The brain-gut axis allows bidirectional communication between the central nervous system (CNS) an... more The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scienti c Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These ndings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the eld of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro-and prebiotics.
Alongside other risk factors for the development of type 2 diabetes, the presence of severe menta... more Alongside other risk factors for the development of type 2 diabetes, the presence of severe mental illness is often overlooked. A person with schizophrenia has a two to four times greater risk of developing diabetes than the general population and the prevalence of type 2 diabetes is between 15 and 18% in the schizophrenia population. A full understanding of this issue is vital.
To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants wi... more To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction i...
Journal of psychopharmacology (Oxford, England), 1995
Resistance to antidepressant treatment is a controversial field and therapy resistance has receiv... more Resistance to antidepressant treatment is a controversial field and therapy resistance has received a wide range of definitions. The field has suffered from a lack of consensus on how to classify treatment resistance and from the related failure to standardise clinical criteria in trials of new therapeutic approaches. A significant proportion of tricyclic antidepressant (TCA)-resistant depression results from the failure to sustain an adequate course of therapy. This can be due to either inadequate prescribing or the poor tolerability of TCAs. The majority of cases of treatment resistance, however, involve antidepressant therapy at a dose and duration that would normally be expected to be effective. In these cases, therapy may fail for many reasons. Refractory depression may occur in patients with medical conditions such as subclinical hypothyroidism, stroke and closed head injuries. Patients with alcoholism may prove refractory to treatment, as may those receiving certain medicatio...
Alongside other risk factors for the development of type 2 diabetes, the presence of severe menta... more Alongside other risk factors for the development of type 2 diabetes, the presence of severe mental illness is often overlooked. A person with schizophrenia has a two to four times greater risk of developing diabetes than the general population and the prevalence of type 2 diabetes is between 15 and 18% in the schizophrenia population. A full understanding of this issue is vital.
Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TL... more Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24 h. Cell supernatants were analysed using a multiplex enzyme-linked immunosorbent assay approach to measure IL-1β, IL-6, IL-8 and tumour necrosis factor-α (TNFα). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1β, IL-6, IL-8 and TNFα) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1β, IL-6 and TNFα following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1β for both disorders coupled with TNFα increases for bipolar patients were observed. TLR8-induced increases in IL-1β for both disorders as well as IL-6 and TNFα increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNFα levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders.
International Journal of Neuropsychopharmacology, 2013
The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhance... more The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ≥ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ≤ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2010
BACKGROUND A growing body of data implicates increased life stresses with the initiation, persist... more BACKGROUND A growing body of data implicates increased life stresses with the initiation, persistence and severity of symptoms associated with functional gut disorders such as irritable bowel syndrome (IBS). Activation of central and peripheral corticotropin-releasing factor (CRF) receptors is key to stress-induced changes in gastrointestinal (GI) function. METHODS This study utilised immunofluorescent and Western blotting techniques to investigate colonic expression of CRF receptors in stress-sensitive Wistar Kyoto (WKY) and control Sprague Dawley (SD) rats. KEY RESULTS No intra-strain differences were observed in the numbers of colonic CRFR1 and CRFR2 positive cells. Protein expression of functional CRFR1 was found to be comparable in control proximal and distal colon samples. Sham levels of CRFR1 were also similar in the proximal colon but significantly higher in WKY distal colons (SD: 0.38 +/- 0.14, WKY: 2.06 +/- 0.52, P < 0.01). Control levels of functional CRFR2 were simila...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2011
Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and dist... more Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice....
Anxiety and depression are devastating mental illnesses that are a significant public health conc... more Anxiety and depression are devastating mental illnesses that are a significant public health concern. Selective serotonin-reuptake inhibitors are the first-line treatment strategy for these disorders, which despite being a significant advantage over older treatments, are hampered by a limited efficacy in a significant subset of patients, delayed onset of action and side effects that affect compliance. Thus, there is much impetus to develop novel therapeutic strategies. However, this goal can only be rationally realised with a better understanding of the molecular pathophysiology of these disorders. MicroRNAs (miRNAs) are a newly discovered class of gene-expression regulators that may represent a novel class of therapeutic targets to treat a variety of disorders including psychiatric diseases. miRNAs are heavily involved in regulating many physiological processes including those fundamental to the functioning of the central nervous system. Evidence collected to date has already demon...
Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-... more Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB.
The brain-gut axis allows bidirectional communication between the central nervous system (CNS) an... more The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scienti c Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These ndings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the eld of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro-and prebiotics.
Alongside other risk factors for the development of type 2 diabetes, the presence of severe menta... more Alongside other risk factors for the development of type 2 diabetes, the presence of severe mental illness is often overlooked. A person with schizophrenia has a two to four times greater risk of developing diabetes than the general population and the prevalence of type 2 diabetes is between 15 and 18% in the schizophrenia population. A full understanding of this issue is vital.
To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants wi... more To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction i...
Journal of psychopharmacology (Oxford, England), 1995
Resistance to antidepressant treatment is a controversial field and therapy resistance has receiv... more Resistance to antidepressant treatment is a controversial field and therapy resistance has received a wide range of definitions. The field has suffered from a lack of consensus on how to classify treatment resistance and from the related failure to standardise clinical criteria in trials of new therapeutic approaches. A significant proportion of tricyclic antidepressant (TCA)-resistant depression results from the failure to sustain an adequate course of therapy. This can be due to either inadequate prescribing or the poor tolerability of TCAs. The majority of cases of treatment resistance, however, involve antidepressant therapy at a dose and duration that would normally be expected to be effective. In these cases, therapy may fail for many reasons. Refractory depression may occur in patients with medical conditions such as subclinical hypothyroidism, stroke and closed head injuries. Patients with alcoholism may prove refractory to treatment, as may those receiving certain medicatio...
Alongside other risk factors for the development of type 2 diabetes, the presence of severe menta... more Alongside other risk factors for the development of type 2 diabetes, the presence of severe mental illness is often overlooked. A person with schizophrenia has a two to four times greater risk of developing diabetes than the general population and the prevalence of type 2 diabetes is between 15 and 18% in the schizophrenia population. A full understanding of this issue is vital.
Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TL... more Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24 h. Cell supernatants were analysed using a multiplex enzyme-linked immunosorbent assay approach to measure IL-1β, IL-6, IL-8 and tumour necrosis factor-α (TNFα). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1β, IL-6, IL-8 and TNFα) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1β, IL-6 and TNFα following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1β for both disorders coupled with TNFα increases for bipolar patients were observed. TLR8-induced increases in IL-1β for both disorders as well as IL-6 and TNFα increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNFα levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders.
International Journal of Neuropsychopharmacology, 2013
The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhance... more The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ≥ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ≤ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2010
BACKGROUND A growing body of data implicates increased life stresses with the initiation, persist... more BACKGROUND A growing body of data implicates increased life stresses with the initiation, persistence and severity of symptoms associated with functional gut disorders such as irritable bowel syndrome (IBS). Activation of central and peripheral corticotropin-releasing factor (CRF) receptors is key to stress-induced changes in gastrointestinal (GI) function. METHODS This study utilised immunofluorescent and Western blotting techniques to investigate colonic expression of CRF receptors in stress-sensitive Wistar Kyoto (WKY) and control Sprague Dawley (SD) rats. KEY RESULTS No intra-strain differences were observed in the numbers of colonic CRFR1 and CRFR2 positive cells. Protein expression of functional CRFR1 was found to be comparable in control proximal and distal colon samples. Sham levels of CRFR1 were also similar in the proximal colon but significantly higher in WKY distal colons (SD: 0.38 +/- 0.14, WKY: 2.06 +/- 0.52, P < 0.01). Control levels of functional CRFR2 were simila...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2011
Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and dist... more Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice....
Anxiety and depression are devastating mental illnesses that are a significant public health conc... more Anxiety and depression are devastating mental illnesses that are a significant public health concern. Selective serotonin-reuptake inhibitors are the first-line treatment strategy for these disorders, which despite being a significant advantage over older treatments, are hampered by a limited efficacy in a significant subset of patients, delayed onset of action and side effects that affect compliance. Thus, there is much impetus to develop novel therapeutic strategies. However, this goal can only be rationally realised with a better understanding of the molecular pathophysiology of these disorders. MicroRNAs (miRNAs) are a newly discovered class of gene-expression regulators that may represent a novel class of therapeutic targets to treat a variety of disorders including psychiatric diseases. miRNAs are heavily involved in regulating many physiological processes including those fundamental to the functioning of the central nervous system. Evidence collected to date has already demon...
Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-... more Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB.
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Papers by Ted Dinan