Biomedical subjects

Gavin P Reynolds

Publications and source records attributed to Gavin P Reynolds.

At least 19 recordsLinked to original sources

PubMed2006

Clozapine, but not haloperidol, increases neuropeptide Y neuronal expression in the rat hypothalamus.

Many atypical antipsychotic drugs, such as clozapine, can induce significant weight gain which can have serious implications for drug compliance and morbidity. Food intake and weight gain are regulated primarily by the hypothalamus; the arcuate nucleus (ARC) of the hypothalamus is the region initially mediating the effects of circulating hormones on food intake. Neuropeptide Y (NPY) is an important hypothalamic peptide involved in body weight regulation. Immunohistochemical staining of NPY in the ARC was carried out in male Sprague-Dawley rats treated with haloperidol (1.5 mg/kg, i.p.) or clozapine (25 mg/kg, i.p.) for 3 weeks. Clozapine, but not haloperidol, produced an increase in NPY immunoreactivity in the ARC, suggesting that effects on NPY may be involved in increases in body weight following clozapine treatment.

Animals↗

PubMed2005

An in vitro model of inflammatory neurodegeneration and its neuroprotection.

Inflammation has been implicated in a variety of acute and chronic neurodegenerative diseases in which the inflammatory processes are considered not only to result from neurodegenerative effects, but also to contribute to these effects. To investigate the primary effect of inflammation on neuronal survival, a co-culture system of neuronal cells (differentiated SH SY5Y human neuroblastoma cells or primary cortical/striatal neurons) and monocytic cells (THP-1) in direct cell-cell contact was set up. After 5 days, THP-1 activation by lipopolysaccharide and phorbol 12-myristate 13-acetate resulted in a significant increase of neuronal cell death compared to co-culture without activation. In neuroprotection studies using this model, ascorbic acid and EDTA demonstrated a highly significant reduction in activated THP-1 induced cell death. Glutathione and NBQX, but not the protease inhibitor, PMSF, and catalase, also significantly reduced this inflammatory neurotoxicity. Indomethacin was protective of the primary cultured neurons but not the SH SY5Y cells. This co-culture of neuronal cells and activated THP-1 provides a useful model for the study of inflammatory mechanisms resulting in neuronal cell death.

Animals↗

PubMed2005

Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain.

Administration of phencyclidine (PCP) to both humans and animals models the symptoms of schizophrenia. Brain concentrations of N-acetylaspartate (NAA) are reduced in this disease, reflecting neuronal dysfunction. This study investigates the effects in rats of a chronic intermittent regime of PCP on NAA and its precursor N-acetylaspartylglutamate (NAAG) in rat frontal and temporal cortex, hippocampus and striatum, determined by HPLC. We found significant PCP-induced deficits of NAA and NAAG only in the temporal cortex; NAAG was significantly elevated in the hippocampus. These changes closely reflect postmortem findings reported in schizophrenia.

Animals↗

PubMed2005

Chronic haloperidol or clozapine treatment does not alter parvalbumin immunoreactivity in the rat frontal cortex or hippocampus.

GABAergic neuronal subpopulations, defined by the presence of the calcium binding proteins, parvalbumin (PV) and calretinin (CR) are differentially affected in schizophrenia, with selective PV deficits reported in the prefrontal cortex and hippocampus. To assess the possible contribution of antipsychotic treatment to these effects we examined the size and density of PV-and CR-IR neurons in the rat frontal cortex and hippocampus following three weeks of chronic haloperidol or clozapine administration. Neither antipsychotic significantly altered PV- or CR-IR neuronal cell parameters in these areas or in any of their subregions, relative to controls. These results suggest antipsychotic exposure does not contribute to PV-IR neuronal deficits in schizophrenic patients, providing further evidence in support of a developmental abnormality in specific subpopulations of GABAergic neurons in schizophrenia.

Animals↗

PubMed2005

Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response.

We have been studying the pharmacogenetic correlates of side effects and early response to antipsychotic treatment in a series of Chinese Han first-episode drug-naive patients with schizophrenia. Here, we report the association of three functional polymorphisms of receptor genes on initial symptom severity and outcome in these patients. We studied the dopamine D3 receptor ser9gly, the dopamine D2 receptor Taq IA and the 5-HT2C receptor promoter -759C/T polymorphisms in 117 patients who had symptoms assessed by Positive and Negative Syndrome Scale (PANSS) on admission and following 10-week antipsychotic treatment, primarily with risperidone or chlorpromazine. The D2 polymorphism was found not to be significantly associated with baseline levels or changes in total PANSS in these patients. The D3 genotype is associated with the change in total PANSS (p<0.01), an effect reflecting positive and general (each p<0.01) but not negative symptom improvement. However, symptom improvement at 10 weeks strongly correlates with total PANSS score on admission, in which the greater improvement is seen with the more severe initial symptom score. The D3 genotype is also related to severity on admission, i.e. to total baseline PANSS (p<0.05), including baseline PANSS score as a covariate, the association of the genotype to change over 10 weeks remains significant for total PANSS (p<0.05) and for positive and general, but not negative, symptom scores. The 5-HT2C promoter polymorphism was also associated with improvement in PANSS (p<0.05), but reflecting effects on negative and general, but not positive, symptom scores. This polymorphism was not associated with PANSS score on admission, although after controlling for the effect of this parameter on 10-week outcome, a stronger association with change in total PANSS (p<0.01) was apparent, again reflecting improvements in negative and general symptoms but not changes in positive symptoms.

Alleles↗

PubMed2005

The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment.

The development of novel, atypical antipsychotics has been welcomed due to their lower incidence of extrapyramidal side effects. However, as with all pharmacotherapy, patient response is often varied and these novel compounds are not without their own side effect profile, most notably weight gain. Inter-individual variations in response to drug treatment are, in part, due to polymorphisms of the genes encoding drug targets. The importance of the serotonin system in psychiatric symptomatology and several side effects of antipsychotic drugs is well established. Thus genetic polymorphisms of two central 5-HT receptors (5-HT2A and 2C), at which many of the newer antipsychotic drugs act, are prime candidates for pharmacogenetic analysis of the effects of these drugs in the treatment of schizophrenia. To date, much work has focussed on the 5-HT2A receptor subtype. However, pharmacological evidence and recent molecular genetic studies would suggest a role for the 5-HT2C receptor in the consequences of antipsychotic treatment, particularly in relation to the development of both drug-induced dyskinesias and weight gain. This review briefly examines the pharmacology and physiology of the 5HT2C receptor in the context of its genetics, with discussion of known polymorphisms of this receptor gene and its promoter region. Associations between these polymorphisms and the development of schizophrenia, the symptom responses to antipsychotic treatment and side effects of such treatment, notably tardive dyskinesia and weight gain, are assessed and related to the presumed functionality of these polymorphisms. Such studies clearly demonstrate the potential of pharmacogenetics in optimising treatment for the individual patient.

Animals↗

PubMed2005

Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis.

OBJECTIVES: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment. METHODS: Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor -759C/T and leptin -2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment. RESULTS: Patients with the -759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The -2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C -759 genotype was significantly associated with pre-treatment plasma leptin levels. CONCLUSIONS: These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.

Adult↗

PubMed2005

Actions of antipsychotic drugs on pancreatic beta-cell function: contrasting effects of clozapine and haloperidol.

The use of antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function, although the underlying mechanisms are unknown. We have studied the effects of the atypical antipsychotic clozapine and of the conventional drug haloperidol on electrical and secretory activity in rat pancreatic beta-cells. At a low glucose concentration (4mM), clozapine (5microM) had little or no effect on membrane potential. However, at a stimulatory glucose concentration (16mM), clozapine was found to hyperpolarize the cell membrane potential, resulting in a complete inhibition of electrical activity. In contrast, haloperidol (5microM) was found to cause a marked depolarization of the membrane potential in the presence of both low and high concentrations of glucose. Clozapine and haloperidol were found, respectively, to increase and decrease-cell input conductance, an index of K(+) permeability. Single channel recordings indicated that changes in K(ATP) channel activity contributed towards these effects. Neither clozapine nor haloperidol affected basal insulin release, although clozapine inhibited glucose-induced insulin release. It is concluded that clozapine and haloperidol exert contrasting actions on electrical activity in rat pancreatic -cells as a result of opposing effects on K(+) permeability. These findings may relate to the increased incidence of diabetes associated with clozapine treatment.

Animals↗

PubMed2004

The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders.

The NMDA receptor has been implicated in the pathophysiology of several diseases including schizophrenia and affective disorders. We have investigated the NR1 subunit of the NMDA receptor in a well-defined series of psychiatric cases using radioligand binding and quantitative immunoblotting techniques. Saturable radioligand binding of [(3)H]L-689,560 to the glycine site on this subunit of the NMDA receptor was undertaken in superior temporal cortex of patients with schizophrenia, bipolar disorder, depression and matched control subjects. A tendency towards an increased receptor density was found in schizophrenia. A significant decrease in NMDA receptor density below control value was found in both bipolar and depressive disorders. The immunoblotting technique was used to identify NR1 protein in the same series of cases of which two bands were identified consistent with NR1 splice variants. A tendency to a decrease in the density of the NR1 upper band below control values was found in bipolar and depressed patients, but not schizophrenics. Consistent with this observation, the ratio between the upper and lower NR1-immunoreactive bands showed a significant decrease in bipolar disorder, although the ratio in depression did not reach significance. No significant difference was found in the NR1 lower band in any patient group compared with control. The finding of an increase NMDA receptor density in schizophrenia is consistent with the previous reports, with a possible compensatory response to glutamatergic deficits in superior temporal cortex in schizophrenia. The findings in affective disorders are interesting in respect of reports of cortical NMDA receptor deficits in suicide victims, although antidepressant drug treatment may contribute to these changes.

Analysis of Variance↗

PubMed2004

Ziprasidone suppresses olanzapine-induced increases in ingestive behaviour in the rat.

Many atypical antipsychotic drugs, such as olanzapine, induce significant weight gain. However, ziprasidone produces minimal weight gain, the mechanism of which remains unclear. The aim of the present study was to investigate whether ziprasidone would reduce the acute effect of olanzapine on feeding behaviour. The results suggest that ziprasidone suppresses the significant increases in food intake produced by olanzapine, indicating that it has an intrinsic protective mechanism against drug-induced increases in food intake.

Animals↗

PubMed2004

Reduced N-acetylaspartate in the temporal cortex of rats reared in isolation.

BACKGROUND: Isolation rearing of rats is a nonpharmacologic, nonlesion manipulation that leads to deficits in prepulse inhibition (PPI) and other behavioral and neurochemical alterations reminiscent of schizophrenia. N-acetylaspartate (NAA) is present in high concentrations in the central nervous system and is found primarily in neurons. N-acetylaspartate is considered to be a marker of both neuronal loss and cellular dysfunction. Magnetic resonance spectroscopy studies have shown reductions of cortical and hippocampal NAA in schizophrenia, and a recent postmortem study has demonstrated a regionally selective temporal cortex deficit. METHODS: The aim of the present study was to determine whether rats reared in isolation exhibit deficits in PPI and reductions in NAA in discrete brain regions, namely the temporal cortex, frontal cortex, hippocampus, and striatum. RESULTS: Compared with socially housed rats, isolation rearing resulted in PPI deficits (p <.05) and reductions in NAA in the temporal cortex (p <.001), with no significant change in the other regions investigated. CONCLUSION: These results suggest a disturbance of neuronal function, reflected by NAA reductions in the temporal cortex in isolation-reared rats, providing further evidence that isolation rearing can mimic aspects of the neuronal pathology of schizophrenia.

Animals↗

PubMed2004

Calcium binding protein markers of GABA deficits in schizophrenia--postmortem studies and animal models.

As quantitative neuroimaging continues to elucidate the gross neuropathology of schizophrenia, neurochemical and histological studies have contributed to defining this pathology in terms of neurotransmitter dysfunction. Increasingly, there is evidence implicating neurons containing the major inhibitory neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the first to demonstrate deficits in some morphological subtypes of interneurons in the frontal cortex in schizophrenia. We identified that this was specific to a subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal cells. PV is notable in being expressed late in development; the late expression of this protective calcium binding protein (CBP) may impart an early vulnerability to these neurons, indicating a possible mechanism for the developmental origins of schizophrenia. Cortical GABAergic neurons expressing the CBP calretinin (CR) are unaffected in schizophrenia, although those containing calbindin (CB) are also diminished in number. These deficits in PV and CB are notable in also being observed in bipolar disorder, indicating how the close aetiological relationship of these two psychiatric disorders is reflected in their pathology. One of the most substantial abnormalities seen in post-mortem brain tissue is the hippocampal deficit of PV-containing neurons, again in the absence of effects on CR-positive cells. This deficit occurring in a structure implicated in cognitive symptomatology may well have functional relevance, and we find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP) administration, that can also produce cognitive disturbances. This PCP model, like schizophrenia, demonstrates other neurochemical changes which include indicators of glutamatergic dysfunction. The temporal and aetiological relationships between glutamatergic and GABAergic deficits remains unclear, but may well relate to an initial loss/dysfunction of GABA/PV neurons that subsequently gives rise to a glutamatergic pathology.

Animals↗

PubMed2004

Receptor mechanisms in the treatment of schizophrenia.

There remain many limitations to the treatment of schizophrenia. In addition to the poor response of negative and cognitive symptoms to antipsychotics, and the substantial proportion of poor- or non-responders, there are a variety of unpleasant and restricting side-effects of these drugs. The introduction of several 'atypical' drugs, with diminished propensity to cause extrapyramidal motor effects (EPS), has greatly improved the tolerability of antipsychotic treatments. The pharmacology of atypical antipsychotics is varied and, although dopamine D2 receptor antagonism is common to all antipsychotics, the mechanisms of a typicality are complex and not fully understood. Thus, antagonism at 5-HT2 and/or other receptors, weak dopamine receptor affinity and, most recently, partial agonism at dopamine D2 receptors, have been variously implicated. However, because EPS have diminished with improvements in drug treatment, drug-induced weight gain has emerged as a major concern, and the pharmacological basis of this problem, involving effects at 5-HT2c and perhaps other receptors, is yielding to investigation. Some drugs, notably the D2 partial agonists, can provide antipsychotic effects without the emergence of several of the seproblematic side-effects, which bodes well for future treatment.

Animals↗

PubMed2004

Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia.

BACKGROUND: Weight gain is a common consequence of antipsychotic drug treatment and can lead to further morbidity. AIMS: To assess the effects of antipsychotic drug therapy on abdominal fat deposition, on insulin and leptin secretion, and on circulating glucose and lipids. METHOD: Abdominal body fat was determined by magnetic resonance imaging in a group of previously untreated patients with schizophrenia, before and after 10 weeks' antipsychotic drug treatment. Body mass and blood concentrations of glucose, insulin, leptin and lipids were also measured. RESULTS: Significant increases in both subcutaneous and intra-abdominal fat were identified after antipsychotic drug treatment. A three-fold increase in leptin secretion as well as significant increases in levels of circulating lipids and non-fasting glucose were also identified. CONCLUSIONS: Patients first receiving antipsychotic drugs experience substantial deposition of both subcutaneous and intra-abdominal fat, reflecting a loss of the normal inhibitory control of leptin on body mass. Along with fat deposition, the increase in levels of fasting lipids and in non-fasting glucose may provide early signs of drug-induced progression towards the metabolic syndrome.

Abdomen↗

PubMed2003

N-acetylaspartate and N-Acetylaspartylglutamate deficits in superior temporal cortex in schizophrenia and bipolar disorder: a postmortem study.

BACKGROUND: N-acetylaspartylglutamate is found in neurons and its metabolite N-acetylaspartate, which can be measured by magnetic resonance spectroscopy, is considered a marker of neuronal integrity. Several magnetic resonance spectroscopy studies have found evidence of N-acetylaspartate deficits in schizophrenia. METHODS: We employed a high-pressure liquid chromatography method to determine N-acetylaspartate and N-acetylaspartylglutamate in postmortem brain tissues taken from a well-defined series of psychiatric cases. N-acetylaspartate and N-acetylaspartylglutamate concentrations were measured in superior temporal and frontal cortices of patients with schizophrenia, bipolar disorder, and depression and control subjects. RESULTS: N-acetylaspartate was significantly decreased below controls in superior temporal cortex in schizophrenia (p <.01) and bipolar disorder (p <.01), but no deficits were found in frontal cortex. N-acetylaspartylglutamate was significantly decreased only in superior temporal cortex in schizophrenia. CONCLUSIONS: The results are consistent with evidence of superior temporal cortex abnormalities in schizophrenia. The finding in bipolar disorder suggests that temporal cortex N-acetylaspartate deficits may be a common feature of psychotic disorders.

Aspartic Acid↗

PubMed2003

Interaction between polymorphisms of the dopamine D3 receptor and manganese superoxide dismutase genes in susceptibility to tardive dyskinesia.

OBJECTIVES: To investigate the influence of a functional polymorphism of the dopamine D3 receptor (DRD3), and assess its interaction with a Mn superoxide dismutase (MnSOD) polymorphism, in contributing to tardive dyskinesia in a chronic inpatient population with schizophrenia. METHODS: Chinese Han patients with schizophrenia were assessed for abnormal involuntary movements, and subgroups of 42 patients with persistent tardive dyskinesia and 59 consistently without dyskinesias were assessed for the DRD3 ser9gly and the MnSOD ala-9val polymorphisms. RESULTS: A higher, but not significant, frequency of DRD3 ser/gly heterozygotes was observed in the tardive dyskinesia group (0.52 versus 0.33, chi2=5, degrees of freedom=2, P=0.08). However, assessment of the combined influence of the two polymorphisms demonstrated a significant effect (chi2=8.09, degrees of freedom=3, P=0.04), whereby the combination of the MnSOD -9val and DRD3 9ser alleles was associated with tardive dyskinesia. CONCLUSIONS: These results indicate a possible synergistic effect of genetic factors influencing mitochondrial free radical scavenging and dopamine receptor function on the susceptibility to tardive dyskinesia.

Age of Onset↗

PubMed2003

Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain.

OBJECTIVE: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. A recent study showed that a polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene is associated with antipsychotic-induced weight gain. The authors determined whether this association held true for weight gain after clozapine treatment. METHOD: Thirty-two Chinese Han patients with first-episode schizophrenia were genotyped for the -759C/T polymorphism and had weight changes monitored after 6 weeks of clozapine treatment. RESULTS: The authors found that the 10 patients with the -759T variant allele showed significantly less weight gain than those without this allele. The effect was strongest in the male patients and not apparent in the female patients. CONCLUSIONS: These findings identify an important genetic factor associated with clozapine-induced weight increases in schizophrenia.

Antipsychotic Agents↗

PubMed2002

Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins.

BACKGROUND: Postmortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia, including deficits of GABA-containing interneurons. The calcium-binding proteins parvalbumin, calbindin, and calretinin can be used as markers for specific subpopulations of cortical GABAergic interneurons. METHODS: Following our previous observation of a reduction in the density of parvalbumin- but not calretinin-immunoreactive cells in the prefrontal cortex (Brodmann area 10) in schizophrenia, we have quantified the laminar density of neurons immunoreactive for the calcium-binding proteins parvalbumin, calbindin, and calretinin in a further prefrontal cortical region (Brodmann area 9) in patients with schizophrenia, bipolar disorder, major depression, and in matched control subjects (each group n = 15). RESULTS: Initial statistical analysis revealed reductions in the total cortical density of parvalbumin- and calbindin- but not calretinin-immunoreactive neurons in schizophrenia relative to control subjects. Further analysis comparing individual laminar densities between groups indicated that, following correction for multiple comparisons, only a reduction in calbindin-immunoreactive neurons in cortical layer II in the schizophrenic group attained statistical significance. CONCLUSIONS: These findings suggest that deficits of specific GABAergic neurons, defined by the presence of calcium-binding proteins, are present in schizophrenia. Trends toward similar reductions are observed in bipolar disorder.

Adult↗