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Network interactions in schizophrenia--Therapeutic implications
Abstract
Research into the role of neurotransmitters and neural networks in the pathogenesis of schizophrenia has been remarkably successful in recent years. The hypothesis postulating a dopamine dysfunction, which has for a long time been supported only by indirect evidence, has received direct support by means of sophisticated imaging techniques. Interactions between dopamine and several other neurotransmitters in complex neural networks have been revealed, largely thanks to the advent of an array of new pharmacological probes. Two major pharmacological models of schizophrenia, based on hyperdopaminergia and hypoglutamatergia, respectively, are ready for clinical testing. In addition, the hypothesis of network stabilization as a major therapeutic strategy in psychiatry and neurology has now reached the 'proof-of-concept' level. From a therapeutic perspective, several ongoing and forthcoming clinical trials, using drugs acting on dopaminergic, serotonergic and glutamatergic receptors, give rise to optimism.
... In tight correlation with the hyper-dopaminergia observed in schizophrenic patients (Carlsson et al., 2000;Kapur, 2003), MAP6 KO mice present increased dopamine overflow in the mesolimbic pathway. This system plays a significant role in mediating pleasure and rewarding experiences (Brun et al., 2005;Bouvrais-Veret et al., 2007. ...
... Negative symptoms in schizophrenia are mediated by alterations in both the glutamatergic and serotoninergic (5-HT) neurotransmission systems (Aghajanian and Marek, 2000;Carlsson et al., 2000). MAP6 KO mice exhibited abnormal glutamatergic neurotransmission with altered synaptic plasticity in the hippocampus, leading to totally defective Long-Term Potentiation (LTP) and Long-Term Depression (LTD), as measured by electrophysiology techniques (Andrieux et al., 2002). ...
The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.
... Based on these connections, glutamate is crucial in the integration of neurotransmission in the brain, including the regulation of monoaminergic nuclei located in the brainstem and cholinergic neurotransmission originating from the pedunculopontine and laterodorsal tegmental nucleus [106,107]. This excitatory system remains under the inhibitory control of GABAergic neurotransmission in a type of homeostatic balance. ...
... Based on these connections, glutamate is crucial in the integration of neurotransmission in the brain, including the regulation of monoaminergic nuclei located in the brainstem and cholinergic neurotransmission originating from the pedunculopontine and laterodorsal tegmental nucleus [106,107]. ...
Schizophrenia is a mental disorder that affects approximately 1–2% of the population and develops in early adulthood. The disease is characterized by positive, negative, and cognitive symptoms. A large percentage of patients with schizophrenia have a treatment-resistant disease, and the risk of developing adverse effects is high. Many researchers have attempted to introduce new antipsychotic drugs to the clinic, but most of these treatments failed, and the diversity of schizophrenic symptoms is one of the causes of disappointing results. The present review summarizes the results of our latest papers, showing that the simultaneous activation of two receptors with sub-effective doses of their ligands induces similar effects as the highest dose of each compound alone. The treatments were focused on inhibiting the increased glutamate release responsible for schizophrenia arousal, without interacting with dopamine (D2) receptors. Ligands activating metabotropic receptors for glutamate, GABAB or muscarinic receptors were used, and the compounds were administered in several different combinations. Some combinations reversed all schizophrenia-related deficits in animal models, but others were active only in select models of schizophrenia symptoms (i.e., cognitive or negative symptoms).
... However, the neurobiological underpinning of schizophrenia in general as well as that of TRS may involve complex interactions of these neurotransmitters. colleagues (2000, 2001) proposed that alterations in cortical glutamate levels, either acting directly as an "accelerator" or via GABA interneuron projections as a "brake," modulates the firing of dopaminergic neurons that can in turn lead to either decrease or increase in dopaminergic activity (51,52). Thus, for instance, the reduced glutamate activity enhances DA release in dopaminergic pathways, which then via negative feedback, mediated, at least in part, via the striatum and the thalamus, regulates glutamate release that would then act as "a brake" on cortical DA production (51,52). ...
... colleagues (2000, 2001) proposed that alterations in cortical glutamate levels, either acting directly as an "accelerator" or via GABA interneuron projections as a "brake," modulates the firing of dopaminergic neurons that can in turn lead to either decrease or increase in dopaminergic activity (51,52). Thus, for instance, the reduced glutamate activity enhances DA release in dopaminergic pathways, which then via negative feedback, mediated, at least in part, via the striatum and the thalamus, regulates glutamate release that would then act as "a brake" on cortical DA production (51,52). How this mechanism operates in TRS remains to be determined in precise future pre-clinical models. ...
Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.
... There is a possibility that PFC inputs to SN/VTA cause activation of mesopre frontal DA neurons, while through GABAergic mechanism cause inhibition of me solimbic DA neurons (Sesack et al. 2003). As pointed out by Sesack et al. (2003), this implies that prefrontal hypofunction, for example, in schizophrenia, would de crease DA input to the PFC while causing a hyperdopaminegic state in mesolimbic structures (also see Carlsson et al. 2000). Thus, theoretically, functional imaging of LDT and SN/VTA activity and their covariation with PFC activity could provide a means to distinguish prefrontal activity that targets mesoprefrontal DA circuitry from those that targets mesolimbic DA circuitry. ...
... There is a possibility that PFC inputs to the SN/VTA cause activation of mesoprefrontal DA neurons, while through GABAergic mechanisms cause inhibition of mesolimbic DA neurons (Sesack et al. 2003). As pointed out by Sesack et al. (2003), the implication of this is that prefrontal hypofunction, for example, in schizophrenia, would decrease DA input to the PFC while causing a hyperdopaminegic state in mesolimbic structures (also see Carlsson et al. 2000). ...
The human midbrain and pons contain nuclei of major neurotransmitter systems that send long-range projections to regulate brain activity in cortical and subcortical structures. Despite being small structures, these nuclei are critically implicated in a very wide range of cognitive and bodily functions, and their dysfunction plays an important role in a number of neurological and neuropsychiatric conditions. Hence, there is a considerable interest to develop functional MRI approaches that allow to image their activity in health and disease.
... The cooccurrence of high and low dopamine activity in different neural circuits may explain the coexistence of negative and positive symptoms of schizophrenia (Davis et al., 1991). A subcortical/cortical imbalances and the involvement of several other neurotransmitters in the pathophysiology of schizophrenia are thought (Carlsson et al., 2000). The hypothesis was formulated based on the observation that (i) that dopamine concentrations and dopamine receptors activity in various subcortical areas in the brains of schizophrenic patients are increased, (ii) antipsychotics act by reducing dopamine activity in mesolimbic dopamine neurons, and (iii) negative symptoms of schizophrenia are associated with decreased dopamine activity in the prefrontal cortex, with prefrontal dopamine neurons inhibiting subcortical dopamine activity. ...
Both the discovery of biomarkers of schizophrenia and the verification of biological hypotheses of schizophrenia are an essential part of the process of understanding the etiology of this mental disorder. Schizophrenia has long been considered a neurodevelopmental disease whose symptoms are caused by impaired synaptic signal transduction and brain neuroplasticity. Both the onset and chronic course of schizophrenia are associated with risk factors-induced disruption of brain function and the establishment of a new homeostatic setpoint characterized by biomarkers. Different risk factors and biomarkers can converge to the same symptoms of schizophrenia, suggesting that the primary cause of the disease can be highly individual. Schizophrenia-related biomarkers include measurable biochemical changes induced by stress (elevated allostatic load), mitochondrial dysfunction, neuroinflammation, oxidative and nitrosative stress, and circadian rhythm disturbances. Here is a summary of selected valid biological hypotheses of schizophrenia formulated based on risk factors and biomarkers, neurodevelopment, neuroplasticity, brain chemistry, and antipsychotic medication. The integrative neurodevelopmental-vulnerability-neurochemical model is based on current knowledge of the neurobiology of the onset and progression of the disease and the effects of antipsychotics and psychotomimetics and reflects the complex and multifactorial nature of schizophrenia.
... They are the consequence of abnormal transmission of a series of neurotransmitters, particularly long-lasting hyper-secretion of dopamine and glutamate. It has the direct impact upon limbic and thalamo-cortical pathways, a phenomenon that leads to psychosis (Carlsson et al. 2000(Carlsson et al. , et al. 2001). ...
Background:
Brain maturation is considered completed around the age of 25, when prefrontal cortex maturation has been achieved. The aim of our study was to investigate the alterations of grey matter (GM) in patients with the onset of schizophrenia before and after the completion of brain maturation.
Subjects and methods:
The study group included 100 schizophrenia patients, while the control group comprised 50 healthy individuals. Brain magnetic resonance imaging was acquired on a 1.5 T scanner. Voxel-based morphometry (VBM) analyses were performed between groups.
Results:
GM of the schizophrenic patients is reduced in many regions (p<0.005 FDR corrected). Most widespread reduction is detected in frontal cortex and cerebellum, the other regions being limbic cortex, insula, cuneus, precuneus, superior temporal gyrus and motor cortex. The decrease of grey matter volume (GMV) increases with the increase in number of psychotic episodes and is more pronounced in the patients with earlier onset of the disease.
Conclusions:
The age of the onset of the disease is important for both total and relative loss of GMV. Earlier onset of schizophrenia, prior to full brain maturation results in significant reduction of GM in comparison with healthy subjects and patients with later, post full brain maturation onset of the disease.
... Upregulation of D2 receptors within the caudate nucleus is also reported to correlate with cognitive dysfunction (116). Additionally, indirect dopamine agonists, such as amphetamine and cocaine, have been shown to induce positive symptoms in the general population (117) with schizophrenia patients displaying an increased sensitivity to the dopamine-releasing effects of these drugs (118)(119)(120). ...
Schizophrenia is associated with increased levels of oxidative stress, as reflected by an increase in the concentrations of damaging reactive species and a reduction in anti-oxidant defences to combat them. Evidence has suggested that whilst not the likely primary cause of schizophrenia, increased oxidative stress may contribute to declining course and poor outcomes associated with schizophrenia. Here we discuss how oxidative stress may be implicated in the aetiology of schizophrenia and examine how current understanding relates associations with symptoms, potentially via lipid peroxidation induced neuronal damage. We argue that oxidative stress may be a good target for future pharmacotherapy in schizophrenia and suggest a multi-step model of illness progression with oxidative stress involved at each stage.
... The first and second generation antipsychotic drugs are well Excitatory glutamatergic and inhibitory GABA-ergic systems are both involved in the pathogenesis of schizophrenia (Carlsson, Waters, Waters, & Carlsson, 2000;Coyle, 1996;Olney, Newcomer, & Farber, 1999). The GABA-ergic neurons with hypofunctional N-methyl-Daspartate (NMDA) receptors have a key importance (Nakazawa, Jeevakumar, & Nakao, 2017). ...
Objective
Modulation of glutamatergic neurotransmission in schizophrenia by sarcosine leads to a reduction in primary negative symptoms, while its metabolic profile is safe. In order to extend research in the area, we assessed serum levels of neuropeptide Y (NPY), a hypothalamic hormone related to anxiety and depression, also involved in mechanisms inducing weight gain. Additionally, we analyzed associations between NPY concentrations and its changes with severity of symptoms and metabolic parameters.
Methods
A prospective 6‐month, randomized, double‐blind placebo‐controlled trial was completed by 57 subjects with chronic schizophrenia with predominant negative symptoms and stable antipsychotic treatment. The participants received 2 g of sarcosine (n = 28) or placebo (n = 29) daily. We assessed serum NPY concentrations and severity of symptoms (with the Positive and Negative Syndrome Scale [PANSS] and Calgary Depression Scale for Schizophrenia) at the beginning of the study, after 6 weeks and 6 months.
Results
Sarcosine did not affect NPY levels in all time points. The highest decrease in NPY concentrations was observed in the subjects who were initially depressed, who became euthymic at the last visit. We noticed an improvement in the total PANSS score, and negative symptom and general psychopathology subscales in the sarcosine group, however, without any correlation with NPY levels.
Conclusion
The use of sarcosine does not change NPY levels. Peripheral NPY concentrations may be related to depressive symptoms in schizophrenia.
... Memantine may modulate the neurotoxic glutamate activity while allowing normal activation of the receptor system. [41][42][43][44][45][46][47] Siskind et al 48 found memantine effective in the treatment of negative symptoms (PANSS, BPRS) SMD ¼ -0.56; 95% CI: -0.93, -0.20). Single studies have explored the use of memantine in the treatment of schizophrenia and as an augmenter of clozapine treatment. ...
Clozapine is established as the gold standard for antipsychotic treatment of patients suffering from treatment-resistant schizophrenia. Over virtually 3 decades, the level of inadequate response to clozapine was found to range from 40% to 60%. A heightened interest developed in the augmentation of clozapine to try to achieve response or maximize partial response. A large variety of drug groups have been investigated. This article focuses on the meta-analyses of these trials to discover reasonable evidence-based approaches to the management of patients not responding to clozapine.
... Abnormal behavior can be observed in juveniles, e.g. increased locomotor responsiveness to stress, novel environment, or amphetamine; N-methyl-D-aspartate glutamate receptor hypofunction that may account for both positive and negative symptoms of schizophrenia; spatial working memory deficits; and neuroinflammatory impairments [63][64][65]. Oral administration of risperidone (0.45 mg/kg/day) or paliperidone (0.05 mg/kg/day) stabilized the response of rat offspring (during peri-pubertal development (35-70 postnatal days) pretreated with poly I:C) to amphetamine exposure, which can be correlated with a longstanding stabilization of the mesolimbic dopamine system [61]. The ability of paliperidone (0.05 mg/kg/day) to prevent/reverse psychopathology in mice prenatally challenged with LPS was also investigated. ...
Introduction: Paliperidone is approved in the United States and Europe for the short- and long-term treatment of schizophrenia in adults and adolescents as well as for the acute treatment of schizoaffective disorder either as monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants. It is recommended in patients with hepatic impairment and evokes less drug–drug interactions.
Areas covered: This review article focuses on the preclinical discovery of paliperidone, the major active metabolite of risperidone. It provides details regarding paliperidone’s pharmacological and neurochemical mechanisms, and their contribution to therapeutic benefits and adverse effects, based on the available literature with respect to the preclinical and clinical findings and product labels.
Expert opinion: Paliperidone exhibits a high affinity and antagonistic activity toward D2 and 5-HT2A receptors, followed by 5-HT7, H1, α1, and α2 receptors. In preclinical studies, paliperidone produces antidepressant, anxiolytic, mood-stabilizing, analgesic actions, and affects the endocannabinoid system. It is also known to evoke procognitive, antioxidant, and anti-inflammatory activities. Its positive activity on neurogenesis, neuronal, and synaptic plasticity deserves to be emphasized. The clinical superiority of paliperidone is based primarily on the available formulations of the drug rather than in the subtle differences in its pharmacokinetic/pharmacodynamic properties compared to risperidone.
... Glutamate is the largest excitatory neurotransmitter in the brain. The glutamatergic system, comprising approximately 50% of all brain neurons, is responsible for the transmission and modulation of the majority of brain signals (Carlsson et al., 2000), but is also one of the major factors mediating schizophrenia-induced neurotoxicity, and glutamate-mediated excitotoxicity may account for certain structural changes present in schizophrenia (Plitman et al., 2014). Also, glutamate may regulate the activation of various DAMP molecules (e.g., S100B, HMGB1) (Tramontina et al., 2006;Faraco et al., 2007), which ultimately activate TLRs. ...
Increasing evidence suggests that in addition to neurochemical abnormalities, various immunological alterations are related to the pathogenesis of schizophrenia. Toll-like receptors (TLRs) actively mediate immune/inflammatory processes and play a pivotal role in damage/danger recognizing. Therefore, the aim of this study was to compare the expression of TLRs in peripheral blood mononuclear cells (PBMCs) in schizophrenic patients with those of healthy subjects. It also measures the metabolic status of the study subjects. Twenty-seven adult European Caucasian patients with paranoid schizophrenia and twenty-nine healthy volunteers were included in this prospective study. qRT-PCR assessed TLR mRNA expression levels. Body composition was measured using two methods: bioimpedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). The TLR1, TLR2, TLR4, TLR6, and TLR9 expression were down-regulated, in opposite to TLR3 and TLR7 which manifested higher expression in patients with schizophrenia. TLR5 and TLR8 mRNAs did not differ between groups. TLR mRNA expression was highly correlated. Decreased TLR expression may protect against excessive cell stimulation via exogenous and/or endogenous ligands, and may be recognized as a counterbalancing mechanism limiting the excessive development of inflammation.
... A key role in the pathophysiology of schizophrenia is played by the glutamatergic system, the main excitatory system of the human brain (Carlsson et al., 2000;Coyle, 1996;Olney et al., 1999). It is clearly important to understand the influence of glutamatergic dysfunction on negative, cognitive and affective pathologies, and the practical possibilities of its modulation are particularly encouraging (Hashimoto et al., focused on cognition and global functioning, both domains improved when both sarcosine and benzoate (1 g/day) were added. ...
Sarcosine, glycine transporter inhibitor, increases glycine levels around NMDA receptor, improving primary negative symptoms of schizophrenia. The aim of our study was to find a potential relationship between initial TNF-alpha level, its changes and schizophrenia symptoms severity, resulting from adding sarcosine to a stable antipsychotic treatment. Sixty subjects with stable schizophrenia were randomized to receive either 2 grams of sarcosine or placebo and completed a 6-month, double blind, placebo-controlled study. Three patients on sarcosine and one taking placebo did not complete TNF-alpha tests, planned at the beginning, after 6 weeks and after 6 months. For clinical assessments we used PANSS and CDSS scales. No changes in TNF-alpha serum concentrations in both groups at any time-points was noted. The sarcosine group achieved significant improvement in negative symptoms, general psychopathology and total PANSS score group, however without any significant correlations between TNF-alpha levels and PANSS scores in all assessments. Positive correlations between TNF-alpha levels and CDSS score were found in the placebo group and total study group. Initial TNF-alpha concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine. Sarcosine does not significantly affect TNF-alpha levels. TNF-alpha may be involved in mechanisms related to depressive symptomatology in schizophrenia.
... The dopaminergic and glutamatergic system of the brain are interconnected, and thus, inhibition of one system will influence the functioning of the other system [52]. The NMDA receptor antagonist diminishes the corticofugal inhibition of subcortical dopamine neurons and hence enhances dopaminergic transmission [53]. ...
Schizophrenia (SCZ) is a major debilitating, complex, and costly illness that strikes 1% of the world’s population. It is characterized by three general types of symptoms: Atypical symptoms (aggressiveness, agitation, delusions, hallucinations), depressive symptoms (alogia, avolition, anhedonia, apathy), and cognitive symptoms (impaired attention, learning, memory). The etiology of SCZ has still not been fully understood. Alteration in various neurochemical systems such as dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate are involved in the pathophysiology of SCZ. The lack of understanding regarding the exact pathogenic process may be the likely a reason for the non-availability of effective treatment, which can prevent onset and progression of the SCZ. The tools of modern neuroscience, drawing from neuroanatomy, neurophysiology, brain imaging, and psychopharmacology, promise to provide a host of new insights into the etiology and treatment of SCZ. In this review, we will discuss the role of the various neurotransmitter concerned and brain parts exaggerated in the SCZ.
... The role of both the closely related glutamatergic and GABA-ergic systems in the onset of schizophrenia is well established regarding its negative, positive, cognitive, and affective symptomatology ( Carlsson, Waters, Waters, & Carlsson, 2000;Coyle, 1996;Olney, Newcomer, & Farber, 1999). On this basis, the Polish Sarcosine Study in Schizophrenia (PULSAR) project was designed, with the dual aim of assessing the clinical effects of the substance modulating the function of glutamatergic system and observing various parameters associated with it. ...
Objective:
Augmentation of sarcosine, a natural inhibitor of the glycine transporter type I, normalizes glutamatergic neurotransmission, having beneficial impact on primary negative symptoms in schizophrenia and may also influence immune system and interleukin 6 (IL-6) levels.
Aim:
Finding a relationship between initial IL-6 serum concentrations or its changes and severity of symptoms as a result of sarcosine addition to stable antipsychotic treatment.
Method:
Fifity-eight individuals with schizophrenia with predominantly negative symptoms completed a 6-month randomized, double-blind placebo-controlled prospective study. Patients received 2 g of sarcosine (n = 29) or placebo (n = 30) daily per os. We measured IL-6 levels and severity of symptoms at the beginning, after 6 weeks and 6 months. As main clinical tools, we used Positive and Negative Syndrome Scale (PANSS) and Calgary depression scale for schizophrenia (CDSS).
Results:
Augmentation with sarcosine had no effect on IL-6 serum levels in all time points. We noted significant improvements in negative symptoms, general psychopathology, and total PANSS score in the sarcosine group. We found correlation of initial serum IL-6 with severity of positive symptoms and negative association between IL-6 levels reduction and positive symptoms reduction.
Conclusions:
Sarcosine does not significantly affect IL-6 concentrations but IL-6 may be involved in mechanisms related to the presence of positive symptoms.
... For example, Arvid Carlson, Paul Greengard, and Eric Kandel won the 2000 Nobel Prize in medicine after discovering that dopamine molecules act as a signal transduction and in the regulation of motor function, cognitive activity, drug addiction, and other physiological and pathological processes. 12 In 2010, the only crystal protein structure of the dopamine third receptor (D 3 R) was reported after problems with membrane protein stability and crystallization had been overcome. 19 In a previous study, we had obtained the D 3 R complex protein structure based on the crystal structure to furthermore study the interaction between D 3 R and dopamine and analyze how DA affects neurotransmitter function within the D 3 R spatial structure, which is considered to be surrounded by seven transmembrane helices. ...
In this article, the trajectories of S-deoxyephedrine (SBD) along molecular channels within the complex protein structure of third dopamine receptor (D3R) are analyzed via molecular dynamic techniques, including potential mean force calculations of umbrella samplings from the 4.5 version of the GROMACS program. Changes in free energy due to the movement of SBD within D3R are determined, and the molecular dynamic mechanisms of SBD transmitting along molecular channels are probed. Molecular simulated results show that the change in free energy is calculated as 171.7 kJ·mol–1 for the transmission of SBD toward the outside of the cell along the y+ axis functional molecular channel and is 275.0 kJ·mol–1 for movement toward the intracellular structure along the y– axis. Within the internal structure of D3R, the changes in free energy are determined to be 103.6, 242.1, 459.7, and 127.8 kJ·mol–1 for transmission of SBD along the x+, x–, z+, and z– axes, respectively, toward the cell bilayer membrane, which indicates that SBD leaves much more easily along the x+ axis through the gap between the TM5 (the fifth transmembrane helix) and TM6 (the sixth transmembrane helix) from the internal structure of D3R. The values of free-energy changes indicate that SBD molecules can clear the protective channel within D3R, which helps dopamine molecules to leave the D3R internal structure along the x+ axis and to prevent them for exerting excessive neurotransmitter function. Therefore, our results suggest that SBD is effective for development as a drug for treating schizophrenia and its pharmacology is closely related to its dynamics and mechanisms within the molecular pathway of dopamine receptors.
... In this study, the author argued that the left hemisphere released from right hemispheric influence domination over gestalt and emotional familiarity would be overbiased related to categorization, resulting in delusional thinking. However, other studies have suggested that a lack of frontal and right hemispheric inhibition, respectively, unleashes a "creative narrator" from the monitoring of self, memory, and reality leading to excessive and false explanations (30). Overall, these observations support the possibility that decreased gray matter volumes in the left hemisphere maybe primarily mediating delusions in patients diagnosed with schizophrenia. ...
Background
Delusional thinking is one of the hallmark symptoms of schizophrenia. However, the underlying neural substrate for delusions in schizophrenia remains unknown. In an attempt to further our understanding of the neural basis of delusions, we explored gray matter deficits and their clinical associations in first-episode schizophrenia patients with and without delusions.
Methods
Twenty-four first-episode schizophrenia patients with delusions and 18 without delusions as well as 26 healthy controls (HC) underwent clinical assessment and whole-brain structural imaging which were acquired a 3.0 T scanner. Voxel-based morphometry was used to explore inter-group differences in gray matter volume using analysis of covariance, and Spearman correlation coefficients (rho) between the Scale for the Assessment of Positive Symptoms (SAPS)-delusion scores and mean regional brain volumes was obtained.
Results
Patients with delusions showed decreased brain gray matter volumes in the left putamen, thalamus, and caudate regions compared with HC. Patients with delusions also showed decreased regional volume in the left putamen and thalamus compared with patients without delusions. SAPS-delusion scores were negatively correlated with the gray matter volumes of the left putamen and thalamus.
Discussion
Left putamen and thalamus volume loss may be biological correlates of delusions in schizophrenia.
... The 'glutamate hypothesis of SZ' posits that a dysfunctional glutamatergic system is a key pathophysiological mechanism contributing to the clinical symptoms seen in patients with SZ (Luby et al., 1959;Carlsson et al., 2000;Farber et al., 2002;Javitt, 2007;Javitt et al., 2012). The 'NMDA receptor hypofunction hypothesis of SZ', a more specific theory of the glutamate dysfunction hypothesis, has its origins in the observation that acute administration of NMDA receptor antagonists, such as ketamine and PCP, induces psychotic-like symptoms (delusions and hallucinations) in healthy controls (HCs) that are similar to those seen in patients with SZ (Krystal et al., 1994;Abi-Saab et al., 1998). ...
The pharmacological modulation of glutamatergic neurotransmission to improve cognitive function has been a focus of intensive research, particularly in relation to the cognitive deficits seen in schizophrenia. Despite this effort there has been little success in the clinical use of glutamatergic compounds as procognitive drugs. Here we review a selection of the drugs used to modulate glutamatergic signalling and how they impact on cognitive function in rodents and humans. We highlight how glutamatergic dysfunction, and NMDA receptor hypofunction in particular, is a key mechanism contributing to the cognitive deficits observed in schizophrenia, and outline some of the glutamatergic targets that have been tested as putative procognitive targets for the disorder. Using translational research in this area as a leading exemplar, namely models of NMDA receptor hypofunction, we discuss how the study of functional brain network connectivity can provide new insight into how the glutamatergic system impacts on cognitive function. Future studies characterising functional brain network connectivity will increase our understanding of how glutamatergic compounds regulate cognition and could contribute to the future success of glutamatergic drug validation.
... Taken together, an integration of the hyper-dopamine [75,76] and hypo-glutamate [77][78][79] theories of schizophrenia is needed. Current reviews on anatomical and pharmacological studies suggest that alterations in limbic thalamocortical pathways using dopamine, glutamate, and GABA as neurotransmitters contribute to psychosis [80][81][82][83]. ...
The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.
... DRD1 and DRD2, expressed by the medium spiny neurons in the striatum, are the predominant dopamine receptor subtypes in the brain that are activated by dopamine, and their integrative function is responsible for the majority of dopaminergic effects. A number of neurologic and psychiatric disorders, including drug addiction, attention deficit/hyperactivity disorder, depression, and schizophrenia, are associated with imbalances in dopaminergic signaling (6)(7)(8)(9)(10)(11); therefore, several antipsychotic and neuroleptic drugs that target dopamine receptors have been developed, some acting as antagonists of D2-like receptors (12)(13)(14)(15), whereas mood-stabilizing drugs exert their effects by regulating DRD2 functional expression (16). ...
The dopaminergic system plays an essential role in various functions of the brain, including locomotion, memory, and reward, and the deregulation of dopaminergic signaling as a result of altered functionality of dopamine D2 receptor (DRD2) is implicated in multiple neurologic and psychiatric disorders. Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Here, we tested the hypothesis that TSPAN7 may be a binding partner of DRD2 that is involved in the regulation of its functional activity. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization. Immunocytochemical analysis revealed that TSPAN7 that resides in the plasma membrane and early and late endosomes promoted internalization of DRD2 and its localization to endosomal compartments of the endocytic pathway. Furthermore, we observed that TSPAN7 deficiency increased surface localization of DRD2 concurrent with the decrease of its endocytosis, regardless of dopamine treatment. Finally, TSPAN7 negatively affects DRD2-mediated signaling. These results disclosed a previously uncharacterized role of TSPAN7 in the regulation of the expression and functional activity of DRD2 by postendocytic trafficking.-Lee, S.-A., Suh, Y., Lee, S., Jeong, J., Kim, S. Je., Kim, S. Ju., Park, S. K. Functional expression of dopamine D2 receptor is regulated by tetraspanin 7-mediated postendocytic trafficking.
... Fifty percent of brain neurons belong to this system, which, along with inhibitory GABAergic (γ-aminobutyric acid) system, is responsible for transmitting information and modulation of other system functioning. Glutamate with diverse population of its receptors-e.g., NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-is involved in the pathogenesis of schizophrenia [1,2]. Antagonists of NMDA receptor such as phencyclidine (commonly known as "angel dust") or ketamine cause symptoms mimicking schizophrenia [3] and exacerbate psychosis in schizophrenic patients including also negative and cognitive symptomatology [4]. ...
Aim:
Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9.
Method:
Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective RCT (randomized controlled trial). The patients received two grams of sarcosine (n = 28) or placebo (n = 30) daily. At the beginning, after six weeks and after six months MMP-9 levels were measured. Severity of symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS).
Results:
MMP-9 serum levels were stable after six weeks and six months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group compared to placebo; however, there was no correlations between serum MMP-9 concentrations and PANSS scores in all assessments. Initial serum MMP-9 concentrations cannot be used as an improvement predictor acquired during sarcosine augmentation.
Conclusions:
Our results indicate that either MMP-9 is not involved in the N-methyl-d-aspartate (NMDA)-dependent mechanism of sarcosine action in terms of clinical parameters or sarcosine induced changes in peripheral MMP-9 concentrations cannot be detected in blood assessments.
... On the basis of the finding that NMDA receptor open-channel blockers such as phencyclidine (PCP) cause severe symptoms of hallucination and psychosis, it is now well established that an impaired glutamatergic function in the brain and more specifically an unbalanced input of dopaminergic and glutamatergic projections in the limbic system and cortex are probably the most prominent features contributing to the pathophysiology of schizophrenia [17]. Several principles addressing glutamatergic pathways are currently under clinical investigation. ...
Definition and Diagnosis of Schizophrenia Etiology and Pathophysiology of Schizophrenia Epidemiology Medical Practice and Treatment Options Case Studies CATIE Conclusions References
... The role of the white matter (WM) in the pathogenesis of schizophrenia is underestimated and relatively poorly explored, compared with other brain regions, perhaps as a consequence of attributing the etiology of schizophrenia chiefly to grey matter dysfunctions. The approach resembles an evolving concept of the hierarchy of transmitter systems playing a key role in pathogenesis of schizophrenia [1][2][3][4][5]. It used to be believed that dopaminergic system impairment was responsible for the development of schizophrenia, followed later by the serotoninergic system disturbances and dysfunction of stimulatory/inhibitory role of the glutamatergic and GABAergic (GABA, γ-aminobutyric acid) systems [6]. ...
Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. 1H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.
... From the neurochemical perspective, negative and cognitive symptoms are associated with impairment of the glutamatergic system, especially in the PFC, where ionotropic NMDA receptors are abundant [10][11][12]. Glycine is a necessary co-agonist of the NMDA receptor, and sarcosine (N-methylglycine) is an exogenous amino acid that acts as an inhibitor of glycine transporter type 1 (GlyT-1) [13]. Thus, sarcosine should improve the inadequate function of NMDA receptors [12]: a hypothesis confirmed by the observed reduction of schizophrenia symptoms (negative and total symptomatology) associated with the augmentation of antipsychotic therapy with sarcosine [14][15][16][17][18] excluding clozapine [19] or treatment with sarcosine alone [20]. ...
The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (1H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla 1H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.
... One consequence of hyperstimulation of this and limbic loops may be the prevalence of visual hallucinations and psychosis during dopaminergic treatments. Note that increased dopamine function has been implicated in schizophrenia and psychosis (Carlsson et al., 2000). ...
... DA is used to help cells transmit pulse and mainly responsible for the brain's desire, feel the excitement and fun of information transmission, but also with addiction-related and plays an important role in the function of human metabolism, cardiovascular, renal, central nervous and hormonal systems. [1][2][3][4] However, abnormal levels of DA may be related to Schizophrenia, Huntington's disease, and Parkinson's disease, the latter of which has symptoms of tremor, rigid posture, slow movements, and a shuffling unbalanced walk. [5][6][7] So it is essential to develop methods to detect DA in biological fluids. ...
In this paper, we determined dopamine using screen-printed carbon electrodes (SPCEs) which was activated by 0.1 mol L-1 NaOH solution deposited on the electrode to improve the capabilities of detection. Cyclic voltammetry and differential pulse voltammetry were used to investigate the electrochemical behavior of dopamine. Cyclic voltammetry studies indicated that electrochemical oxidation of dopamine at the surface of SPCEs was decided by pH value. Different pulse voltammetry for dopamine oxidation at the SPCEs yielded a well-defined oxidation peak at 0.2V in 0.1 mol L-1phosphate buffer (pH 5.0). The proposed electrodes showed good selectivity for dopamine and a good linear relationship between dopamine concentration and oxidation current was obtained within the range of 2.0 × 10-7 mol L-1-300.0 × 10-6 mol L-1 with a detection limit of 6.7 × 10-8 mol L-1 (S/N = 3). In addition, the results showed that the precision in terms of reproducibility was 2.8% in the case of the activated SPCEs. The recovery rates of this technology were 95.40 to 103.4% with a relative standard deviation (RSD) was 2.7%-4.6%, indicating that this method can completely be used for detecting the practical dopamine injection sample. © 2015 The Electrochemical Society of Japan, All rights reserved.
... The increasing amount of data indicates a significant involvement of the glutamate, the main excitatory neurotransmitter of the human central nervous system in the pathogenesis of schizophrenia. Particular importance is attributed to hypofunction of ionotropic NMDA (N-methyl-D aspartate) receptor located on inhibitory GABAergic interneurons, morphologically and functionally closely related to glutamatergic neurons (Olney et al., 1999, Carlsson et al., 2000, Murray et al., 2014. ...
This study was undertaken with the purpose to determine if there are changes in metabolic parameters during 6-month add-on treatment with sarcosine in patients with schizophrenia. This was a randomized double blind, placebo-controlled and parallel group study. Eligible participants were randomly assigned to receive 2 g of sarcosine (n=30) or placebo (n=29). Sarcosine was administered as supplementation to the ongoing antipsychotic treatment. Augmentation with sarcosine had no effect on any of the analyzed cardiometabolic parameters. Also, augmentation with sarcosine had no effect on any of the analyzed body composition parameters. This is the first randomized placebo-controlled study to examine the metabolic safety of sarcosine in patients with schizophrenia. Clinically, this observation is of high importance considering how prevalent are metabolic abnormalities in patients with schizophrenia.
Prefrontal and striatal glutamate plays an important role in modulating striatal dopamine levels and an imbalance in regional glutamate has been identified in several psychiatric conditions. We hypothesized that this imbalance also exists in cannabis use disorder (CUD). We recently quantified the difference in regional glutamate of dorsal anterior cingulate (dACC) and striatum regions in the frontostriatal pathway using proton MRS at baseline and on verified abstinent days 7 and 21 in chronic users of cannabis (n = 20) in comparison with age- and sex- matched non-using controls (n = 10). In addition, the Barratt Impulsiveness Scale-11 (BIS) was collected as a measure of inhibitory impulse control of the participants. We found that the difference in glutamate concentrations between the dACC and striatum (ΔdACC-strGlu) of the controls was significantly higher than that of cannabis users across the study timeline (F(1,28) = 18.32, p < 0.0005). The group difference was not affected by age, sex, or alcohol/cigarette consumption. On abstinent day 7, ΔdACC-strGlu was significantly correlated with the corresponding ΔdACC-strGABA among the users (r = 0.837, p < 0.00001). On day 21, ΔdACC-strGlu was negatively associated with monthly cannabis use days (Spearman's rho = -0.444, p = 0.05). Self-reported BIS and its subscales were significantly altered among the users compared to the controls across the study timeline (total F(1,28) = 7.0, p = 0.013; non-planning F(1,28) = 16.1, p < 0.0005; motor F(1,28) = 5.9, p = 0.022; cognitive F(1,28) = 6.1, p = 0.019). These data provide preliminary evidence that chronic cannabis use may lead to a dACC-striatal glutamate imbalance in conjunction with poor impulse control.
Aberrant dopamine system function is thought to contribute to the positive symptoms of schizophrenia. Clinical imaging studies have demonstrated that the largest dopamine abnormality in patients appears to be an increase in presynaptic dopamine activity. Indeed, studies utilizing [18F]DOPA positive emission tomography (PET) reliably report increases in presynaptic dopamine bioavailability in patients and may serve as a biomarker for treatment response. The mechanisms contributing to this increased presynaptic activity in human patients is not yet fully understood, which necessitates the use of preclinical models. Dopamine system function can be directly examined in experimental animals using in vivo electrophysiology. One consistent finding from preclinical studies in rodent models used to study schizophrenia-like neuropathology is a two-fold increase in the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), termed population activity. We posit that increased striatal dopamine synthesis capacity is attributed to an augmented VTA dopamine neuron population activity. Here, we directly test this hypothesis using [ 3H]DOPA ex-vivo autoradiography, to quantify striatal dopamine synthesis capacity, in the methyazoxymethanol acetate (MAM) model, a validated rodent model displaying neurophysiological and behavioral alterations consistent with schizophrenia-like symptomatologies. Consistent with human imaging studies, dopamine synthesis capacity was significantly increased in dorsal and ventral striatal subregionis, including the caudate putamen (CPU) and nucleus accumbens (NAc), of MAM-treated rats and associated with specific increases in dopamine neuron population activity. Taken together, these data provide a link between mechanistic studies in rodent models and clinical studies of increased presynaptic dopamine function in human subjects.
The mGlu7 receptor belongs to the III group of metabotropic glutamatergic (mGlu) receptors and physiologically serves as an “emergency” receptor that is activated by high, almost pathological, glutamate concentrations. Of all mGlu receptors, this receptor is most highly expressed in the brain. Additionally, relatively intense expression of the receptor was found at the periphery, for example in the bowels or in the reproductive system of male mice, but this review will be focused predominantly on its role in the brain.
In the CNS, the receptor is expressed presynaptically, in the center of the synaptic cleft, at the terminals of both excitatory glutamatergic and inhibitory GABAergic neurons. Thus, it may regulate the release of both glutamate and GABA.
Schizophrenia is thought to develop as a consequence of a disturbed glutamatergic-GABAergic balance in different parts of the brain. Thus, the mGlu7 receptor may be involved in the pathophysiology of schizophrenia and consequently constitute the target for antipsychotic drug discovery.
In this review, we summarize the available data about mGlu7 receptor ligands and their activity in animal models of schizophrenia. At present, only a few ligands are available, and negative allosteric modulators (NAMs) appear to exert antipsychotic-like efficacy, indicating that the inhibition of the receptor could constitute a promising target in the search for novel drugs. Additionally, the data concerning the expression of the receptor in the CNS and putative mechanisms by which its inhibition may contribute to the treatment of schizophrenia will be discussed. Finally, the polymorphisms of genes encoding the receptor in schizophrenic patients will also be provided.
The precise molecular basis of schizophrenia is not completely understood. In this chapter, we will describe and examine the evidence from PET and SPECT imaging findings on the key role that dopamine, the neurotransmitter most strongly associated with schizophrenia, plays in its pathophysiology. We will review the evidence for presynaptic dopamine pathway dysfunction, which is most apparent in the associative striatum and involves abnormal elevations of dopamine synthetic capacity, dopamine release and synaptic dopamine levels. This dysfunction is well correlated with the increased likelihood, onset and worsening severity of schizophrenia. Furthermore, this association appears to be crucial in relation to the therapeutic response to dopamine antagonists.
Here, in addition we review the evidence for the mechanism of action of current antipsychotics, by examining the roles that pre- and postsynaptic dopamine modulation play in their clinical efficacy. Furthermore treatment resistance, current understanding about its neurological underpinnings and treatment strategies will be outlined. Finally, we explore the dopamine and non-dopaminergic mechanisms of potential novel therapies.
The catatonic syndrome is an example of a multifactorial neurobehavioral disorder that causes much morbidity and mortality but also has the potential to unlock the mystery of how motivation and movement interact to produce behavior. In this chapter, an attempt is made to understand better the catatonic syndrome through the lens of neurobiology and neuropathophysiology updated by recent studies in molecular biology, genomics, inflammasomics, neuroimaging, neural network theory, and neuropsychopathology. This will result in a neurostructural model for the catatonic syndrome that centers on paralimbic regions including the anterior and midcingulate cortices, as they interface with striatal and thalamic nodes in the salience decision-making network. Examination of neurologic disorders like the abulic syndrome, which includes in its extreme catatonic form, akinetic mutism, will identify the cingulate cortex and paralimbic neighbors as regions of interest. This exploration has the potential to unlock mysteries of the brain cascade from motivation to movement and to clarify catatonia therapeutics. Such a synthesis may also help us discern meaning inherent in this complex neurobehavioral syndrome.
Four years ago, at the beginning of my thesis in Neuropharmacology, the functional role of the central serotonin2B receptor (5-HT2BR) remained poorly investigated. Indeed, in light of the relatively recent discovery of its presence in the mammalian brain, as compared to other 5-HT receptors, only few studies had explored its impact within the central nervous system. Interestingly, it had been shown that 5-HT2BRs, while having no effect at the level of the nigrostriatal dopaminergic (DA) pathway, afford a tonic excitatory control on the activity of the mesoaccumbal DA tract. This differential influence on subcortical DA brain regions had led to the proposal that 5-HT2BR antagonists may be a useful tool for improved treatment of DA-related disorders requiring an independent modulation of the activity of ascending DA pathways, such ass chizophrenia. However, the effect of 5-HT2BR blockade at the level of themesocortical DA pathway, which plays a pivotal role in the the rapeutic benefit of atypical antipsychotic drugs (APDs), had never been studied. In addition,analysis of the literature revealed that 5-HT2BR blockade suppresses amphetamine and 3,4-methylenedioxymethamphetamine-induced neurochemical and behavioral responses, suggesting that this receptor may also be a relevant pharmacological target for treating drug addiction. Nevertheless,its possible implication in the effects induced by cocaine, one of the most worldwide abused drugs, remained unknown.Thus, the aim of the present thesis was to study the regulatory control exerted by the 5-HT2BR on both basal and cocaine-induced stimulation of DA activity,in order to evaluate its therapeutic relevance for improved treatment of schizophrenia and drug abuse and dependence. To this purpose, we assessed the effects of potent and selective 5-HT2BR antagonists (RS 127445 and LY266097) on DA activity, by using biochemical, electrophysiological and behavioral approaches in rats.In a first group of experiments, we found that 5-HT2BRs exert a tonic inhibitory control on DA outflow in the medial prefrontal cortex (mPFC). This finding, by showing that 5-HT2BRs afford differential controls over the three ascending DA pathways, indicates that 5-HT2BR antagonists display an ideal pattern of effects to restore normal DA function in schizophrenia. Accordingly, 5-HT2BRantagonists were efficient in several behavioral models aimed at predicting APD efficacy, and had no effect in a behavioral task reflecting APD propensity to induce motor side effects. In a second group of experiments performed to determine the mechanisms under lying the differential control exerted by 5-HT2BRs on DA activity, we demonstrated that 5-HT2BR antagonist-induced opposite effects on DA ouflow in the mPFC and the nucleus accumbens (NAc)involve a functional interplay with 5-HT1ARs expressed in the mPFC. Finally,we found that 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion.This effect, which occurs independently from changes of DA outflow in theNAc and the striatum, where DA activity is tightly related to cocaine-induced behavioral responses, likely involves a post-synaptic interaction in subcorticalDA brain regions.To conclude, the work accomplished over the past four years provides substantial information with regards to the functional role of 5-HT2BRs in the regulation of the activity of ascending DA pathways. In addition, while improving the understanding of the interaction between DA and 5-HT systems,the present findings altogether highlight the therapeutic potential of 5-HT2BRantagonists for treating schizophrenia and cocaine addiction.
The serotonin2B receptor (5-HT2BR), which was first cloned and characterized in the rat stomach fundus, is the most recent addition to the 5-HT2R family. While its involvement in the regulation of gastrointestinal, vascular, pulmonary and cardiac physiology has been widely investigated, its functional role within the central nervous system (CNS) has received much less attention. Nevertheless, when considering the data available in the literature with regards to the regulatory control exerted by the central 5-HT2BR on dopamine (DA) and serotonin (5-HT) neuron activity, a very interesting picture emerges and highlights the key role of these receptors for future therapeutic strategies of DA-related neuropsychiatric disorders.
Thus, the present review, by compiling molecular, biochemical, electrophysiological and behavioral findings from the literature of the past twenty years, aims at providing a sound analysis of the current knowledge supporting the interest of the central 5-HT2BR for future therapeutic avenues. First, we recall the neuroanatomical and functional data supporting the therapeutic relevance of the 5-HT/DA interaction in the CNS. Thereafter, after a short overview of the central expression and molecular properties of the 5-HT2BR, as well as of the 5-HT2BR agonists and antagonists available in the market, we will focus on the functional role of this receptor in the control of 5-HT, DA and neuroglia activity in the rodent brain. Finally, the therapeutic potential of 5-HT2BR antagonists for improved treatment of schizophrenia and drug addiction will be discussed.
In this paper, based on the complex protein structure of third dopamine receptor (D3R) with dopamine (DOP), we have studied the trajectories with the free energy changes of D3R for DOP to move along its molecular channels and then probed the molecular dynamics mechanism of DOP transmitting along molecular channels, using molecular dynamics techniques including the potential mean force (PMF) of umbrella samplings from the GROMACS program (version 4.5). Simulation results show that for DOP located in the space region of D3R to act as a neurotransmitter transmitting toward the outside of cell, the free energy change is 134.6 kJ∙mol⁻¹ along the functional molecular channel of y+ axis within D3R, and 211.5 kJ∙mol⁻¹ along the y－ axis towards the intracellular part. Within the structure of D3R, the free energy changes are 65.8, 245.0, 551.4, 172.8 kJ∙mol⁻¹ for DOP to transmit along the x+, x－, z+, z－ axes, respectively, towards cell bilayer membrane, indicating that DOP leaves more easily along the x+ axis through the gap between TM5 (the fifth transmembrane helix) and TM6 (the sixth transmembrane helix) from the internal structure of D3R. When free DOP molecules are located in the intercellular spaces, once they start moving along the inverse y+ axis direction under constant pressure and temperature, they spontaneously pass through the functional molecular channel to reach the space region of D3R to act as a neurotransmitter, because the free energy change between DOP and D3R along the inverse y+ axis direction is negative (−134.6 kJ·mol⁻¹). Therefore, DOP interacting with D3R can easily play the role of a neurotransmitter. After DOP molecules have performed the actions of a neurotransmitter, they leave the internal structure of D3R along the x+ axis of a protective molecular channel through the gap between TM5 and TM6 to avoid excessive function as transmitter. According to dopamine functional and protective molecular channels, we suggest new pathologies and the finding and development of new drugs for Parkinson’s disease and schizophrenia.
Aim:
Finding a relationship between schizophrenia symptoms severity and initial level of BDNF and its changes during augmentation of antipsychotic treatment with sarcosine.
Method:
57 individuals with schizophrenia with predominantly negative symptoms completed a 6-month RCT prospective study. The patients received 2g of sarcosine (n=27) or placebo (n=30) daily. At the beginning, after 6 weeks and 6 months BDNF levels were measured. Severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS).
Results:
BDNF serum levels were stable after 6 weeks and 6 months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group comparing to placebo, however there was no correlations between serum BDNF concentrations and PANSS scores in all assessments. Initial serum BDNF concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine.
Conclusions:
Our results indicate that either BDNF is not involved in the NMDA-dependent mechanism of sarcosine action or global changes in BDNF concentrations induced by amino-acid cannot be detected in blood assessments.
Dex-benzedrine (known as D-benzedrine or SAT) acts in dopamine receptors of central nerve cell system. In clinic, SAT is used to treat a variety of diseases; meanwhile, it has dependence and addiction. In order to investigate the pharmacology and addiction mechanisms of SAT as a medicine, in this paper, we have studied the structure of D3R complex protein with SAT, and based on which, by using potential mean force (PMF) with umbrella samplings and the simulated phospholipid bilayer membrane (or POPC bilayer membrane), the molecular dynamics simulation was performed to obtain free energy changes upon the trajectories for SAT moving along the molecular channels within D3R. The free energy change for SAT transmitting toward the outside of cell along the functional molecular channel within D3R is 83.5 kJ.mol−1. The change of free energy for SAT to permeate into the POPC bilayer membrane along the protective molecular channel within D3R is 87.7 kJ.mol−1. Our previous work gave that the free energy for Levo-Benzedrine (RAT) transmitting toward the outside of cell along the functional molecular channel within D3R is 91.4 kJ.mol−1, while it is 117.7 kJ.mol−1 for RAT to permeate into the POPC bilayer membrane along the protective molecular channel within D3R. The values of free energy suggest that SAT relatively prefers likely to pass through the functional molecular channel within D3R for increasing the release of dopamine molecules resulting in a variety of functional effects for SAT. The obtained results show that the pharmacology and addiction mechanisms of SAT as a drug are closely related to the molecular dynamics and mechanism for SAT transmitting along molecular channels within D3R.
Polypharmazie in der Behandlung der Schizophrenie ist – wie häufig auch in der Behandlung anderer psychischer Störungen – das Resultat einer Therapieresistenz. Bis zu 70% der schizophrenen Patienten erreichen keine Vollremission, mindestens 30% der Betroffenen sprechen auf zwei oder mehr Monotherapien mit modernen Antipsychotika nicht an.
Nach wie vor ist die Frage, ob eine Polypharmazie in der Behandlung der Schizophrenie Vorteile gegenüber einer Monotherapie hat, nicht eindeutig geklärt. Die klinische Praxis zeigt jedoch, dass entgegen wiederholt formulierter, plausibler Empfehlungen, z. B. in den Leitlinien von Fachgesellschaften, eine Monotherapie mit Antipsychotika zu verordnen, auch weiterhin häufig und regional sogar mit steigender Tendenz Kombinationstherapien durchgeführt werden. Obwohl bereits vor mehr als 10 Jahren das Fehlen kontrollierter Studien zur Polypharmazie und die daraus resultierende geringe wissenschaftliche Evidenz für eine weltweit in großem Umfang angewandte Praxis als „a dirty little secret“ kritisiert wurde, stellt Polypharmazie weiterhin eher die Regel als die Ausnahme dar und wird umso häufiger angewandt, je schwerer und je länger der Patient erkrankt ist.
Bis heute basiert die Diagnose der Schizophrenie auf der Beschribung psychopathologischer Veränderungen des Erlebens und Verhaltens [5, 27, 40]. Durch die Entdeckung der Neuroleptika wurde zugleich eine Verbindung dieses Krankheitsbildes zur Neurobiologie des Dopaminsystems hersgestellt [9, 11, 12]. Dieser Sachverhalt ließ die Psychiatrie in Bezug auf ihre wichtigste Erkrankungen über mehrere Jahrzehnte in einem höchst unzufriedenen Zustand. Einerseits ist die Schizophrenie durch ausgeprägte Veränderungen des Erlebens von Bedeutungsgehalten, vor allem in Bezug auf andere Menschen und auf ganz grundlegende Erfahrungen von Welt charakterisiert [2]. Andererseits wird die Erkrankung mit Substanzen therapiert, deren zerebrale Wirkungsweise bis vor Jahrzehnten, außer für Bewegungs- und hormonelle Abläufe, kaum bekannt war, und mit Nebenwirkungen, jedoch nicht mit therapeutischen Effekten in Verbindung gebracht wurde. In dieser Arbeit werden einige wichtige Entdeckungen bezüglich der Funktion des präfrontalen Kortex sowie der mesokortikalen und mesolimbisehen Wirkungsweise von Dopamin beschrieben und diese Befunde in Bezug zur Psychopathologie der Schizophrenie gesetzt. Es wird sich zeigen, dass Funktionsmodelle neuronaler Systeme bereits heute in Bezug auf pharmakologische und nicht pharmakologische Behandlungsstrategien sowie auf das Langzeitmanagement dieser Erkrankung anwendbar sind.
Halluzinogen wirkende Substanzen können in vier Gruppen eingeteilt werden: in die Indolalkylamine mit dem Grundgerüst der Aminosäure Tryptophan (Vorstufe von Tryptamin und Serotonin), die Phenylalkylamine mit dem Grundgerüst der Aminosäure Tyrosin (Vorstufe von Dopamin, Noradrenalin und Adrenalin) sowie bei einer umfassenderen Definition auch Anticholinergika und NMDA-Glutamatrezeptor-Antagonisten [15]. Zu den halluzinogen wirkenden Tryptamin-Abkömmlingen sind N,N-Dimethyltryptamin (DMT), (+)Lyserg-säurediethylamid ((+)LSD) und die β-Carboline Harmalin und Harmin zu rechnen. Zu den Phenylalkylaminen gehören Meskalin, Amphetamin und seine Derivate wie z.B. Ecstasy. Beispiele für Anticholinergika sind Atropin und Scopolamin und solche für nicht-kompetitiv wirkende NMDA-Rezeptor-Antagonisten Phencyclidin (PCP), Ketamin, Dextromethorphan und Dizocilpin (MK 801).
Bei Untersuchungen von Strukturvarianten bekannter Neuroleptika wurden vor über 40 Jahren die antidepressiven Wirkungen von Imipramin entdeckt. Mit der überzeugenden Wirksamkeit des Imipramin und seinen Analogen — den trizyklischen Antidepressiva — wurde eine neue Ära in der medikamentösen Behandlung der Depression eingeläutet. Alle trizyklischen Antidepressiva hemmen die Wiederaufnahme von Neurotransmittern, insbesondere von den biogenen Aminen Serotonin, Noradrenalin und Dopa-min. Ihre anticholinerge Wirkung ist therapeutisch unerwünscht und verursacht typische Nebenwirkungen wie Mundtrockenheit, verschwommenes Sehen und Harnverhalten. Bald danach wurden die Monoaminoxidase-Inhibitoren entdeckt, die durch Hemmung des Abbauenzyms der biogenen Amine eine vergleichbare Wirkung erzielten. Die zufällige Beobachtung der stimmungsaufhellenden Wirkung des Tuberkulosemedikaments Iproniazid in den frühen 50er Jahren und die Bestätigung der Wirkung bei depressiven Patienten führte zu der Erkenntnis, daß eine Nebenwirkung — die Hemmung der Monoaminoxidase — ein neues Prinzip zur Behandlung der Depression darstelle. Diese beiden Substanzklassen bildeten über viele Jahre die Standardtherapie der Depression. Hauptproblem sind die zum Teil schweren kardiotoxischen Nebenwirkungen, wobei etwa nach Suizidversuchen die Herzrhythmusstörungen schwer in den Griff zu bekommen sind.
Use of atypical antipsychotics in treatment of schizophrenia has given clinicians new alternatives in treatment. Although atypical antipsychotics have strong D2 antagonism and effects on the other receptors, particularly serotonergic receptors, one would suppose less extrapyramidal side effects and a lesser degree of prolactin increase, two side effects that would interfere with compliance also have been noted. Aripiprazole has a different receptor profile and show both agonistic and antagonistic effects on D2 receptors. Aripiprazole have been found a tolerable and safe new agent with different dopaminergic mechanisms, different effects on other receptors, sedation, extrapyramidal side effects, metabolic abnormalities, weight gain and cardiac rythym abnormalities. Moreover aripiprazole may normalize some metabolic abnormalities and glucose dysregulation. As aripiprazole can be administered without titration and have a favorable side effect profile, it may increase compliance of the patients in both acute slates and long term of treatment of schizophrenia.
The recent advances of molecular genetics in basic science, the number of genetic studies in the psychiatric field has been increasing in the last years. Clinical genetic studies revealed that not only schizophrenia and mood disorders but also some of the neurotic disorders such as anxiety disorders have a genetic component. Genetic knowledge obtained by genetic research must be applicable in clinical practice. Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of schizophrenia and bipolar disorder. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. The genetic mutations and chromosomal regions related to schizophrenia and bipolar disorder have been evaluated in this review.
Dopamine is produced as a neurotransmitter in the central nervous system (CNS) and as an intermediate in the synthesis of norepinephrine in peripheral sympathetic and CNS noradrenergic nerves and of epinephrine in adrenal chromaffin cells. L-dopa is then converted to dopamine by L-aromatic amino acid decarboxylase, an enzyme with a wide tissue distribution. After this step, dopamine is translocated by vesicular monoamine transporters into storage vesicles from where the amine is available for release by exocytosis. Dopaminergic neurons within the brain are sparse, representing less than one thousandth of a percent of all CNS neurons. Nevertheless, dopaminergic neurotransmission is crucial for regulating numerous aspects of brain function. Deranged CNS dopaminergic neurotransmission also contributes to several devastating neurological and psychiatric disorders. Mesencephalon dopaminergic neurons localized in the substantia nigra project mainly to the striatum to form the neostriatal pathway, whereas those of the ventral tegmental area project to cortical and limbic regions to form respective mesocortical and mesolimbic pathways.
Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.
Since the serendipitous discovery of typical antipsychotics in the treatment of schizophrenia, several molecules have been developed for their tolerance and a specific action. However, before any prescription of these molecules, in the spirit of the disorder, the concept of resistance to the treatment was evoked. Indeed, there is an inter-individual variation of response to antipsychotics in schizophrenic subjects that was described by specific scales of evaluation. It appears that clinical factors seem to contribute to the non response of treatment and they are not appreciated so well. Psychotics follow specific pathways and it is know that physiological and biochemical effects depend on factors. Thus, smoking habits, alcohol and diet have been described as factors influencing variability in drug response. While age, gender and genetic factors seem to contribute to the quality of therapeutic response. Evidence from family, twin and adoption studies clearly demonstrate the involvement of genetic factors in schizophrenia. Both linkage and association studies support this hypothesis. Although the results of such studies remain inconsistent regarding the heterogeneity of the disease. Refinement of the phenotype using the pharmacogenetic approach could thus be useful in the genetic studies of schizophrenia. Pharmacogenetic research claim to assess a possible interaction between the therapeutic targets of antispychotics and their specific mutations in candidate genes. High affinity of atypical antipsychotics for 5-HT2A receptors may explain their specific efficacy/tolerability profile compared to conventional antipsychotics. A number of reports have associated a silent 5-HT2A polymorphism (T102) with response to clozapine or risperidone. This polymorphism is in complete linkage disequilibrium with a -1438A/G polymorphism, located within the promoter region of the gene, with conflicting results. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response. On this basis, we re-assessed the possible influence of the −1438A/G polymorphism of the 5-HT2A receptor gene on the clinical efficacy of atypical antipsychotics with focus on several relevant dimensions. The A allele and the AA genotype of the −1438A/G polymorphism of the gene coding for the 5-HT2A receptor were not associated with therapeutic response to atypical antipsychotics in our sample. Furthermore, the AA genotype appeared to be associated with the SANS score, raising the possibility that negative symptoms in schizophrenia constitute a confounding factor between the 5-HT2A gene and atypical antipsychotic response. Traditionally, dopaminergic and serotoninergic sytems have been used as targets for antipsychotic therapy. Although, most available antipsychotics have a multitarget profile without any clear mechanism of action. Recently, atypical antispychotics have been found to display a wide range of affinities for several neurotransmitters. Neurobiological research suggest a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Epidemiology studies show that patients consume twice more of cannabis than the general population. An increase of the density of receptors is observed in the dorsolateral prefrontal cortex of schizophrenic post mortem samples. The CNR1 gene, that encodes the CB1 receptor, is located on chromosome 6q14-15, which has been considered as a susceptibility locus for schizophrenia. Recent progress in pharmacogenetics, evaluating the individual risk for antipsychotic refractoriness, has focused notably on the dopaminergic and serotoninergic systems. However, so far, these studies led to discrepant data. This led us to assess the possible influence of the 1359G/A polymorphism as a haplotype tagging SNP of the CNR1 gene, in comparison with three other SNPs covering 14kb across this gene, on the risk of schizophrenia and/or therapeutic response to atypical antipsychotics. We found no difference in 1359G/A polymorphism between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. Pharmacogenetics may in future lead to individualized pharmacotherapy based on the specific genetic, environmental and demographic characteristics of each patient. Pharmacogenetics could thus increase the patient comfort in terms of both higher initial response rates and reduced propensity to developing debilitating side-effects.
The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZM binding potential was associated with emergence or worsening of positive psychotic symptoms. This result suggests that psychotic symptoms elicited in this experimental setting in schizophrenic patients are associated with exaggerated stimulation of dopaminergic transmission. Such an observation would be compatible with an abnormal responsiveness of dopaminergic neurons in schizophrenia.
A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outflow. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D2/D3 positron-emission tomography radioligand [11C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n = 4), doubling the amphetamine dose produced a doubling in [11C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg/kg) was 44:1, demonstrating that relatively small binding changes reflect large changes in dopamine outflow. In the clinical study, patients with schizophrenia (n = 11) compared with healthy volunteers (n = 12) had significantly greater amphetamine-related reductions in [11C]raclopride specific binding (mean +/- SEM): -22.3% (+/-2.7) vs. -15.5% (+/-1.8),P = 0.04, respectively. Inferences from the preclinical study suggest that the patients' elevation in synaptic dopamine concentrations was substantially greater than controls. These data provide direct evidence for the hypothesis of elevated amphetamine-induced synaptic dopamine concentrations in schizophrenia.
The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments.
PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP).
On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment.
The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA.
These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism.
Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone.
Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.
Background:
According to the D2 dopamine receptor hypothesis of schizophrenia, there is an increased number of D2 receptors in the brains of schizophrenic patients than in those of healthy controls. We tested this hypothesis in 13 newly admitted neuroleptic-naive schizophrenic patients and 10 healthy volunteers using positron emission tomography.Method:
The quantification of striatal D2 dopamine receptor density (Bmax) and affinity (Kd) was done using an equilibrium model described for raclopride labeled with carbon 11.Results:
No statistically significant alterations were found in D2 receptor densities or affinities between the patient and control groups. However, a subgroup of four patients with a relatively high striatal D2 dopamine density was identified. Two patients, especially, had D2 dopamine densities almost twice as high as the mean control Bmax value. The Kd values also tended to be higher in this subset of patients than in the controls. No consistent striatal D2 dopamine receptor laterality was observed in schizophrenic patients or controls. However, an association of high D2 dopamine density in the left striatum and the mass of raclopride injected in the scan with low-specific radioactivity was observed in patients but not in controls.Conclusion:
There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.
Objective:
The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects.
Method:
Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM.
Results:
No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms.
Conclusions:
In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.
Muscimol (3-hydroxy-5-aminomethylisoxazole), originally isolated from 'Amanita muscaria', is the structural analogue of GABA. Muscimol was administered to six patients in a double-blind, placebo-controlled design. All subjects were diagnosed as having chronic schizophrenia. During high-dose muscimol treatment, all study subjects evidenced diffuse myoclonic twitching or somnolence, and many experienced vivid dreams, dizziness, and confusion. At dose levels below 5 mg, many patients experienced a tranquilizing effect from muscimol. These subjects, when receiving the active drug, reported feeling more relaxed and less anxious and claimed a positive drug experience, despite their lack of relief from psychotic thinking. No significant change in vital signs or routine laboratory studies occurred.
Recent animal experiments suggest that dopamine plays a less crucial role than formerly supposed in the regulation of psychomotor functions. This is illustrated by the finding that even in the almost complete absence of brain dopamine, a pronounced behavioural activation is produced in mice following suppression of glutamatergic neurotransmission. This paper discusses the possibility that a deficient activity within the corticostriatal glutamatergic/aspartergic pathway may be an important pathophysiological component in schizophrenia, and that glutamatergic agonists may be beneficial in the treatment of this disease. In addition, it is suggested that glutamatergic antagonists may be valuable supplements in the treatment of Parkinson's disease.
Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.
The precursor of serotonin, L-5-hydroxytryptophan (L-5-HTP), was radiolabelled with 11C in the beta-position, yielding [beta-11C]serotonin after decarboxylation, allowing positron emission tomography studies of L-5-HTP uptake across the blood-brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM-III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5-HTP across the blood-brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5-HTP across the blood-brain barrier is compromised in major depression.
In the present paper it is shown that when either of the noncompetitive NMDA antagonists MK-801 or ketamine are combined with the alpha-adrenergic agonist clonidine, a pronounced stimulation of locomotion is produced in monoamine-depleted mice. Likewise, when a subthreshold dose of MK-801 is combined with the muscarinic antagonist atropine, a forceful synergism with regard to locomotor activity in monoamine-depleted mice is observed. Furthermore, the present study shows that also in monoamine-depleted rats MK-801, as well as the competitive NMDA antagonist AP-5 (DL-2-amino-5-phosphonovaleric acid), interact synergistically with clonidine to enhance locomotor activity. Taken together, our findings suggest that central glutamatergic systems exert a powerful inhibitory influence on locomotion. Interfering with this inhibitory force by administration of an NMDA antagonist promotes locomotion and discloses the activational potential of other transmitter systems. The results are discussed in relation to 1) the pathophysiology of schizophrenia, with emphasis on the glutamate hypothesis of schizophrenia, and 2) implications for the treatment of Parkinson's disease.
It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.
The dopamine hypothesis of schizophrenia is still almost entirely based on pharmacologic evidence. Even though a disturbed dopamine function has not yet been established beyond doubt in schizophrenia, recent basic research on dopaminergic mechanisms opens up possibilities for the development of more sophisticated pharmacologic tools, capable of discovering subtypes of dopamine receptors, which may turn out to be abnormal in schizophrenia. Such tools may also prove therapeutically useful. Schizophrenia is probably a heterogeneous group of disorders with mixed biopathology. To facilitate the search for nondopaminergic mechanisms of possible pathogenetic importance in subgroups of schizophrenia, a hypothetical model is presented that tries to explain the role of subcortical dopaminergic pathways for mental functions and their interaction with other systems. It is proposed that corticostriatothalamocortical negative feedback loops, also involving the mesencephalic reticular formation, are modulated by mesostriatal dopamine pathways to control a thalamic filter mechanism. The psychotomimetic actions of dopaminergic agents and phencyclidine may be due to interference with these feedback mechanisms.
The (+)- and (−)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series ofin vivo biochemical and behavioral experiments. These studies showed that the (+)- and (−)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (−)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (−)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (−)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+)-forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors.
(+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission),e.g. in geriatric practice.
In the cerebrospinal fluid of 20 schizophrenic patients the glutamate level was found to be about half the normal value, whereas the serum glutamate was not altered. Preliminary evidence indicates that this reduced glutamate content is not due to neuroleptic treatment. The glutamate decrease is interpreted by the hypothesis that there is a dysfunction or degeneration of glutamatergic neurons in schizophrenia.
The quantitative structure-activity relationship between physicochemical properties and effects on dopamine (DA) synthesis and release in the rat brain, in a series of meta-substituted (S)-phenylpiperidines, has been investigated by means of partial least squares regression (PLS). The effect on DA synthesis caused by the drugs, in both non-pretreated and reserpine-pretreated rats, was assessed by measurements of tissue levels of L-DOPA accumulated in the striatum following treatment with a decarboxylase inhibitor. Assessment of effects on DA release was performed by analysis of perfusates collected from implanted microdialysis probes. The numerical characterization of the variation in physicochemical features of the phenylpiperidines used in the regression modeling was accomplished by using common tabulated aromatic and aliphatic substituent constants in combination with a set of property descriptors derived from molecular mechanics and semiempirical calculations. It was found that the biochemical responses could be accurately predicted by the regression models based on these molecular feature measures. The molecular features exerting influence on DA synthesis were found to be markedly different from those influencing DA release. This finding is discussed in terms of the possible existence of a dopamine receptor-mediated DA release-controlling mechanism, which may not involve the synthesis regulating DA D2 autoreceptor. Some findings regarding the impact of the piperidine N substituent on agonist properties of the drugs are reported. The regression models were also used for guidance in the search for a phenylpiperidine with a lower intrinsic activity, at the DA D2 type autoreceptor, than the partial DA agonist preclamol (3).
A previously performed post-mortem study comparing monoaminergic indices in the brains of 14 schizophrenic patients and 10 patients with psychosis not diagnosed as schizophrenia, with age-matched control cases without any known neuropsychiatric illness, was re-investigated, using multivariate analysis. The monoaminergic patterns showing up in this analysis suggested the existence of at least two different forms of the disease, both of which could be distinguished from the controls as well as from each other. One of the schizophrenic groups consisted of paranoid cases, and had a relatively mild family history, whereas the other group, mainly consisting of hebephrenic cases, had a severe family history. The former group showed low levels of dopamine and high levels of serotonergic precursor and metabolite, whereas the latter group in some respects tended to show the opposite aberrations. Neuroleptic treatment did not seem to account for the different biochemical profiles, unless one assumes that this treatment can cause completely different monoaminergic aberrations in different individuals. Instead, one could argue that the different biochemical profiles found are characteristic of the disease.
The correlation between the clinical activity of antipsychotic agents and their affinity for the D2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additional receptor systems. In particular, the high affinity of clozapine for the 5HT2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.
According to the D2 dopamine receptor hypothesis of schizophrenia, there is an increased number of D2 receptors in the brains of schizophrenic patients than in those of healthy controls. We tested this hypothesis in 13 newly admitted neuroleptic-naive schizophrenic patients and 10 healthy volunteers using positron emission tomography.
The quantification of striatal D2 dopamine receptor density (Bmax) and affinity (Kd) was done using an equilibrium model described for raclopride labeled with carbon 11.
No statistically significant alterations were found in D2 receptor densities or affinities between the patient and control groups. However, a subgroup of four patients with a relatively high striatal D2 dopamine density was identified. Two patients, especially, had D2 dopamine densities almost twice as high as the mean control Bmax value. The Kd values also tended to be higher in this subset of patients than in the controls. No consistent striatal D2 dopamine receptor laterality was observed in schizophrenic patients or controls. However, an association of high D2 dopamine density in the left striatum and the mass of raclopride injected in the scan with low-specific radioactivity was observed in patients but not in controls.
There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.
Corticostriatal glutamatergic neurons impinging on the so-called "direct" striato-thalamic pathways appear to act as a driving force with respect to psychomotor functions, whereas corticostriatal glutamatergic neurons projecting to the "indirect" striato-thalamic route appear to mediate inhibition of the thalamus and thus act as a "brake" with respect to psychomotor functions. The GABAergic striatal projection neurons pertaining to the "direct" pathway mediating behavioural stimulation appear to be phasically activated, whereas GABAergic striatal projection neurons pertaining to the "indirect" pathway mediating suppression of behaviour must be assumed to display a high tonic activity. Such an organization could explain some of the behavioural differences between competitive and un-competitive NMDA antagonists, since the binding of competitive NMDA antagonists is inhibited by glutamate, whereas the binding of un-competitive NMDA antagonists is enhanced by the presence of NMDA receptor agonists, a phenomenon called use/agonist dependence.
A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.
In vivo microdialysis was used to examine the effects of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801) on basal and d-amphetamine (AMPH)-induced release of dopamine (DA) in the striatum of freely moving rats. MK-801 [0.2 or 0.5 mg/kg, intraperitoneally (IP)] significantly increased spontaneous DA release in the striatum, whereas treatment with vehicle elicited no change in this variable. These data suggest that endogenous NMDA receptor activation exerts a tonic inhibitory influence upon striatal DA efflux. Systemic administration of AMPH (2.0 mg/ kg, IP) produced an 18-fold increase in extracellular DA; this effect was potentiated to 33-fold by pretreatment with 0.5 mg/kg MK-801. Pretreatment with 0.2 mg/kg MK-801 did not alter AMPH-induced DA release in striatum. Intrastriatal application, via the microdialysis probe, of 10 microM AMPH increased striatal DA efflux by 19-fold, but this local effect of AMPH was not altered by the MK-801 pretreatment. Thus, MK-801 increased DA efflux in response to systemic but not local AMPH, suggesting that a mechanism requiring the involvement of basal ganglia circuitry underlies this effect. It is hypothesized that NMDA receptor blockade indirectly activates the nigrostriatal DA system by opposing activation of inhibitory striatonigral GABAergic projection neurons.
The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the α-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2a
receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12 909. A putative “permissive” role of the 5-HT2 receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.
The present study was aimed at investigating the effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists D-CPPene (3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) on dopamine (DA) transmission and motor activity in mice and rats. As measures of DA release we used mouse brain 3-methoxytyramine (3-MT) levels, and indirect estimate of DA release, and striatal dialysate measures of DA in conscious and freely moving rats by means of microdialysis. To obtain additional information about monoaminergic neurotransmission, brain tissue levels of DA, DOPAC, HVA, 5-HT and 5-HIAA were measured in both mice and rats. The animals were sacrificed at the time when NMDA antagonist-induced locomotor stimulation was maximal. In mice, D-CPPene and CGS 19755 decreased striatal 3-MT levels, whereas, in general, 3-MT levels in the limbic forebrain were not significantly altered. Treatment with CGS 19755 decreased rat striatal dialysate levels of DA but increased 5-HIAA at time points when locomotor activity was increased. D-CPPene and CGS 19755 have been observed to produce psychotic symptoms in man. The present study suggests that these symptoms are not a result of an increase in central dopamine release.
The dopaminergic hypothesis of schizophrenia postulates increased brain dopaminergic activity. Two previous studies reported increased 18F-DOPA uptake with positron emission tomography in schizophrenic patients (n = 5, n = 7). In the present study, striatal dopaminergic function was assessed in vivo in six untreated schizophrenics and seven control subjects, comparable for age and sex. The 18F-fluoro-L-DOPA (18F-DOPA) uptake rate constant Ki was determined in the caudate and putamen using coregistered positron emission tomography and magnetic resonance imaging. No difference between groups for mean Ki was found. The variability of the 18F-DOPA uptake values was higher in the caudate (p < 0.01) and in the putamen (p < 0.001) in schizophrenic patients than in control subjects, suggesting that schizophrenia is a disorder involving heterogeneous states of the striatal presynaptic dopaminergic function.
In an ongoing effort to characterize the clinical pharmacologic profile of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP], we administered it to drug-free schizophrenic patients in two consecutive studies.
In a preliminary dose-finding study, 9 patients were treated using a 6-week placebo-controlled crossover design. Then, to properly demonstrate the antipsychotic effect, we carried out an early efficacy study; here 10 patients received (-)-3PPP, 300 mg B.I.D., in a 1-week placebo-controlled crossover study.
Dose-Finding Study: (-)-3PPP showed apparent antipsychotic effect in repeated dosing, with 300 mg B.I.D. being the most effective dose for antipsychotic action; however, the apparent antipsychotic action was not sustained for longer than 1 week, presumably because of desensitization of the receptor by the agonist. Early Efficacy Study: Positive symptoms as measured by the Psychosis Change Scale decreased in 1 week by 30% with (-)-3PPP compared to placebo, and negative symptoms measured with the Brief Psychiatric Rating Scale Withdrawal subscale decreased by 28% with the drug. In both studies, (-)-3PPP lacked any evidence of motor side effects.
These data show that psychotic symptoms decrease with (-)-3PPP and suggest that the treatment of schizophrenia with partial dopamine agonist is a promising strategy. Future attention will be directed toward testing techniques to diminish the tachyphylaxis to allow an ongoing therapeutic effect.
The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects.
Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM.
No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms.
In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.
Glutamatergic abnormalities have been associated with several psychiatric disorders, including schizophrenia and addiction.
Group II metabotropic glutamate receptors were targeted to normalize glutamatergic disruptions associated with an animal model
of schizophrenia, the phencyclidine model. An agonist of this group of receptors, at a dose that was without effects on spontaneous
activity and corticolimbic dopamine neurotransmission, attenuated the disruptive effects of phencyclidine on working memory,
stereotypy, locomotion, and cortical glutamate efflux. This behavioral reversal occurred in spite of sustained dopamine hyperactivity.
Thus, targeting this group of receptors may present a nondopaminergic therapeutic strategy for treatment of psychiatric disorders.
THE NMDA receptor antagonist phencyclidine (PCP) has low micromolar affinity for the 5-HT reuptake site, but it is uncertain whether PCP blocks 5-HT reuptake when given systemically to rats in behaviourally stimulating doses. We here report for the first time that systemically administered PCP (5 mg/kg, s.c.) increases extracellular 5-HT levels in the rat medial prefrontal cortex (to 322%) and dorsal hippocampus (to 233%). Increases were found also when citalopram (1 microM) was included in the perfusion medium (to 184 and 180%, respectively). Extracellular 5-HIAA concentrations increased during both conditions, and extracellular GABA decreased in the dorsal hippocampus. It is concluded that systemic PCP treatment elevates extracellular 5-HT levels, probably through mechanisms other than a blockade of 5-HT reuptake.
The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
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