The prevalence of some mental illnesses, including major depression, anxiety-, trauma-, and stres... more The prevalence of some mental illnesses, including major depression, anxiety-, trauma-, and stress-related disorders , some substance use disorders, and later onset of schizophrenia, is higher in women than men. While the higher prevalence in women could simply be explained by socioeconomic determinants, such as income, social status, or cultural background, extensive studies show sex differences in biological, pharmacokinetic, and pharmacological factors contribute to females' vulnerability to these mental illnesses. In this review, we focus on es-trogens, chronic stress, and neurotoxicity from behavioral, pharmacological, biological, and molecular perspectives to delineate the sex differences in these mental illnesses. Particularly, we investigate a possible role of mitochondrial function, including biosynthesis, bioenergetics, and signaling, on mediating the sex differences in psychiatric disorders.
Social confrontation is a form of social interaction in animals where two conspecific individuals... more Social confrontation is a form of social interaction in animals where two conspecific individuals confront each other in dispute over territory, during the formation of hierarchies, and during breeding seasons. Typically, a social confrontation involves a prevailing individual and a yielding individual. The prevailing individual often exhibits aggressive postures and launches attacks, whereas the yielding individual often adopts postures of defeat. The yielding or defeated animals experience a phenomenon known as social defeat stress, in which they show exaggerated stress as well as autonomic and endocrine responses that cause impairment of both the brain and body. In laboratorysettings, one can reliably generate social defeat stress by allowing a naïve (or already defeated) animal to intrude into a home cage in which its resident has already established a territory or is nursing. This resident-intruder paradigm has been widely used in both males and females to study mechanisms in the brain that underlie the stress responses. Stress has profound effects on drug reward for cocaine, methamphetamine, alcohol, and opioids. Particularly, previous experiences with social defeat can exaggerate subsequent addiction-like behaviors. The extent of these addiction-like behaviors depends on the intensity, duration, frequency, and intermittency of the confrontation episodes. This chapter describes four types of social defeat stress: acute, repeated, intermittent, and chronic. Specifically, it focuses on social defeat stress models used in laboratories to study individual, sex, and animal strain differences in addiction-like behaviors.
—Substance use disorders (SUD) often co-occur with other mental disorders such as major depressio... more —Substance use disorders (SUD) often co-occur with other mental disorders such as major depression (MD). Our previous findings revealed sex-dependent changes in extracellular levels of glutamate (Glu) and glu-tamine (Gln) in the nucleus accumbens (NAc) in Long–Evans rats that were exposed to 21 days of chronic social defeat stress (CSDS), which models MD. The current study investigated the role of a Gln transporter called sodium-coupled neutral amino acid transporter subtype 1/2 (SNAT 1/2), phosphate-activated glutaminase (PAG), and astrocytic glutamate transporter-1 (GLT-1) on CSDS animals exposed to cocaine. Before cocaine exposure , CSDS males already showed decreased levels of SNAT 1/2 in the NAc and prefrontal cortex (PFC) compared to non-CSDS controls. The reduction in SNAT 1/2 levels was associated with an increase in Gln localization in the mitochondrial outer membrane in accumbal glutamatergic nerve terminals projecting from the PFC. CSDS females showed increased GLT-1 levels in the NAc and PFC compared to non-CSDS controls. Both acute and repeated cocaine exposure attenuated locomotor responses in CSDS males but increased those in CSDS females. Cocaine reduced SNAT 1/2 levels in the NAc but increased them in the PFC in CSDS males. Additionally, both PAG and GLT-1 levels were increased in the PFC in CSDS males. On the other hand, cocaine reduced SNAT 1/2 and GLT-1 levels in the NAc and PFC in CSDS females. Our results show that CSDS altered locomotor responses upon cocaine exposure in a sex-dependent manner that may be mediated by molecules associated with the Glu-Gln transfer.
Background: Women are twice as likely as men to develop major depression. The brain mechanisms un... more Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate– glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression.
Biochimica et Biophysica Acta (BBA) - General Subjects, 1999
We have found that the gel filtration fraction of porcine heart extract clearly promoted the surv... more We have found that the gel filtration fraction of porcine heart extract clearly promoted the survival of NIH3T3 fibroblast cells in the serum-free medium condition. A structural analysis showed that the active fraction contained a novel peptide, porcine Cox17p (p-Cox17p), which was recently reported by Chen et al. as dopuin (Z. W. Chen et al., Eur. J. Biochem. 249 (1997) 518-522). Porcine Cox17p/dopuin possesses high sequence homology to the product of human COX17 gene (h-Cox17p). Although Cox17p has been implied to be involved in copper recruitment to mitochondria and in the functional assembly of cytochrome oxidase in yeast, its role in mammalian cells is unknown. In this study, we chemically synthesized p-Cox17p to investigate its biological effects. Refolding experiments of synthesized linear p-Cox17p revealed the existence of mostly one pattern of three intrachain disulfide bridges similar to that of native p-Cox17p, because the main oxidized p-Cox17p was completely co-eluted with the natural product. The addition of heavy metal ions such as copper, zinc and cadmium significantly inhibited the formation of the oxidized form, suggesting that reduced p-Cox17p may interact directly with these metal ions. The reduced and oxidized forms of p-Cox17p were also confirmed to promote the survival of NIH3T3 cells in serum-free medium as observed with the natural product, indicating that Cox17p may be a bioactive peptide.
Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress... more Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress can induce depression in some vulnerable individuals, while others are resistant to depressive-like symptoms after equivalent levels of chronic stress. In female rats, individual differences in saccharin intake during chronic social defeat stress may predict subsequent cocaine self-administration, and may be attributed to alterations in mesolimbic dopamine activity. Female rats were exposed to 21 days of chronic social defeat stress, during which they were evaluated for their anhedonia-like responses in the form of saccharin intake. After chronic social defeat stress, the rats were tested for behavioral cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h "binge." A separate group of animals underwent in vivo microdialysis of the nucleus accumbens (NAc) shell to assess dopamine (DA) in response to acute cocaine challenge. Cluster analysis revealed...
The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of cons... more The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of considerable interest. Intermittent social defeat stress induces both locomotor and dopaminergic cross-sensitization to cocaine, as well as escalated cocaine self-administration. The current study examines the role of corticotropin releasing factor receptor subtypes 1 and 2 (CRFR1, CRFR2) within the ventral tegmental area (VTA) during social defeat stress. This study investigated whether injecting either a CRFR1 or CRFR2 antagonist directly into the VTA before each social defeat would prevent the development of later (1) locomotor sensitization, (2) dopaminergic sensitization, and (3) escalated cocaine self-administration in rats. CRFR1 antagonist CP376395 (50 or 500 ng/side), CRFR2 antagonist Astressin2-B (100 or 1000 ng/side), or vehicle (aCSF) was microinjected into the VTA 20 min before social defeat stress (or handling) on days 1, 4, 7, and 10. Ten days later, rats were injected with cocaine (10 mg/kg, i.p.) and assessed for either locomotor sensitization, measured by walking activity, or dopaminergic sensitization, measured by extracellular dopamine (DA) in the nucleus accumbens shell (NAcSh) through in vivo microdialysis. Locomotor sensitization testing was followed by intravenous cocaine self-administration. Intra-VTA antagonism of CRFR1, but not CRFR2, inhibited the induction of locomotor cross-sensitization to cocaine, whereas both prevented dopaminergic cross-sensitization and escalated cocaine self-administration during a 24 h "binge." This may suggest dissociation between locomotor sensitization and cocaine taking. These data also suggest that interactions between CRF and VTA DA neurons projecting to the NAcSh are essential for the development of dopaminergic cross-sensitization to cocaine.
The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter fo... more The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of ...
The prevalence of some mental illnesses, including major depression, anxiety-, trauma-, and stres... more The prevalence of some mental illnesses, including major depression, anxiety-, trauma-, and stress-related disorders , some substance use disorders, and later onset of schizophrenia, is higher in women than men. While the higher prevalence in women could simply be explained by socioeconomic determinants, such as income, social status, or cultural background, extensive studies show sex differences in biological, pharmacokinetic, and pharmacological factors contribute to females' vulnerability to these mental illnesses. In this review, we focus on es-trogens, chronic stress, and neurotoxicity from behavioral, pharmacological, biological, and molecular perspectives to delineate the sex differences in these mental illnesses. Particularly, we investigate a possible role of mitochondrial function, including biosynthesis, bioenergetics, and signaling, on mediating the sex differences in psychiatric disorders.
Social confrontation is a form of social interaction in animals where two conspecific individuals... more Social confrontation is a form of social interaction in animals where two conspecific individuals confront each other in dispute over territory, during the formation of hierarchies, and during breeding seasons. Typically, a social confrontation involves a prevailing individual and a yielding individual. The prevailing individual often exhibits aggressive postures and launches attacks, whereas the yielding individual often adopts postures of defeat. The yielding or defeated animals experience a phenomenon known as social defeat stress, in which they show exaggerated stress as well as autonomic and endocrine responses that cause impairment of both the brain and body. In laboratorysettings, one can reliably generate social defeat stress by allowing a naïve (or already defeated) animal to intrude into a home cage in which its resident has already established a territory or is nursing. This resident-intruder paradigm has been widely used in both males and females to study mechanisms in the brain that underlie the stress responses. Stress has profound effects on drug reward for cocaine, methamphetamine, alcohol, and opioids. Particularly, previous experiences with social defeat can exaggerate subsequent addiction-like behaviors. The extent of these addiction-like behaviors depends on the intensity, duration, frequency, and intermittency of the confrontation episodes. This chapter describes four types of social defeat stress: acute, repeated, intermittent, and chronic. Specifically, it focuses on social defeat stress models used in laboratories to study individual, sex, and animal strain differences in addiction-like behaviors.
—Substance use disorders (SUD) often co-occur with other mental disorders such as major depressio... more —Substance use disorders (SUD) often co-occur with other mental disorders such as major depression (MD). Our previous findings revealed sex-dependent changes in extracellular levels of glutamate (Glu) and glu-tamine (Gln) in the nucleus accumbens (NAc) in Long–Evans rats that were exposed to 21 days of chronic social defeat stress (CSDS), which models MD. The current study investigated the role of a Gln transporter called sodium-coupled neutral amino acid transporter subtype 1/2 (SNAT 1/2), phosphate-activated glutaminase (PAG), and astrocytic glutamate transporter-1 (GLT-1) on CSDS animals exposed to cocaine. Before cocaine exposure , CSDS males already showed decreased levels of SNAT 1/2 in the NAc and prefrontal cortex (PFC) compared to non-CSDS controls. The reduction in SNAT 1/2 levels was associated with an increase in Gln localization in the mitochondrial outer membrane in accumbal glutamatergic nerve terminals projecting from the PFC. CSDS females showed increased GLT-1 levels in the NAc and PFC compared to non-CSDS controls. Both acute and repeated cocaine exposure attenuated locomotor responses in CSDS males but increased those in CSDS females. Cocaine reduced SNAT 1/2 levels in the NAc but increased them in the PFC in CSDS males. Additionally, both PAG and GLT-1 levels were increased in the PFC in CSDS males. On the other hand, cocaine reduced SNAT 1/2 and GLT-1 levels in the NAc and PFC in CSDS females. Our results show that CSDS altered locomotor responses upon cocaine exposure in a sex-dependent manner that may be mediated by molecules associated with the Glu-Gln transfer.
Background: Women are twice as likely as men to develop major depression. The brain mechanisms un... more Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate– glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression.
Biochimica et Biophysica Acta (BBA) - General Subjects, 1999
We have found that the gel filtration fraction of porcine heart extract clearly promoted the surv... more We have found that the gel filtration fraction of porcine heart extract clearly promoted the survival of NIH3T3 fibroblast cells in the serum-free medium condition. A structural analysis showed that the active fraction contained a novel peptide, porcine Cox17p (p-Cox17p), which was recently reported by Chen et al. as dopuin (Z. W. Chen et al., Eur. J. Biochem. 249 (1997) 518-522). Porcine Cox17p/dopuin possesses high sequence homology to the product of human COX17 gene (h-Cox17p). Although Cox17p has been implied to be involved in copper recruitment to mitochondria and in the functional assembly of cytochrome oxidase in yeast, its role in mammalian cells is unknown. In this study, we chemically synthesized p-Cox17p to investigate its biological effects. Refolding experiments of synthesized linear p-Cox17p revealed the existence of mostly one pattern of three intrachain disulfide bridges similar to that of native p-Cox17p, because the main oxidized p-Cox17p was completely co-eluted with the natural product. The addition of heavy metal ions such as copper, zinc and cadmium significantly inhibited the formation of the oxidized form, suggesting that reduced p-Cox17p may interact directly with these metal ions. The reduced and oxidized forms of p-Cox17p were also confirmed to promote the survival of NIH3T3 cells in serum-free medium as observed with the natural product, indicating that Cox17p may be a bioactive peptide.
Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress... more Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress can induce depression in some vulnerable individuals, while others are resistant to depressive-like symptoms after equivalent levels of chronic stress. In female rats, individual differences in saccharin intake during chronic social defeat stress may predict subsequent cocaine self-administration, and may be attributed to alterations in mesolimbic dopamine activity. Female rats were exposed to 21 days of chronic social defeat stress, during which they were evaluated for their anhedonia-like responses in the form of saccharin intake. After chronic social defeat stress, the rats were tested for behavioral cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h "binge." A separate group of animals underwent in vivo microdialysis of the nucleus accumbens (NAc) shell to assess dopamine (DA) in response to acute cocaine challenge. Cluster analysis revealed...
The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of cons... more The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of considerable interest. Intermittent social defeat stress induces both locomotor and dopaminergic cross-sensitization to cocaine, as well as escalated cocaine self-administration. The current study examines the role of corticotropin releasing factor receptor subtypes 1 and 2 (CRFR1, CRFR2) within the ventral tegmental area (VTA) during social defeat stress. This study investigated whether injecting either a CRFR1 or CRFR2 antagonist directly into the VTA before each social defeat would prevent the development of later (1) locomotor sensitization, (2) dopaminergic sensitization, and (3) escalated cocaine self-administration in rats. CRFR1 antagonist CP376395 (50 or 500 ng/side), CRFR2 antagonist Astressin2-B (100 or 1000 ng/side), or vehicle (aCSF) was microinjected into the VTA 20 min before social defeat stress (or handling) on days 1, 4, 7, and 10. Ten days later, rats were injected with cocaine (10 mg/kg, i.p.) and assessed for either locomotor sensitization, measured by walking activity, or dopaminergic sensitization, measured by extracellular dopamine (DA) in the nucleus accumbens shell (NAcSh) through in vivo microdialysis. Locomotor sensitization testing was followed by intravenous cocaine self-administration. Intra-VTA antagonism of CRFR1, but not CRFR2, inhibited the induction of locomotor cross-sensitization to cocaine, whereas both prevented dopaminergic cross-sensitization and escalated cocaine self-administration during a 24 h "binge." This may suggest dissociation between locomotor sensitization and cocaine taking. These data also suggest that interactions between CRF and VTA DA neurons projecting to the NAcSh are essential for the development of dopaminergic cross-sensitization to cocaine.
The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter fo... more The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of ...
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Papers by Akiko Shimamoto
defeated) animal to intrude into a home cage in which its resident has already established a territory or is nursing. This resident-intruder paradigm has been widely used in both males and females to study mechanisms in the brain that underlie the stress responses.
Stress has profound effects on drug reward for cocaine, methamphetamine, alcohol, and opioids. Particularly, previous experiences with social defeat can exaggerate subsequent addiction-like behaviors. The extent of these addiction-like behaviors depends on the intensity, duration, frequency, and intermittency of the confrontation
episodes. This chapter describes four types of social defeat stress: acute, repeated, intermittent, and chronic. Specifically, it focuses on social defeat stress models used in laboratories to study individual, sex, and animal strain differences in addiction-like behaviors.
defeated) animal to intrude into a home cage in which its resident has already established a territory or is nursing. This resident-intruder paradigm has been widely used in both males and females to study mechanisms in the brain that underlie the stress responses.
Stress has profound effects on drug reward for cocaine, methamphetamine, alcohol, and opioids. Particularly, previous experiences with social defeat can exaggerate subsequent addiction-like behaviors. The extent of these addiction-like behaviors depends on the intensity, duration, frequency, and intermittency of the confrontation
episodes. This chapter describes four types of social defeat stress: acute, repeated, intermittent, and chronic. Specifically, it focuses on social defeat stress models used in laboratories to study individual, sex, and animal strain differences in addiction-like behaviors.