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1.
Brain Behav Immun ; 118: 236-251, 2024 May.
Article in English | MEDLINE | ID: mdl-38431238

ABSTRACT

Dopamine dysregulation contributes to psychosis and cognitive deficits in schizophrenia that can be modelled in rodents by inducing maternal immune activation (MIA). The selective estrogen receptor (ER) modulator, raloxifene, can improve psychosis and cognition in men and women with schizophrenia. However, few studies have examined how raloxifene may exert its therapeutic effects in mammalian brain in both sexes during young adulthood (age relevant to most prevalent age at diagnosis). Here, we tested the extent to which raloxifene alters dopamine-related behaviours and brain transcripts in young adult rats, both control and MIA-exposed females and males. We found that raloxifene increased amphetamine (AMPH)-induced locomotor activity in female controls, and in contrast, raloxifene reduced AMPH-induced locomotor activity in male MIA offspring. We did not detect overt prepulse inhibition (PPI) deficits in female or male MIA offspring, yet raloxifene enhanced PPI in male MIA offspring. Whereas, raloxifene ameliorated increased startle responsivity in female MIA offspring. In the substantia nigra (SN), we found reduced Drd2s mRNA in raloxifene-treated female offspring with or without MIA, and increased Comt mRNA in placebo-treated male MIA offspring relative to placebo-treated controls. These data demonstrate an underlying dopamine dysregulation in MIA animals that can become more apparent with raloxifene treatment, and may involve selective alterations in dopamine receptor levels and dopamine breakdown processes in the SN. Our findings support sex-specific, differential behavioural responses to ER modulation in MIA compared to control offspring, with beneficial effects of raloxifene treatment on dopamine-related behaviours relevant to schizophrenia found in male MIA offspring only.


Subject(s)
Prenatal Exposure Delayed Effects , Raloxifene Hydrochloride , Humans , Young Adult , Rats , Female , Male , Animals , Adult , Raloxifene Hydrochloride/pharmacology , Dopamine/metabolism , Receptors, Estrogen , Selective Estrogen Receptor Modulators/pharmacology , Amphetamine/pharmacology , RNA, Messenger , Behavior, Animal/physiology , Poly I-C/pharmacology , Disease Models, Animal , Mammals/metabolism
2.
J Psychiatr Res ; 160: 204-209, 2023 04.
Article in English | MEDLINE | ID: mdl-36848775

ABSTRACT

The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls. Overall, GRIN2B mRNA was increased in both MDD with (+32%) and without psychosis (+40%) compared to controls along with a trend increase in GRIN1 mRNA in MDD overall (+24%). Furthermore, in MDD with psychosis there was a significant decrease in the GRIN2A:GRIN2B mRNA ratio (-19%). Collectively these results suggest dysfunction of the glutamatergic system at the gene expression level in the ACC in MDD. Increased GRIN2B mRNA in MDD, along with an altered GRIN2A:GRIN2B ratio in psychotic depression, suggests a disruption to NMDAR composition could be present in the ACC in MDD; this could lead to enhanced signalling via GluN2B-containing NMDARs and greater potential for glutamate excitotoxicity in the ACC in MDD. These results support future research into GluN2B antagonist-based treatments for MDD.


Subject(s)
Depressive Disorder, Major , Receptors, N-Methyl-D-Aspartate , Humans , Depression/psychology , Depressive Disorder, Major/genetics , Gene Expression , Gyrus Cinguli/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , RNA, Messenger/metabolism
3.
J Psychiatr Res ; 147: 203-211, 2022 03.
Article in English | MEDLINE | ID: mdl-35063739

ABSTRACT

Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls. In parallel, we tested for diagnostic differences in gene expression of relevant glial markers. We used total RNA isolated from the ACC from depression subjects with psychosis (n = 12) and without psychosis (n = 12), and non-psychiatric controls (n = 12) provided by the Stanley Medical Research Institute. In the ACC, KYAT1 (KAT I), AADAT (KAT II), and the astrocytic SLC1A2 (EAAT2) mRNAs, were significantly increased in depression, when combining those with and without psychosis. The increased KYAT1 and AADAT mRNA indicates that depression is associated with increased activation of the kynurenic acid arm of the kynurenine pathway in the ACC, suggesting an astrocyte response in depression. Considering EAAT2 and KATs increase astrocytic glutamate uptake and production of the NMDA receptor antagonist kynurenic acid, the observed increases of these markers may relate to changes in glutamatergic signalling in depression. These results suggest dysfunction of the kynurenine pathway in the brain in depression and point to the kynurenine pathway as a possible driver of glutamate dysfunction in depression.


Subject(s)
Depressive Disorder, Major , Psychotic Disorders , Astrocytes/metabolism , Depression , Depressive Disorder, Major/metabolism , Humans , Kynurenic Acid/metabolism , Kynurenine
4.
J Neuroimmunol ; 364: 577813, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35093761

ABSTRACT

Maternal immune activation (MIA) with poly(I:C) is a preclinical paradigm for schizophrenia and autism research. Methodological variations, including poly(I:C) molecular weight, contribute to inconsistencies in behavioural and molecular outcomes. We established in Wistar rats that 4 mg/kg high molecular weight (HMW)-poly(I:C) on GD19 induces maternal sickness, smaller litters and maternal elevations of serum cytokines, including increases in monocyte chemoattractants. In adult offspring, we found that males have higher serum cytokines than females, and MIA did not alter peripheral cytokines in either sex. Our study will contribute to the effective use of the MIA model to elucidate the neurobiology of neurodevelopmental disorders.


Subject(s)
Monocyte Chemoattractant Proteins/immunology , Neurodevelopmental Disorders/immunology , Poly I-C/toxicity , Pregnancy Complications, Infectious/immunology , Prenatal Exposure Delayed Effects/immunology , Animals , Cytokines/blood , Cytokines/immunology , Disease Models, Animal , Female , Male , Poly I-C/immunology , Pregnancy , Rats , Rats, Wistar
5.
Mol Brain ; 14(1): 96, 2021 06 26.
Article in English | MEDLINE | ID: mdl-34174930

ABSTRACT

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABAA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 - 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABAA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABAA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < - 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.


Subject(s)
Biomarkers/metabolism , Dopaminergic Neurons/pathology , GABAergic Neurons/pathology , Mesencephalon/pathology , Schizophrenia/pathology , Adult , Aged , Cohort Studies , Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Gene Expression Regulation , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Humans , Inflammation/genetics , Inflammation/pathology , Male , Middle Aged , Neuroinflammatory Diseases/genetics , Neuroinflammatory Diseases/pathology , Parvalbumins/metabolism , Protein Subunits/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Schizophrenia/genetics , Somatostatin/genetics , Somatostatin/metabolism , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Vesicular Inhibitory Amino Acid Transport Proteins/genetics , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism , Young Adult , gamma-Aminobutyric Acid
6.
Mol Psychiatry ; 26(3): 849-863, 2021 03.
Article in English | MEDLINE | ID: mdl-31168068

ABSTRACT

The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1ß, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02-0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1ß mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.


Subject(s)
Prenatal Exposure Delayed Effects , Schizophrenia , Animals , Behavior, Animal , Disease Models, Animal , Female , Mesencephalon , Mice , Microglia , Pregnancy , Schizophrenia/genetics
7.
Front Immunol ; 11: 2002, 2020.
Article in English | MEDLINE | ID: mdl-33133060

ABSTRACT

Increased cytokine and inflammatory-related transcripts are found in the ventral midbrain, a dopamine neuron-rich region associated with schizophrenia symptoms. In fact, half of schizophrenia cases can be defined as having a "high inflammatory/immune biotype." Recent studies implicate both complement and macrophages in cortical neuroinflammation in schizophrenia. Our aim was to determine whether measures of transcripts related to phagocytosis/macrophages (CD163, CD64, and FN1), or related to macrophage adhesion [intercellular adhesion molecule 1 (ICAM1)], or whether CD163+ cell density, as well as protein and/or gene expression of complement pathway activators (C1qA) and mediators (C3 or C4), are increased in the midbrain in schizophrenia, especially in those with a high inflammatory biotype. We investigated whether complement mRNA levels correlate with macrophage and/or microglia and/or astrocyte markers. We found CD163+ cells around blood vessels and in the parenchyma and increases in ICAM1, CD163, CD64, and FN1 mRNAs as well as increases in all complement transcripts in the midbrain of schizophrenia cases with high inflammation. While we found positive correlations between complement transcripts (C1qA and C3) and microglia or astrocyte markers across diagnostic and inflammatory subgroups, the only unique strong positive correlation was between CD163 and C1qA mRNAs in schizophrenia cases with high inflammation. Our study is the first to suggest that more circulating macrophages may be attracted to the midbrain in schizophrenia, and that increased macrophages are linked to increased complement pathway activation in tissue and may contribute to dopamine dysregulation in schizophrenia. Single-cell transcriptomic studies and mechanistic preclinical studies are required to test these possibilities.


Subject(s)
Complement C1q/metabolism , Complement C3/metabolism , Macrophages/physiology , Mesencephalon/physiology , Schizophrenia/immunology , Adult , Aged , Cohort Studies , Complement C1q/genetics , Complement C3/genetics , Complement C4/genetics , Complement C4/metabolism , Female , Humans , Male , Middle Aged , Up-Regulation , Young Adult
8.
Psychiatry Res ; 280: 112503, 2019 10.
Article in English | MEDLINE | ID: mdl-31446215

ABSTRACT

Anxiety and depressive disorders are more prevalent in hypogonadal men. Low testosterone levels are associated with greater negative symptoms and impaired cognition in men with schizophrenia. Thus, androgens may contribute to brain pathophysiology in psychiatric disorders. We investigated androgen-related mRNAs in post-mortem dorsolateral prefrontal cortex of psychiatric disorders. We also assessed androgen receptor (AR) CAG trinucleotide repeat length, a functional AR gene variant associated with AR gene expression, receptor activity, and circulating testosterone. AR CAG repeat length was determined from genomic DNA and AR and 5α-reductase mRNAs measured using quantitative PCR in schizophrenia, bipolar disorder and control cases [n = 35/group; Stanley Medical Research Institute (SMRI) Array collection]. Layer-specific AR gene expression was determined using in situ hybridisation in schizophrenia, bipolar disorder, major depressive disorder and control cases (n = 15/group; SMRI Neuropathology Consortium). AR mRNA was increased in bipolar disorder, but was unchanged in schizophrenia, relative to controls. AR and 5α-reductase mRNAs were significantly positively correlated in bipolar disorder. AR CAG repeat length was significantly shorter in bipolar disorder relative to schizophrenia. AR mRNA expression was highest in cortical layers IV and V, but no layer-specific diagnostic differences were detected. Together, our results suggest enhanced cortical androgen action in people with bipolar disorder.


Subject(s)
Bipolar Disorder/metabolism , Depressive Disorder, Major/metabolism , Prefrontal Cortex/metabolism , Receptors, Androgen/biosynthesis , Schizophrenia/metabolism , Adult , Aged , Androgens/biosynthesis , Androgens/genetics , Bipolar Disorder/genetics , Bipolar Disorder/psychology , Case-Control Studies , Depressive Disorder, Major/genetics , Depressive Disorder, Major/psychology , Female , Humans , Male , Middle Aged , Receptors, Androgen/genetics , Schizophrenia/genetics , Schizophrenic Psychology , Testosterone/metabolism
9.
Mol Neuropsychiatry ; 5(1): 28-41, 2019 Mar.
Article in English | MEDLINE | ID: mdl-31019916

ABSTRACT

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene's effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

10.
Handb Clin Neurol ; 150: 221-235, 2018.
Article in English | MEDLINE | ID: mdl-29496143

ABSTRACT

Schizophrenia is a disabling disease impacting millions of people around the world, for which there is no known cure. Current antipsychotic treatments for schizophrenia mainly target psychotic symptoms, do little to ameliorate social or cognitive deficits, have side-effects that cause weight gain, and diabetes and 30% of people do not respond. Thus, better therapeutics for schizophrenia aimed at the route biologic changes are needed and discovering the underlying neurobiology is key to this quest. Postmortem brain studies provide the most direct and detailed way to determine the pathophysiology of schizophrenia. This chapter outlines steps that can be taken to ensure the best-quality molecular data from postmortem brain tissue are obtained. In this chapter, we also discuss targeted and high-throughput methods for examining gene and protein expression and some of the strengths and limitations of each method. We briefly consider why gene and protein expression changes may not always concur within brain tissue. We conclude that postmortem brain research that investigates gene and protein expression in well-characterized and matched brain cohorts provides an important foundation to be considered when interpreting data obtained from studies of living schizophrenia patients.


Subject(s)
Biomedical Research/methods , Brain/pathology , Molecular Medicine , Schizophrenia/genetics , Schizophrenia/pathology , Humans , Neurobiology
12.
Schizophr Res ; 168(3): 661-70, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26088421

ABSTRACT

Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Frontal Lobe/growth & development , Frontal Lobe/metabolism , Interneurons/metabolism , Receptor, trkB/metabolism , Testosterone/metabolism , Animals , Hormones/administration & dosage , Macaca mulatta , Male , Nerve Growth Factors/metabolism , Orchiectomy , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Somatostatin/metabolism , Species Specificity , Testosterone/administration & dosage
13.
BMC Neurosci ; 16: 4, 2015 Feb 18.
Article in English | MEDLINE | ID: mdl-25886766

ABSTRACT

BACKGROUND: Testosterone attenuates postnatal hippocampal neurogenesis in adolescent male rhesus macaques through altering neuronal survival. While brain-derived neurotropic factor (BDNF)/ tyrosine kinase receptor B (TrkB) are critical in regulating neuronal survival, it is not known if the molecular mechanism underlying testosterone's action on postnatal neurogenesis involves changes in BDNF/TrkB levels. First, (1) we sought to localize the site of synthesis of the full length and truncated TrkB receptor in the neurogenic regions of the adolescent rhesus macaque hippocampus. Next, (2) we asked if gonadectomy or sex hormone replacement altered hippocampal BDNF and TrkB expression level in mammalian hippocampus (rhesus macaque and Sprague Dawley rat), and (3) if the relationship between BDNF/TrkB expression was altered depending on the sex steroid environment. RESULTS: We find that truncated TrkB mRNA+ cells are highly abundant in the proliferative subgranular zone (SGZ) of the primate hippocampus; in addition, there are scant and scattered full length TrkB mRNA+ cells in this region. Gonadectomy or sex steroid replacement did not alter BDNF or TrkB mRNA levels in young adult male rat or rhesus macaque hippocampus. In the monkey and rat, we find a positive correlation with cell proliferation and TrkB-TK+ mRNA expression, and this positive relationship was found only when sex steroids were present. CONCLUSIONS: We suggest that testosterone does not down-regulate neurogenesis at adolescence via overall changes in BDNF or TrkB expression. However, BDNF/TrkB mRNA appears to have a greater link to cell proliferation in the presence of circulating testosterone.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/growth & development , Hippocampus/metabolism , RNA, Messenger/metabolism , Receptor, trkB/metabolism , Testosterone/metabolism , Animals , Bromodeoxyuridine , Hippocampus/drug effects , Hormone Replacement Therapy , Immunohistochemistry , In Situ Hybridization , Ki-67 Antigen/metabolism , Macaca mulatta , Male , Neurogenesis/drug effects , Neurogenesis/physiology , Orchiectomy , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Species Specificity , Stem Cell Niche/drug effects , Stem Cell Niche/physiology , Testosterone/administration & dosage
14.
Horm Behav ; 70: 73-84, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25747465

ABSTRACT

Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and amphetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion. Male Sprague-Dawley rats at postnatal day 45 were gonadectomised (G) or sham-operated (S) prior to the typical adolescent testosterone increase. Gonadectomised rats were either given testosterone replacement (T) or blank implants (B) for six weeks and sham-operated (i.e. intact or endogenous testosterone group) were given blank implants. Subgroups of sham-operated, gonadectomised and gonadectomised/testosterone-replaced rats were treated with raloxifene (R, 5mg/kg) or vehicle (V), daily for the final four weeks. There were six groups (SBV, GBV, GTV, SBR, GBR, GTR). Saline and amphetamine-induced (1.25mg/kg) locomotion in the open field was measured at PND85. Gonadectomy increased amphetamine-induced locomotion compared to rats with endogenous or with exogenous testosterone. Raloxifene increased amphetamine-induced locomotion in rats with either endogenous or exogenous testosterone. Amphetamine-induced locomotion was negatively correlated with testosterone and this relationship was abolished by raloxifene. Lack of testosterone during adolescence potentiates and testosterone exposure during adolescence attenuates amphetamine-induced locomotion. Treatment with raloxifene appears to potentiate amphetamine-induced locomotion and to have an opposite effect to that of testosterone in male rats.


Subject(s)
Amphetamine/pharmacology , Central Nervous System Stimulants/pharmacology , Motor Activity/drug effects , Raloxifene Hydrochloride/antagonists & inhibitors , Selective Estrogen Receptor Modulators/pharmacology , Testosterone/pharmacology , Animals , Dopamine/metabolism , Drug Synergism , Male , Neostriatum/drug effects , Neostriatum/metabolism , Orchiectomy , Organ Size/drug effects , Raloxifene Hydrochloride/pharmacology , Rats , Rats, Sprague-Dawley , Seminal Vesicles/anatomy & histology , Seminal Vesicles/drug effects
15.
PLoS One ; 9(3): e91151, 2014.
Article in English | MEDLINE | ID: mdl-24618531

ABSTRACT

Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17ß-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence.


Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Signal Transduction/drug effects , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Testosterone/pharmacology , Animals , Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Gene Expression Regulation , Gonadal Steroid Hormones/blood , Male , Orchiectomy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Receptors, Dopamine/genetics , Receptors, Dopamine/metabolism , Synaptic Transmission/drug effects
16.
Psychopharmacology (Berl) ; 231(8): 1581-99, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24481565

ABSTRACT

RATIONALE: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. OBJECTIVES: In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. RESULTS AND CONCLUSIONS: Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness.


Subject(s)
Brain/growth & development , Brain/physiopathology , Dopamine/metabolism , Gonadal Steroid Hormones/metabolism , Stress, Psychological/physiopathology , Synaptic Transmission/physiology , Adolescent , Animals , Humans
17.
BMC Neurosci ; 13: 95, 2012 Aug 06.
Article in English | MEDLINE | ID: mdl-22867132

ABSTRACT

BACKGROUND: Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17ß-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5α-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels. RESULTS: We find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERß mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. CONCLUSIONS: We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology.


Subject(s)
Androgens/pharmacology , Gene Expression Regulation/drug effects , RNA, Messenger/metabolism , Receptors, Androgen/genetics , Receptors, Estrogen/genetics , Substantia Nigra/metabolism , Tyrosine 3-Monooxygenase/genetics , Androgens/blood , Animals , Catechol O-Methyltransferase/metabolism , Chromatography, Liquid , Dihydrotestosterone/blood , Dihydrotestosterone/pharmacology , Estradiol/blood , Estradiol/pharmacology , Male , Monoamine Oxidase/metabolism , Orchiectomy , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Substantia Nigra/drug effects , Tandem Mass Spectrometry , Testosterone/blood , Testosterone/pharmacology , Tyrosine 3-Monooxygenase/metabolism
18.
J Neurosci ; 25(7): 1682-90, 2005 Feb 16.
Article in English | MEDLINE | ID: mdl-15716404

ABSTRACT

Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo, and cultured embryonic DRG neurons require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-kappaB (NF-kappaB) for survival. In contrast, adult DRG neurons survive permanent axotomy in vivo and in defined culture media devoid of exogenous neurotrophic factors in vitro. Peripheral axotomy in adult rats induces local accumulation of the cytokine tumor necrosis factor alpha (TNFalpha), a potent activator of NF-kappaB activity. We tested the hypothesis that activation of NF-kappaB stimulated by endogenous TNFalpha was required for survival of axotomized adult sensory neurons. Peripheral axotomy of lumbar DRG neurons by sciatic nerve crush induced a very rapid (within 2 h) and significant elevation in NF-kappaB-binding activity. This phenomenon was mimicked in cultured neurons in which there was substantial NF-kappaB nuclear translocation and a significant rise in NF-kappaB DNA-binding activity after plating. Inhibitors of NF-kappaB (SN50 or NF-kappaB decoy DNA) resulted in necrotic cell death of medium to large neurons (> or =40 microm) within 24 h (60 and 75%, respectively), whereas inhibition of p38 and mitogen-activated protein/extracellular signal-regulated kinase did not effect survival. ELISA revealed that these cultures contained TNFalpha, and exposure to an anti-TNFalpha antibody inhibited NF-kappaB DNA-binding activity by approximately 35% and killed approximately 40% of medium to large neurons within 24 h. The results show for the first time that cytokine-mediated activation of NF-kappaB is a component of the signaling pathway responsible for maintenance of adult sensory neuron survival after axon damage.


Subject(s)
NF-kappa B/metabolism , Neurons, Afferent/drug effects , Tumor Necrosis Factor-alpha/physiology , Animals , Autocrine Communication , Axotomy , Cell Survival , Cells, Cultured/cytology , Cells, Cultured/drug effects , DNA/metabolism , Ganglia, Spinal/cytology , I-kappa B Proteins/genetics , MAP Kinase Signaling System , Male , NF-kappa B/antagonists & inhibitors , Nerve Crush , Nerve Degeneration , Neurons, Afferent/cytology , Oligodeoxyribonucleotides, Antisense/pharmacology , Paracrine Communication , Peptides/pharmacology , Protein Binding , Protein Subunits , Rats , Rats, Wistar , Sciatic Nerve/injuries , Transcription, Genetic/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
19.
Ann N Y Acad Sci ; 1010: 95-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15033701

ABSTRACT

Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition of this activation for the ERK and p38 groups prevents nerve damage, and agents that improve neuronal function in diabetic rats-antioxidants and aldose reductase inhibitors-also inhibit activation of ERK and p38 in dorsal root ganglia (DRG). However, these same treatments consistently increase activation of JNK. Thus, in DRG from rats with streptozotocin (STZ)-induced diabetes of 12-week duration, the p54/56 isoforms of JNK were activated by 2.75 compared to controls (P <.05). In DRG from diabetic rats treated with a gamma-linolenic acid and alpha-lipoic acid diester (GLA/LA), the activity of the p54/56 isoform was 3.75 that of controls and the p46 isoform was also increased to 1.75 that of controls (both P <.05 compared to both controls and untreated diabetics). We therefore tested the hypothesis that JNK activation is protective. Exposure of rats to diabetes increased activation of JNK in DRG, but treatment with GLA/LA increased this effect (P <.05). Specific inhibition of JNK in primary cultures of DRG neurons using a peptide inhibitor of JNK (JNKi1, 159-600-R100, 7.5 micro M, Alexis Biochemicals) increased the release of LDH and reduced MTT staining; both findings indicate an increase in neuronal damage. Taken together these findings indicate that multiple isoforms of JNK were activated in sensory neurons of diabetic rats, probably by a combination of raised glucose and oxidative stress, and that this activation of JNK serves to protect the neurons from damage.


Subject(s)
Diabetes Mellitus, Experimental/pathology , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinase Kinases/metabolism , Neurons, Afferent/physiology , Oxidative Stress/physiology , Animals , Cell Culture Techniques , Cell Survival , Ganglia, Spinal/pathology , MAP Kinase Kinase 4 , Male , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Rats , Rats, Wistar
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