Bulletin of Experimental Biology and Medicine, 2004
Experiments were performed on knockout Tg8 mice lacking monoamine oxidase A gene that plays a maj... more Experiments were performed on knockout Tg8 mice lacking monoamine oxidase A gene that plays a major role in dopamine catabolism. The study by the method of high-performance liquid chromatography revealed considerable regional differences in the contents of dopamine and its metabolite dihydroxyphenylacetic acid in brain structures of these animals. Tg8 mice differed from the parent C3H/HeJ strain by low level of dihydroxyphenylacetic acid in the striatum, midbrain, hypothalamus, and hippocampus and high concentration of dopamine in the striatum. No differences were revealed in the contents of dopamine and dihydroxyphenylacetic acid in the frontal cortex and amygdala. The 2.4-4.8-fold decrease in the content of dihydroxyphenylacetic acid in various brain structures was not accompanied by changes in dopamine concentration. These data reflect the effective compensation for deficiency of dopamine metabolism. Our results suggest that monoamine oxidases A and B and catechol-O-methyltransferase play different roles in dopamine metabolism in various brain structures.
Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychophar... more Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153.
Studies in recent decades have demonstrated a remarkable multiplicity of serotonin (5-HT) recepto... more Studies in recent decades have demonstrated a remarkable multiplicity of serotonin (5-HT) receptors in the brain. The classification of 5-HT receptors is based on three principles: similarities in receptor structure, the choice of a second messenger and the nature of the relationship with it (inhibition or activation), and the pharmacological profile of the receptor [9, 10]. The 14 known 5-HT receptor variants were classified into seven types and seven subtypes [5]. There is no doubt that the multifunctionality of brain serotonin is associated with the high level of polymorphism of its receptor system. These points have increased interest in the question of the functional roles of different types of 5-HT receptor. Especially intriguing are the related subpeptides of particular receptors. 5-HT 2 receptor subtypes attract attention, i.e., the 5-HT 2A and 5-HT 2C subtypes, as there are data showing the involvement of both of these subtypes in the mechanisms of psychopathology. The 5-HT 2C receptor was initially regarded as a 5-HT 1 receptor, but the error was corrected [6] when its similarity with 5-HT 2 receptors in terms of one of the main principles of the classification-the type of second messenger, having a similar, activatory, response-was recognized. 5-HT 2A and 5-HT 2C receptors belong to the superfamily of G-protein-linked receptors, which have significant structural similarities and propagate signals activating phospholipase C and mobilizing calcium. At the same time, these receptors also show significant differences: 1) the genes encoding them are located on different chromosomes-the 5-HT 2A receptor gene is on chromo
Neonatal treatments can disrupt prepulse inhibition (PPI) of startle response later in life. Alph... more Neonatal treatments can disrupt prepulse inhibition (PPI) of startle response later in life. Alpha2A-adrenergic receptors (alpha2A-ARs) regulate the release of brain neurotransmitters that may influence PPI. The authors examined the effects of short-term reduction in the neonatal brainstem alpha2A-ARs on subsequent development of this receptor system and acoustic startle reflex in rats. Administration of antisense oligodeoxynucleotide complementary to the alpha2A-ARs on Days 2-4 of life reduced receptor expression in the brainstem by Day 5. The treatment increased alpha2-AR numbers in the cortex, hippocampus, and amygdala at 40 days of age, and in cortex and hypothalamus at 90 days of age. Transient increases in hippocampal and amygdalar alpha2-ARs were accompanied by attenuation of acoustic startle response and impairment of PPI.
The influence of genetic background on sensitivity to drugs represents a topical problem of perso... more 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...
Human aggression is a heterogeneous behavior with biological, psychological, and social backgroun... more 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. 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. No differences were found between m...
Glial cell line-derived neurotrophic factor (GDNF) plays an important role in maintenance of neur... more 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 ...
Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA leve... more Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75receptors 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 o...
Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice... more Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice with neurological mutation expressed in demyelinization of the brain neurons and constant shaking. It has been shown that apomorphine in a low dose (0.25 mg/kg) produced a more significant decrease in locomotor activity in Qk than in control mice. Qk mice appeared to be less sensitive to the blockade by haloperidol of apomorphine (2.5 mg/kg)-induced climbing. DA1 receptor agonist, SKF-38393 caused less pronounced climbing in Qk mice than in the control. There were no changes in DA level in striatum and n. accumbens, whereas 3,4-dihydroxyphenylacetic acid in n. accumbens and homovanillic acid level in striatum were elevated. It was suggested that the increased DA metabolism and the altered sensitivity of pre- and postsynaptic DA receptors are involved in the shaking behaviour of Qk mice.
Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool ... more Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool for studies of the molecular mechanisms of behavioral mutations. The 59-70 cM fragment of chromosome 13 containing the locus determining predisposition to freezing reaction (catalepsy) and the gene encoding 5-HT(1A) receptor were transferred from cataleptic CBA/Lac mice into the genome of catalepsy-resistant AKR/J mice. The impact of this fragment for the severity of catalepsy and expression of genes encoding tryptophane hydroxylase-2, serotonin transporter, and 5-HT(1A) receptor was studied. Half of mice of the resultant congenic AKR.CBA-D13Mit76 strain exhibited pronounced catalepsy, similarly to donor CBA animals. The expression of 5-HT(1A) receptor gene in the midbrain of AKR animals was significantly higher than in CBA. The level of 5-HT(1A) receptor mRNA in AKR.CBA-D13Mit76 animals was significantly higher than in the donor strain. Mice of parental AKR and CBA strains did not differ from each other and from AKR.CBA-D13Mit76 animals by the levels of tryptophane hydroxylase-2 and serotonin transporter genes mRNA. These data prove the location of catalepsy regulating gene in the distal fragment of chromosome 13. The recipient strain genome enhanced the expression of 5-HT(1A) receptor gene in the brain without modulating the expression of catalepsy gene.
Neuroscience and Behavioral Physiology, May 21, 2010
The tail suspension test (TST)-induced immobility and hyperthermia and acoustic startle response ... more The tail suspension test (TST)-induced immobility and hyperthermia and acoustic startle response were studied in 11 mouse inbred strains and in MAO A knockout Tg8 mice. Significant genotypic differences in TST-induced immobility rather than hyperthermia and the lack of correlation between the expression of immobility and hyperthermia were found. Positive genotypic correlation between immobility in the TST and Porsolt test as well as TST-induced immobility and acoustic startle response was shown. Genetic knockout of the main enzyme in serotonin and catecholamines metabolism, MAO A, decreased the startle response and TST-induced hyperthermia but had no effect on TST-induced immobility in Tg8 mice indicating the differences in neurochemical regulation of these TST-induced responses. The results support the validity of the TST as dry-land version of the forced swimming test and draw attention to TST-induced hyperthermia as an animal model of response to uncontrollable, inescapable stress demonstrated in humans.
Brain neurotransmitter serotonin is involved in the regulation of many physiological functions an... more Brain neurotransmitter serotonin is involved in the regulation of many physiological functions and types of behavior. The key enzyme of serotonin synthesis in the brain is tryptophan hydroxylase-2 (TPH-2). An association of the C1473G polymorphism in gene tph2 causing the replacement of Pro447 by Arg447 in TPH-2 molecule with enzyme activity in the mouse brain of 10 inbred strains was found. Association of the polymorphism with the TPH-2 activity in the brain of F2 hybrids between strains C57BL/6 and CC57BR was shown. The results indicate that the C1473G polymorphism in gene tph2 is the main factor determining the genetic defined variability of enzyme activity in the mouse brain.
Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically define... more 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 rat...
large enough to create conditions for massive activation of opiate-sensitive neurons in the zone ... more large enough to create conditions for massive activation of opiate-sensitive neurons in the zone of infusion. Despite this fact, selective analgesic (PGM, dorsomedial hypothalamus) and secondary reinforcing (VTR, nucleus accumbens-weaker) responses were obtained from different structures, evidence of the neuroanatomical heterogeneity of the trigger zones for these effects of morphine. LITERATURE CITED i.
The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavio... more The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition. Introduction of the receptive female induced sexual motivation and arousal in males, as evidenced by a prolonged time spent at the partition, unsuccessful attempts to step across it and a significant increase in plasma testosterone levels. Administration of 5-HT2A receptor antagonists ketanserin (1.0 and 2.0 mg/kg i.p.) or cyproheptadine (1.0 and 2.0 mg/kg i.p.) diminished the behavioral components and prevented the hormonal components of male sexual arousal. Administration of the selective 5-HT2C antagonist RS 102221 (1.0 and 2.0 mg/kg) considerably increased the time spent by males at the partition (p < 0.001) and, at the dose of 2.0 mg/kg, increased plasma testosterone levels (p < 0.01). Administration of ritanserin - a nonselective 5-HT2A/2C antagonist and, to a smaller degree, 5-HT2B antagonist - at doses of 0.1 and 0.5 mg/kg did not significantly influence male behavior and the activating effect of the presence of a female on the hypothalamo-pituitary-testicular system, although it increased resting testosterone levels (p < 0.05). The present findings suggest that 5-HT2A/5-HT2C receptors may be involved in the neural control of male sexual motivation and arousal, presumably by exerting reciprocal facilitative (5-HT2A) or suppressive (5-HT2C) influences.
Bulletin of Experimental Biology and Medicine, 2004
Experiments were performed on knockout Tg8 mice lacking monoamine oxidase A gene that plays a maj... more Experiments were performed on knockout Tg8 mice lacking monoamine oxidase A gene that plays a major role in dopamine catabolism. The study by the method of high-performance liquid chromatography revealed considerable regional differences in the contents of dopamine and its metabolite dihydroxyphenylacetic acid in brain structures of these animals. Tg8 mice differed from the parent C3H/HeJ strain by low level of dihydroxyphenylacetic acid in the striatum, midbrain, hypothalamus, and hippocampus and high concentration of dopamine in the striatum. No differences were revealed in the contents of dopamine and dihydroxyphenylacetic acid in the frontal cortex and amygdala. The 2.4-4.8-fold decrease in the content of dihydroxyphenylacetic acid in various brain structures was not accompanied by changes in dopamine concentration. These data reflect the effective compensation for deficiency of dopamine metabolism. Our results suggest that monoamine oxidases A and B and catechol-O-methyltransferase play different roles in dopamine metabolism in various brain structures.
Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychophar... more Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153.
Studies in recent decades have demonstrated a remarkable multiplicity of serotonin (5-HT) recepto... more Studies in recent decades have demonstrated a remarkable multiplicity of serotonin (5-HT) receptors in the brain. The classification of 5-HT receptors is based on three principles: similarities in receptor structure, the choice of a second messenger and the nature of the relationship with it (inhibition or activation), and the pharmacological profile of the receptor [9, 10]. The 14 known 5-HT receptor variants were classified into seven types and seven subtypes [5]. There is no doubt that the multifunctionality of brain serotonin is associated with the high level of polymorphism of its receptor system. These points have increased interest in the question of the functional roles of different types of 5-HT receptor. Especially intriguing are the related subpeptides of particular receptors. 5-HT 2 receptor subtypes attract attention, i.e., the 5-HT 2A and 5-HT 2C subtypes, as there are data showing the involvement of both of these subtypes in the mechanisms of psychopathology. The 5-HT 2C receptor was initially regarded as a 5-HT 1 receptor, but the error was corrected [6] when its similarity with 5-HT 2 receptors in terms of one of the main principles of the classification-the type of second messenger, having a similar, activatory, response-was recognized. 5-HT 2A and 5-HT 2C receptors belong to the superfamily of G-protein-linked receptors, which have significant structural similarities and propagate signals activating phospholipase C and mobilizing calcium. At the same time, these receptors also show significant differences: 1) the genes encoding them are located on different chromosomes-the 5-HT 2A receptor gene is on chromo
Neonatal treatments can disrupt prepulse inhibition (PPI) of startle response later in life. Alph... more Neonatal treatments can disrupt prepulse inhibition (PPI) of startle response later in life. Alpha2A-adrenergic receptors (alpha2A-ARs) regulate the release of brain neurotransmitters that may influence PPI. The authors examined the effects of short-term reduction in the neonatal brainstem alpha2A-ARs on subsequent development of this receptor system and acoustic startle reflex in rats. Administration of antisense oligodeoxynucleotide complementary to the alpha2A-ARs on Days 2-4 of life reduced receptor expression in the brainstem by Day 5. The treatment increased alpha2-AR numbers in the cortex, hippocampus, and amygdala at 40 days of age, and in cortex and hypothalamus at 90 days of age. Transient increases in hippocampal and amygdalar alpha2-ARs were accompanied by attenuation of acoustic startle response and impairment of PPI.
The influence of genetic background on sensitivity to drugs represents a topical problem of perso... more 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...
Human aggression is a heterogeneous behavior with biological, psychological, and social backgroun... more 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. 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. No differences were found between m...
Glial cell line-derived neurotrophic factor (GDNF) plays an important role in maintenance of neur... more 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 ...
Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA leve... more Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75receptors 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 o...
Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice... more Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice with neurological mutation expressed in demyelinization of the brain neurons and constant shaking. It has been shown that apomorphine in a low dose (0.25 mg/kg) produced a more significant decrease in locomotor activity in Qk than in control mice. Qk mice appeared to be less sensitive to the blockade by haloperidol of apomorphine (2.5 mg/kg)-induced climbing. DA1 receptor agonist, SKF-38393 caused less pronounced climbing in Qk mice than in the control. There were no changes in DA level in striatum and n. accumbens, whereas 3,4-dihydroxyphenylacetic acid in n. accumbens and homovanillic acid level in striatum were elevated. It was suggested that the increased DA metabolism and the altered sensitivity of pre- and postsynaptic DA receptors are involved in the shaking behaviour of Qk mice.
Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool ... more Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool for studies of the molecular mechanisms of behavioral mutations. The 59-70 cM fragment of chromosome 13 containing the locus determining predisposition to freezing reaction (catalepsy) and the gene encoding 5-HT(1A) receptor were transferred from cataleptic CBA/Lac mice into the genome of catalepsy-resistant AKR/J mice. The impact of this fragment for the severity of catalepsy and expression of genes encoding tryptophane hydroxylase-2, serotonin transporter, and 5-HT(1A) receptor was studied. Half of mice of the resultant congenic AKR.CBA-D13Mit76 strain exhibited pronounced catalepsy, similarly to donor CBA animals. The expression of 5-HT(1A) receptor gene in the midbrain of AKR animals was significantly higher than in CBA. The level of 5-HT(1A) receptor mRNA in AKR.CBA-D13Mit76 animals was significantly higher than in the donor strain. Mice of parental AKR and CBA strains did not differ from each other and from AKR.CBA-D13Mit76 animals by the levels of tryptophane hydroxylase-2 and serotonin transporter genes mRNA. These data prove the location of catalepsy regulating gene in the distal fragment of chromosome 13. The recipient strain genome enhanced the expression of 5-HT(1A) receptor gene in the brain without modulating the expression of catalepsy gene.
Neuroscience and Behavioral Physiology, May 21, 2010
The tail suspension test (TST)-induced immobility and hyperthermia and acoustic startle response ... more The tail suspension test (TST)-induced immobility and hyperthermia and acoustic startle response were studied in 11 mouse inbred strains and in MAO A knockout Tg8 mice. Significant genotypic differences in TST-induced immobility rather than hyperthermia and the lack of correlation between the expression of immobility and hyperthermia were found. Positive genotypic correlation between immobility in the TST and Porsolt test as well as TST-induced immobility and acoustic startle response was shown. Genetic knockout of the main enzyme in serotonin and catecholamines metabolism, MAO A, decreased the startle response and TST-induced hyperthermia but had no effect on TST-induced immobility in Tg8 mice indicating the differences in neurochemical regulation of these TST-induced responses. The results support the validity of the TST as dry-land version of the forced swimming test and draw attention to TST-induced hyperthermia as an animal model of response to uncontrollable, inescapable stress demonstrated in humans.
Brain neurotransmitter serotonin is involved in the regulation of many physiological functions an... more Brain neurotransmitter serotonin is involved in the regulation of many physiological functions and types of behavior. The key enzyme of serotonin synthesis in the brain is tryptophan hydroxylase-2 (TPH-2). An association of the C1473G polymorphism in gene tph2 causing the replacement of Pro447 by Arg447 in TPH-2 molecule with enzyme activity in the mouse brain of 10 inbred strains was found. Association of the polymorphism with the TPH-2 activity in the brain of F2 hybrids between strains C57BL/6 and CC57BR was shown. The results indicate that the C1473G polymorphism in gene tph2 is the main factor determining the genetic defined variability of enzyme activity in the mouse brain.
Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically define... more 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 rat...
large enough to create conditions for massive activation of opiate-sensitive neurons in the zone ... more large enough to create conditions for massive activation of opiate-sensitive neurons in the zone of infusion. Despite this fact, selective analgesic (PGM, dorsomedial hypothalamus) and secondary reinforcing (VTR, nucleus accumbens-weaker) responses were obtained from different structures, evidence of the neuroanatomical heterogeneity of the trigger zones for these effects of morphine. LITERATURE CITED i.
The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavio... more The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition. Introduction of the receptive female induced sexual motivation and arousal in males, as evidenced by a prolonged time spent at the partition, unsuccessful attempts to step across it and a significant increase in plasma testosterone levels. Administration of 5-HT2A receptor antagonists ketanserin (1.0 and 2.0 mg/kg i.p.) or cyproheptadine (1.0 and 2.0 mg/kg i.p.) diminished the behavioral components and prevented the hormonal components of male sexual arousal. Administration of the selective 5-HT2C antagonist RS 102221 (1.0 and 2.0 mg/kg) considerably increased the time spent by males at the partition (p < 0.001) and, at the dose of 2.0 mg/kg, increased plasma testosterone levels (p < 0.01). Administration of ritanserin - a nonselective 5-HT2A/2C antagonist and, to a smaller degree, 5-HT2B antagonist - at doses of 0.1 and 0.5 mg/kg did not significantly influence male behavior and the activating effect of the presence of a female on the hypothalamo-pituitary-testicular system, although it increased resting testosterone levels (p < 0.05). The present findings suggest that 5-HT2A/5-HT2C receptors may be involved in the neural control of male sexual motivation and arousal, presumably by exerting reciprocal facilitative (5-HT2A) or suppressive (5-HT2C) influences.
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