D2 dopamine receptors, and CREB and NF-κB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the Cc2d1a/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the Cc2d1a/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of Cc2d1a/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT1A serotonin and D2 dopamine receptors and key NF-κB signaling genes (Nfkb1 and Rela). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.

The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference.

Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT7 receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT2A, 5-HT3 and 5-HT7) as well as those providing an antidepressant effect (5-HT1A, 5-HT1B, 5-HT2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT7 receptors. Activation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C receptors attenuate aggressiveness, whereas agonists of 5-HT3 intensify aggressive behavior.

Serotonin 5-HT7 receptor overexpression in the raphe nuclei area produces antidepressive effect and affects brain serotonin system in male mice.

Heterodimerization between 5-HT7 and 5-HT1A receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between 5-HT1A /5-HT7 hetero- and 5-HT1A /5-HT1A homodimers in presynaptic neurons toward 5-HT1A /5-HT1A homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT7 receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT7 receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT7 receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT7 receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT7 receptor overexpression resulted in the reduction of 5-HT1A receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT7 receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT7 receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT7 receptor in the mechanisms underlying depressive behavior.

Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine.

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73-110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice.

Serotonin 5-HT2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT2A/2C receptor agonist DOI, highly selective 5-HT2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT2A agonists.

Spaceflight and brain plasticity: Spaceflight effects on regional expression of neurotransmitter systems and neurotrophic factors encoding genes.

The critical problem of space exploration is the effect of long-term space travel on brain functioning. Current information concerning the effects of actual spaceflight on the brain was obtained on rats and mice flown on five missions of Soviet/Russian biosatellites, NASA Neurolab Mission STS90, and International Space Station (ISS). The review provides converging lines of evidence that: 1) long-term spaceflight affects both principle regulators of brain neuroplasticity - neurotransmitters (5-HT and DA) and neurotrophic factors (CDNF, GDNF but not BDNF); 2) 5-HT- (5-HT2A receptor and MAO A) and especially DA-related genes (TH, MAO A, COMT, D1 receptor, CDNF and GDNF) belong to the risk neurogenes; 3) brain response to spaceflight is region-specific. Substantia nigra, striatum and hypothalamus are highly sensitive to the long-term spaceflight: in these brain areas spaceflight decreased the expression of both DA-related and neurotrophic factors genes. Since DA system is involved in the regulation of movement and cognition the data discussed in the review could explain dysfunction of locomotion and behavior of astronauts and direct further investigations to the DA system.

On the interaction between BDNF and serotonin systems: The effects of long-term ethanol consumption in mice.

We investigated the effect of chronic (6 weeks) consumption of 10% alcohol on the principal elements of BDNF (BDNF, proBDNF, p75, and TrkB receptors) and 5-HT (5-HT, 5-HIAA, tryptophan hydroxylase-2 [Tph-2], 5-HT transporter [5-HTT], 5-HT1A, 5-HT2A, and 5-HT7 receptors) systems in the brain of C57Bl/6 mice. BDNF mRNA level in the raphe nuclei area and BDNF protein level in the hippocampus were lowered in ethanol-treated mice. The increase in proBDNF protein level in the raphe nuclei area, cortex, and amygdala and the increase of p75 receptor protein levels in the raphe nuclei area were revealed after ethanol exposure. Alcohol intake reduced the protein level and increased the activity of Tph-2, the key enzyme for serotonin biosynthesis in the brain, and increased the main 5-HT metabolite 5-HIAA level and 5-HIAA/5-НТ ratio as well as the 5-HT7 receptor mRNA level in the raphe nuclei area. In the cortex, 5-HT2A receptor protein level was reduced, and 5-HIAA/5-HT ratio was increased. These data showed considerable impact of alcoholization on the BDNF system, resulting in proBDNF and p75 receptor expression enhancement. Alcohol-induced changes in BDNF and 5-HT systems were revealed in the raphe nuclei area where the majority of the cell bodies of the 5-HT neurons are localized, as well as in the cortex, hippocampus, and amygdala. Our data suggest that the BDNF/5-HT interaction contributes to the mechanism underlying chronic alcohol-induced neurodegenerative disorders.

Neuronal and behavioral plasticity: the role of serotonin and BDNF systems tandem.

INTRODUCTION: Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known as principal players in different kinds of plasticity. The 5-HT-BDNF interaction in early ontogeny and in adult brain is an intriguing problem. Area covered: This paper concentrates on the interaction between 5-HT and BDNF systems and its implication in different plasticity levels, from neurons to behavior. This review describes (1) different 5-HT functioning in the embryonic (as neurotrophin) and adult brain (as a neurotransmitter); (2) BDNF as a modulator of 5-HT system and vice versa; (3) the prolonged positive effect of BDNF on genetically and epigenetically defined central nervous system disorders; (4) The 5-HT-BDNF interplay contribution to aggressive behavior, depression, drug addiction, suicide, and stress response; and (5) the role of common second messengers for 5-HT and BDNF signaling in the 5-HT-BDNF interaction. Expert opinion: Dysregulation in 5-HT-BDNF interaction may be responsible for development of neuropsychiatric and behavioral abnormalities. 5-HT-BDNF cross-talk is a potential target for the treatment of various neurological diseases. Understanding the function of the members of BDNF system in response to challenges of the environment and the interaction with different 5-HT receptors in health and disease will one day lead to new classes of drugs.

Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3-4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs. Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT1A receptor), (2) the effect of dimerization of 5-HT7 and 5-HT1A receptors on the internalization and functioning of 5-HT1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI. Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.

Genetically defined fear-induced aggression: Focus on BDNF and its receptors.

Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB-FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype.

Role of glial cell line-derived neurotrophic factor in the pathogenesis and treatment of mood disorders.

Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a survival factor for dopaminergic neurons, but GDNF has also been shown to promote development, differentiation, and protection of other central nervous system neurons and was thought to play an important role in various neuropsychiatric disorders. Severe mood disorders, such as primarily major depressive disorder and bipolar affective disorder, attract particular attention. These psychopathologies are characterized by structural alterations accompanied by the dysregulation of neuroprotective and neurotrophic signaling mechanisms required for the maturation, growth, and survival of neurons and glia. The main objective of this review is to summarize the recent findings and evaluate the potential role of GDNF in the pathogenesis and treatment of mood disorders. Specifically, it describes (1) the implication of GDNF in the mechanism of depression and in the effect of antidepressant drugs and mood stabilizers and (2) the interrelation between GDNF and brain neurotransmitters, playing a key role in the pathogenesis of depression. This review provides converging lines of evidence that (1) brain GDNF contributes to the mechanism underlying depressive disorders and the effect of antidepressants and mood stabilizers and (2) there is a cross-talk between GDNF and neurotransmitters representing a feedback system: GDNF-neurotransmitters and neurotransmitters-GDNF.

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders.

BACKGROUND: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. METHODS: Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. RESULTS: No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. CONCLUSIONS: The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed.

Glial cell line-derived neurotrophic factor in genetically defined fear-induced aggression.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in maintenance of neuronal system throughout life. However, there is a lack of data on the involvement of GDNF in the regulation of different kinds of behavior. In this study, GDNF, its precursor (proGDNF) and GDNF mRNA levels were investigated in the brain of rats selectively bred for 85 generations for either high level or for the lack of affective aggressiveness toward human. It was found that GDNF mRNA level was decreased in the frontal cortex, increased in the raphe nuclei area of the midbrain of aggressive rats compared to tame animals and was not detected in the amygdala and hypothalamus. The level of proGDNF was reduced in the raphe nuclei area of the midbrain of highly aggressive rats and was not detected in the striatum, nucleus accumbens of investigated animals. Two forms of mature GDNF - monomer and dimer - were revealed. GDNF monomer level was increased in the raphe nuclei area, substantia nigra and amygdala of aggressive rats and it was not found in the frontal cortex and nucleus accumbens of investigated rats. Dimer GDNF level was found in all investigated brain structures. It was reduced in the hippocampus and increased in amygdala of highly aggressive rats. Thus, considerable structure-specific differences in GDNF expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of both mature GDNF monomer and dimer as well as proGDNF in the mechanism underlying genetically defined aggressiveness.

5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested.

Tryptophan hydroxylase 2 in seasonal affective disorder: underestimated perspectives?

Seasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human TPH2 gene expression and the risk of affective disorder, application of tryptophan to SAD treatment and the animal models of SAD. The main conclusions of this review are as follows: (i) the brain 5-HT deficiency contributes to the mechanism underlying SAD, (ii) TPH2 is involved in the regulation of some kinds of genetically defined affective disorders and (iii) the activation of 5-HT synthesis with exogenous l-tryptophan alone or in combination with light therapy could be effective in SAD treatment. The synergic effect of these combined treatments will have several advantages compared to light or tryptophan therapy alone. First, it is effective in the treatment of patients resistant to light therapy. Secondly, l-tryptophan treatment prolongs the antidepressant effect of light therapy.

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype.

Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects.

Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders.

Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.