The biochemical basis of relapse and drug response in schizophrenia: review and hypothesis

1991 ◽  
Vol 21 (4) ◽  
pp. 881-895 ◽  
Author(s):  
Daniel P. Van Kammen
Keyword(s):  
Drug Response ◽  
Negative Symptoms ◽  
Antipsychotic Drugs ◽  
Signal To Noise Ratio ◽  
Neuronal Firing ◽  
Variable Response ◽  
Biochemical Basis ◽  
State Dependent ◽  
Show Evidence ◽  
Drug Free

SYNOPSISThis review of the literature suggests that antipsychotic drug response is determined by dopamine (DA) turnover and norepinephrine (NE) activity prior to treatment. The data suggest that NE modulates the DA system. Drug-free psychotic patients with relatively increased DA and NE activity, including release, are more likely to be treatment responsive, while patients who show evidence of enhanced DA and NE activity during treatment with antipsychotic drugs are likely to relapse soon after neuroleptic withdrawal. Basal release of DA and NE is decreased and associated with residual positive and negative symptoms. Improvement during neuroleptic treatment is associated with decreases in DA and NE phasic or stimulus induced release. The variable response to antipsychotic drugs is most likely to be a result of dysregulated DA and NE release, i.e. under state-dependent control, rather than evidence of a heterogeneous aetiology. Because catecholamines regulate gain, signal-to-noise ratio and gating in the brain, this model allows for environmental factors to interact with biochemical state and drug treatment. The author proposes that impaired homeostasis of NE and DA in schizophrenia causes instability in NE and DA neuronal firing and release, presumably related to mechanisms down-stream from the receptors, such as G proteins. This instability of catecholamine release may explain the observed variability in clinical states and drug response in schizophrenia.

scholarly journals Interaction of clozapine with metformin in a schizophrenia rat model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
G. Horvath ◽  
G. Kis ◽  
G. Kekesi ◽  
A. Büki ◽  
L. G. Adlan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Function ◽  
Negative Symptoms ◽  
Antipsychotic Drugs ◽  
D1 Receptor ◽  
Antidiabetic Drug ◽  
Beneficial Effects ◽  
Adjuvant Therapies ◽  
Behavioral Parameters ◽  
The Brain

AbstractThe low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Hyperactivity of Associations in Psychosis

1989 ◽  
Vol 23 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Robert Miller
Keyword(s):  
Negative Symptoms ◽  
Inductive Inference ◽  
Great Variability ◽  
Acute Psychosis ◽  
Variable Response ◽  
Neuroleptic Treatment ◽  
High Anxiety ◽  
Associative Processes ◽  
Psychotic State ◽  
Anxiety Levels

Disordered associative processes have long been regarded as central to the psychological description of psychotic states such as acute schizophrenia. Previous work is briefly summarised concerning the idea that hyperactive associative processes of thought underlie many of the symptoms of psychosis. The idea is developed further, with respect to several features of the psychotic state. Schneiderian symptoms are seenas a consequence of hyperactive associations of thought, combined with perceptual hypersensitivity characteristic of many psychotic individuals. Anxiety in psychotic states is seen as arising from the great ambiguity of mental images when associations are loosened. A vicious circle between high anxiety and hyperactive associations is postulated. The slow and variable response to neuroleptic treatment is seen as being determined in part by the dynamics of change of the memories acquired during a period of hyperactive associations. This essay has dealt exclusively with the positive (productive) symptoms of psychosis, and their treatment. It has briefly traced the origin of the idea that hyperactive associations of thought (i.e. of inductive inference) play an important part in the psychology of acute psychosis. Further it has attempted to show that this idea can be extended to give an account of Schneiderian symptoms, the high anxiety levels commonly found in acute psychosis, as well as the great variability in the rate and extent of response to drug treatment. The negative symptoms of schizophrenia are not included in the discussion. Some of these symptoms are not responsive to neuroleptic drugs. This leads one to suspect that other pathological processes in addition to those discussed above may be involved in the genesis of the negative symptoms.

scholarly journals Genetic variations in the drug metabolizing enzyme, CYP2E1, among various ethnic populations of Pakistan

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9721
Author(s):  
Sagheer Ahmed ◽  
Nadeem Altaf ◽  
Mahnoor Ejaz ◽  
Zaira Zulfiqar ◽  
Kholood Janjua ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Adverse Effects ◽  
Drug Response ◽  
Variable Response ◽  
Healthy Human ◽  
Pakistani Population ◽  
Drug Metabolizing Enzyme ◽  
Different Populations ◽  
Metabolizing Enzyme ◽  
Low Activity

Genetic polymorphism in cytochrome P450 (CYP) monooxygenase genes is an important source of interindividual variability of drug response. CYP enzyme activities may change as a result of such polymorphisms which then, may affect drug metabolism. This would result in a change in the severity and frequency of adverse effects in addition to the non-responder phenomenon. CYP2E1, a member of CYP superfamily, affects the metabolism of several clinically important drugs such as halothane, paracetamol, etc. Genetic variation in CYP2E1 is known to cause significant inter-individual differences in drug response and adverse effects. The degree of genetic variation is found to be different in different populations around the world. The frequencies of two important polymorphisms in the CYP2E1*7C, NC_000010.10:g.135340548A>G (rs2070672) and CYP2E1, NC_000010.10:g.135339244G>C (rs3813865), are not known in the Pakistani population. In the present investigation, 636 healthy human volunteers were screened for these two single nucleotide polymorphism. Our results indicate that about 18% (rs2070672) and 28% (rs3813865) of the Pakistani population has a genotype containing at least one low activity allele. A significant interethnic variation in the frequencies of both the polymorphisms was observed. These results suggest that pharmacogenetics screening for low activity genotypes would be a helpful tool for clinicians when they prescribe medications metabolized by CYP2E1, as a significant fraction of the Pakistani population is expected to have a variable response to these drugs.

Indirect Modulation of Dopamine D2 Receptors as Potential Pharmacotherapy for Schizophrenia: II. Glutamate (Ant)Agonists

2000 ◽  
Vol 34 (6) ◽  
pp. 788-797 ◽  
Author(s):  
Michelle L Carfagno ◽  
Lauren A Hoskins ◽  
Marie E Pinto ◽  
Joanne C Yeh ◽  
Robert B Raffa
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Negative Symptoms ◽  
Antipsychotic Drugs ◽  
Brain Regions ◽  
Data Sources ◽  
Alternative View ◽  
Clinical Activity ◽  
Receptor System ◽  
Positive Effects

OBJECTIVE: To summarize the published preclinical and clinical data that suggest the possible use of glutamate receptor agonists or antagonists as novel antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included. DATA SYNTHESIS: The standard antipsychotic drugs, whose clinical activity correlates with affinity for dopamine D2 receptors, alleviate some of the positive symptoms of schizophrenia, but have limited impact on negative symptoms. Several lines of evidence implicate glutamate-receptor system dysfunction(s) in schizophrenia, either as causative or contributory factors. In addition, several standard antipsychotic drugs modulate glutamate or glutamate receptor activity, suggesting an alternative view of their mechanism of antipsychotic action. Preliminary studies have shown that drugs which modulate glutamate brain concentrations have positive effects in animal models of schizophrenia. CONCLUSIONS: A role for glutamate in the pathogenesis or pharmacotherapy of schizophrenia is suggested from anatomic (interactions between glutamatergic and dopaminergic systems in relevant brain regions), physiologic (implication of glutamate-receptor dysfunction), and pharmacologic (modulation of glutamate or glutamate receptors) evidence. Therefore, compounds that function at glutamate receptors might represent a novel approach to the treatment of the disease or to the amelioration of symptoms, either as monotherapy or as an adjunct to dopamine D2 receptor antagonists.

scholarly journals Alterations of the rewarding actions of amphetamine by prior nicotine and alcohol treatment: The role of age and dopamine

2020 ◽  
Author(s):  
Andrea Stojakovic ◽  
Syed Muzzammil Ahmad ◽  
Kabirullah Lutfy
Keyword(s):  
Glutamate Receptors ◽  
Age Groups ◽  
Alcohol Exposure ◽  
Female Adolescent ◽  
D1 Receptors ◽  
Dopaminergic Neurotransmission ◽  
Adult Mice ◽  
State Dependent ◽  
Drug Free

AbstractRationaleNicotine and alcohol each can serve as the gateway to other drugs.ObjectiveThe current study was sought to determine if prior nicotine and alcohol exposure alters amphetamine reward and if age and dopaminergic neurotransmission are involved.MethodsMale and female adolescent and adult C57BL/6J mice were tested for baseline place preference, received six conditioning with saline/nicotine (0.25 mg/kg) twice daily followed by six conditioning with saline/ethanol (2 g/kg) in a counterbalance manner. Control mice were conditioned with saline/saline throughout. Finally, mice were conditioned with amphetamine (3 mg/kg) once in the nicotine-alcohol-paired chamber and then tested for CPP 24 h later. The following day, mice were challenged with amphetamine (1 mg/kg) and tested for CPP under a drugged state. Mice were then immediately euthanized, brain removed and nucleus accumbens isolated and processed for the expression of dopamine receptors and transporter, and glutamate receptors.ResultsWe observed a greater amphetamine-induced CPP in adolescent than adult mice but no change in state-dependent CPP between the two age groups. In contrast, amphetamine-induced CPP in mice with prior nicotine-alcohol exposure was greater in adult than adolescent mice under both drug-free and drugged states. The enhanced response in adult mice was associated with greater expression of dopamine-transporter, reduced D2 receptors, and increased D1 receptors with no changes in glutamate receptors.ConclusionsThese results suggest that prior nicotine and alcohol exposure differentially alters the rewarding action of amphetamine in adult and adolescent mice and alterations in dopaminergic neurotransmission may be involved in this phenotype.

scholarly journals Extended field-of-view ultrathin microendoscopes for high-resolution two-photon imaging with minimal invasiveness

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrea Antonini ◽  
Andrea Sattin ◽  
Monica Moroni ◽  
Serena Bovetti ◽  
Claudio Moretti ◽  
...  
Keyword(s):  
Spatial Resolution ◽  
Neuronal Activity ◽  
Signal To Noise Ratio ◽  
Brain Regions ◽  
Field Of View ◽  
Imaging Data ◽  
Minimal Invasiveness ◽  
Two Photon ◽  
State Dependent ◽  
Set Up

Imaging neuronal activity with high and homogeneous spatial resolution across the field-of-view (FOV) and limited invasiveness in deep brain regions is fundamental for the progress of neuroscience, yet is a major technical challenge. We achieved this goal by correcting optical aberrations in gradient index lens-based ultrathin (≤500 µm) microendoscopes using aspheric microlenses generated through 3D-microprinting. Corrected microendoscopes had extended FOV (eFOV) with homogeneous spatial resolution for two-photon fluorescence imaging and required no modification of the optical set-up. Synthetic calcium imaging data showed that, compared to uncorrected endoscopes, eFOV-microendoscopes led to improved signal-to-noise ratio and more precise evaluation of correlated neuronal activity. We experimentally validated these predictions in awake head-fixed mice. Moreover, using eFOV-microendoscopes we demonstrated cell-specific encoding of behavioral state-dependent information in distributed functional subnetworks in a primary somatosensory thalamic nucleus. eFOV-microendoscopes are, therefore, small-cross-section ready-to-use tools for deep two-photon functional imaging with unprecedentedly high and homogeneous spatial resolution.

scholarly journals All-optical electrophysiology reveals brain-state dependent changes in hippocampal subthreshold dynamics and excitability

2018 ◽  
Author(s):  
Yoav Adam ◽  
Jeong J. Kim ◽  
Shan Lou ◽  
Yongxin Zhao ◽  
Daan Brinks ◽  
...  
Keyword(s):  
High Speed ◽  
Near Infrared ◽  
Neuronal Excitability ◽  
Signal To Noise Ratio ◽  
Brain State ◽  
Promising Tool ◽  
State Dependent ◽  
Subthreshold Voltage ◽  
Targeted Gene Expression

AbstractA technology to record membrane potential from multiple neurons, simultaneously, in behaving animals will have a transformative impact on neuroscience research1. Parallel recordings could reveal the subthreshold potentials and intercellular correlations that underlie network behavior2. Paired stimulation and recording can further reveal the input-output properties of individual cells or networks in the context of different brain states3. Genetically encoded voltage indicators are a promising tool for these purposes, but were so far limited to single-cell recordings with marginal signal to noise ratio (SNR) in vivo4-6. We developed improved near infrared voltage indicators, high speed microscopes and targeted gene expression schemes which enabled recordings of supra- and subthreshold voltage dynamics from multiple neurons simultaneously in mouse hippocampus, in vivo. The reporters revealed sub-cellular details of back-propagating action potentials, correlations in sub-threshold voltage between multiple cells, and changes in dynamics associated with transitions from resting to locomotion. In combination with optogenetic stimulation, the reporters revealed brain state-dependent changes in neuronal excitability, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behavior.

Towards More Effective Antipsychotic Treatment

1994 ◽  
Vol 165 (S25) ◽  
pp. 22-31 ◽  
Author(s):  
John M. Kane ◽  
Hugh L. Freeman
Keyword(s):  
Side Effect ◽  
Negative Symptoms ◽  
Antipsychotic Drugs ◽  
Mechanisms Of Action ◽  
Effective Control ◽  
Antipsychotic Treatment ◽  
Side Effect Profile ◽  
Proven Efficacy ◽  
Dopamine Hypothesis ◽  
Neurological Effects

The development of antipsychotic drugs has followed two complementary approaches, either towards highly specific actions (e.g. on the dopamine receptor) or targeting a broad range of receptors. The properties of ‘atypical’ agents challenge the original dopamine hypothesis and suggest roles for a variety of dopamine receptors and for other pathways, such as serotonin. Older drugs, despite their proven efficacy in relieving many schizophrenic symptoms, have several drawbacks, being ineffective in some patients, relatively ineffective against negative symptoms, and causing adverse neurological effects which may, in turn, be associated with poor compliance. Among newer agents, currently available ones, such as clozapine and risperidone, offer the possibility of more effective control of negative symptoms and an improved side-effect profile, while others are in earlier stages of development. However, much still remains to be understood about their mechanisms of action.

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