Chris Carter

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B.Sc Zoology University of Leeds, 1974
M.Sc Pharmacology and Toxicology University of Bradford, 1976
Ph.D Neuropharmacology University of Bristol 1979
PostDoc department of Neurology, Indstitute of Psychiatry 1979-1984
Lecturer in Pharmacology University of East London 1985
Synthelabo Paris 1985-2005. Group leader Neuroscience Genomics

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Daniel D. Hutto

University of Wollongong

James Elkins

School of the Art Institute of Chicago

Sarah-Jayne Blakemore

University College London

Matthew Broome

University of Oxford

Barry Margulies

Towson University

Michael Spivey

University of California, Merced

Don Ross

University College Cork

Mohd Tariq Salman

Integral University

Vicky Puig

Ivy F. Tso

Ohio State University

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Papers by Chris Carter

Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity

The Journal of pharmacology and experimental therapeutics, 1997

The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at h... more The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D3 and both pre- and postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D2/D3 antagonist [3H]raclopride to the limbic system (ID50 = 17 mg/kg) in comp...

N-Methyl-<i>D</i>-Aspartate Receptor Antagonists: A Novel Therapeutic Perspective for the Treatment of Ischemic Brain Injury

Cerebrovascular Diseases, 1991

Considerable experimental evidence suggests that excessive stimulation of the N-methyl-D-aspartat... more Considerable experimental evidence suggests that excessive stimulation of the N-methyl-D-aspartate (NMDA) receptor subclass of glutamate receptors plays a pivotal role in initiating biochemical processes that lead to neuronal death during cerebral ischemia. Several NMDA receptor antagonists acting at the various sites within the NMDA receptor complex effectively attenuate the neuropathological consequences of brain ischemia in a wide variety of experimental

Genetic, transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimer’s disease

Multiple pathogens have been detected in Alzheimer’s disease (AD) brains. A bioinformatics approa... more Multiple pathogens have been detected in Alzheimer’s disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans,C.Neoformans, Bornavirus,B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza,C.Pneumoniae,P.Gingivalis,H.Pylori,T.Gondii,T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects...

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$Research paper thumbnail of {"__content__"=>"The /Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer's Disease, Diabetes and Cardiovascular Diseases.", "i"=>{"__content__"=>"Porphyromonas gingivalis"}}$

{"__content__"=>"The /Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer's Disease, Diabetes and Cardiovascular Diseases.", "i"=>{"__content__"=>"Porphyromonas gingivalis"}}

Frontiers in aging neuroscience, 2017

Periodontal disease is of established etiology in which polymicrobial synergistic ecology has bec... more Periodontal disease is of established etiology in which polymicrobial synergistic ecology has become dysbiotic under the influence of . Following breakdown of the host's protective oral tissue barriers, migrates to developing inflammatory pathologies that associate with Alzheimer's disease (AD). Periodontal disease is a risk factor for cardiovascular disorders (CVD), type II diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM exacerbates periodontitis. This study analyzed the relationship between the /host interactome and the genes identified in genome-wide association studies (GWAS) for the aforementioned conditions using data from GWASdb ( < 1E-03) and, in some cases, from the NCBI/EBI GWAS database ( < 1E-05). Gene expression data from periodontitis or microarray was compared to microarray datasets from the AD hippocampus and/or from carotid artery plaques. The results demonstrated that the host genes of the interactome were significantly enriched i...

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The Neuropharmacology of Polyamines

NMDA receptor antagonists: Potential agents for the therapy of stroke and head trauma

Interactions of 5-hydroxytryptamine and gamma-aminobutyric acid with dopamine

Advances in biochemical psychopharmacology, 1978

1. Adv Biochem Psychopharmacol. 1978;19:323-41. Interactions of 5-hydroxytryptamine and gamma-ami... more 1. Adv Biochem Psychopharmacol. 1978;19:323-41. Interactions of 5-hydroxytryptamine and gamma-aminobutyric acid with dopamine. Pycock CJ, Horton RW, Carter CJ. PMID: 358783 [PubMed - indexed for MEDLINE]. Publication Types: Review. MeSH Terms. Animals; Brain/drug effects; Brain/metabolism; Catalepsy/chemically induced; Catalepsy/physiopathology; Dopamine/metabolism; Dopamine/physiology*; Humans; Motor Activity/drug effects; Motor Activity/physiology; Serotonin/metabolism; Serotonin/physiology*; Stereotyped Behavior/drug ...

Evidence for gliadin antibodies as causative agents in schizophrenia

Nature Precedings, 2010

Antibodies to gliadin, a component of gluten, have frequently been reported in schizophrenia pati... more Antibodies to gliadin, a component of gluten, have frequently been reported in schizophrenia patients, and in some cases remission has been noted following the instigation of a gluten free diet. Gliadin is a highly immunogenic protein, and B cell epitopes along its entire immunogenic length are homologous to the products of numerous proteins relevant to schizophrenia (p = 0.012 to 3e-25). These include members of the DISC1 interactome, of glutamate, dopamine and neuregulin signalling networks, and of pathways involved in plasticity, dendritic growth or myelination. Antibodies to gliadin are likely to cross react with these key proteins, as has already been observed with synapsin 1 and calreticulin. Gliadin may thus be a causative agent in schizophrenia, under certain genetic and immunological conditions, producing its effects via antibody mediated knockdown of multiple proteins relevant to the disease process. Because of such homology, an autoimmune response may be sustained by the human antigens that resemble gliadin itself, a scenario supported by many reports of immune activation both in the brain and in lymphocytes in schizophrenia. Gluten free diets and removal of such antibodies may be of therapeutic benefit in certain cases of schizophrenia.

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Reduced GABA transaminase activity in the Huntington's disease putamen

Neuroscience Letters, 1984

GABA transaminase activity is reduced in autopsied putamen samples from patients dying with Hunti... more GABA transaminase activity is reduced in autopsied putamen samples from patients dying with Huntington&#39;s disease. Its activity is also reduced in the striatum of rats previously lesioned with kainic acid. In both cases, the reduction in GABA transaminase activity is comparable with the reduction in glutamate decarboxylase activity, supporting the suspected localization of this enzyme to GABA neurones within the basal ganglia.

Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: Eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds

Neurochemistry International, 1996

Ahstract-NMDA increases the release of [~4C]acetylcholine and [3H]spermidine or of [J4C]GABA and ... more Ahstract-NMDA increases the release of [~4C]acetylcholine and [3H]spermidine or of [J4C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, glycine antagonists, competitive antagonists and polyamine antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the l-day-old rat cortex and midbrain (with IC50 values of ~ 2 and 70 pM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.

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The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour, and amphetamine-induced stereotypy

Naunyn-Schmiedeberg's Archives of Pharmacology, 1979

5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in ... more 5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The sterotyped responses to all doses of amphetamine tested (2.5--10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.

Noradrenaline Antagonizes and Ouabain Potentiates the Effects of iV-Methyl-D-Aspartate on Rat Cerebellar Cyclic GMP Production

Journal of Neurochemistry, 1988

Noradrenaline potently antagonizes the effects of N-methyl-D-aspartate (NMDA) (80 microM) on cycl... more Noradrenaline potently antagonizes the effects of N-methyl-D-aspartate (NMDA) (80 microM) on cyclic GMP production in immature rat cerebellar slices in vitro (IC50 = 0.6 microM). The effect is stereospecific (D-noradrenaline, IC50 = 100 microM), and also observed with adrenaline (IC50 = 0.5 microM) and isoprenaline (IC50 = 1.2 microM). The alpha 1-adrenoceptor agonists methoxamine or phenylephrine or the mixed alpha 1/alpha 2 agonists oxymetazoline or xylometazoline (100 microM) do not block the effects of NMDA, but the alpha 2-adrenoceptor agonist clonidine is weakly active (IC50 = 200 microM). Salbutamol and terbutaline were also inactive except at high concentrations (300 microM), as were a number of other catechol and phenylethylamine derivatives. The antagonistic effects of noradrenaline on the NMDA response were insensitive to phentolamine, atenolol, or propranolol (up to 100 microM), but were blocked by the alpha 2 antagonist idazoxan (1-10 microM). The Na+,K+-ATPase inhibitor ouabain (0.1-10 microM) markedly potentiates the effects of NMDA in this model, and also antagonizes and reverses the ability of noradrenaline (10 microM) to block the effects of NMDA. The results suggest that noradrenaline and Na+,K+-ATPase activity have potent modulatory effects on the NMDA response.

S-4-2 Therapeutic potential of drugs acting on excitatory amino acid receptors

European Neuropsychopharmacology, 1995

Abstract: The synaptic responses elicited by excitatory amino acids (EAA) eg L-glutamate and aspa... more Abstract: The synaptic responses elicited by excitatory amino acids (EAA) eg L-glutamate and aspartate in the CNS are mediated by distinct classes of receptors which have been categorized into G-protein coupled metabotropic and ligand-gated ionotropic (NMDA and AMPA-kainate subtypes) receptors. The NMDA receptor has attracted much interest because its plays an important role in processes such as learning and memory and neuronal degeneration. There are a number of distinct sites on the NMDA receptor ...

The effects of N-methyl-d-aspartate and kainate lesions of the rat striatum on striatal ornithine decarboxylase activity and polyamine levels

Brain research, May 24, 1991

The intrastriatal injection ofN-methyl-d-aspartate (NMDA)(250 nmol) produced a delayed and marked... more The intrastriatal injection ofN-methyl-d-aspartate (NMDA)(250 nmol) produced a delayed and marked increase in striatal ornithine decar☐ ylase (ODC) activity and putrescine levels which peaked 6–15 h following the injection of NMDA. Striatal ODC activity subsequently returned to normal values while putrescine levels remained significantly elevated for up to 4 days following the lesion. NMDA produced an early and progressive decline in striatal spermine and spermidine levels, preceding the increase in ODC activity, ...

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The effects of N-methyl-d-aspartate and kainate lesions of the rat striatum on striatal ornithine decarboxylase activity and polyamine levels

Brain research, May 24, 1991

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Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed... more Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans , Cryptococcus neoformans , Bornavirus, Borrelia burgdorferri , cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae , Porphyrymonas gingivalis , Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi ). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

by Chris Carter and R. Blizard

The increasing incidence of autism suggests a major environmental influence. Epidemiology has imp... more The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism susceptibility genes (ASG's) from the Autworks database to interrogate ∼1 million chemical/gene interactions in the comparative toxicogenomics database. Any bias towards ASG's was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI's, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG's, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other suspected endocrine disruptors (over 100) selectively targeted ASG's including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms influence the sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. Pesticides, heavy metals and pollutants also disrupt barrier and/or ciliary function, which is regulated by sex steroids and by bitter/sweet taste receptors. Further epidemiological studies and neurodevelopmental and behavioural research is warranted to determine the relevance of large number of suspect candidates whose addition to the environment, household, food and cosmetics might be fuelling the autism epidemic in a gene-dependent manner.

The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.

Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism i... more Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism in recent decades, in the absence of any known changes in the human gene pool suggests a strong environmental influence. Numerous pollutants have been implicated in epidemiological studies, including pesticides, heavy metals, industrial solvents, air pollutants, particulate matter, bisphenol A, phthalates and flame retardants. Many genes have been implicated in autism, some of which are directly related to detoxification processes. Many are also expressed prenatally in the frontal cortex when the effects of such toxins on neurodevelopment are most relevant. To gain access to the foetal brain, toxins must pass placental and blood/brain barriers and access to maternal or children's blood necessitates passage across skin, airway and intestinal barriers. Literature survey of a subset of 206 genes, defined as prime autism susceptibility candidates from an Autworks/Genotator analysis, revealed that most could be related to barrier function at blood/brain, skin, intestinal, placental or other interfaces. These genes were highly enriched in proteome datasets from blood/brain and placental trophoblast barriers and many localised to skin, intestinal, lung, umbilical and placental compartments. Many were also components of the exosomal/transcytosis pathway that is involved in the transfer of compounds across cells themselves, rather than between them. Several are involved in the control of respiratory cilia that sweep mucus and noxious particles from the airways. A key role of autism susceptibility genes may thus relate to their ability to modulate the access of numerous toxins to children, and adults and, during gestation, to the developing foetal brain.

Susceptibility genes are enriched in those of the HSV-1/host interactome in psychiatric and neurological disorders

Pathogens and disease, 2013

Herpes simplex (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination... more Herpes simplex (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk promoting polymorphisms, (also present in control populations) any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This dataset is heavily enriched in the susceptibility genes for multiple sclerosis (P= 1.3E-99) >Alzheimer's disease > schizophrenia > Parkinsonism > depression> bipolar disorder> childhood obesity> chronic fatigue> autism > and anorexia (P=0.047) but not ADHD, a relationship maintained for GWAS datasets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome datasets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk promoting effects of the genes whose function it disrupts.This article is protected by copyright. All rights reserved.

Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

Journal of Pathogens, Mar 10, 2013

Toxoplasma gondii, is implicated in schizophrenia and related disorders, but also in Alzheimer’s ... more Toxoplasma gondii, is implicated in schizophrenia and related disorders, but also in Alzheimer’s or Parkinson’s disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis > Alzheimer’s disease > schizophrenia > bipolar disorder> depression > childhood obesity > Parkinson’s disease > attention deficit hyperactivity disorder (P from 8.01E-05 (ADHD) to 1.22E-71 (multiple sclerosis), and autism (p=0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself.