Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

Electrophysiological Investigation of Auditory Mismatch Negativity: A Brain-Based Biomarker of N-Methyl-D-Aspartate Signalling

Inconsistent reports on the therapeutic efficacy of increasing synaptic glycine concentration have raised doubt as to the benefit of N-methyl-D-aspartate receptor (NMDAr) mediated treatments for schizophrenia. Categorising individuals based on broad diagnostic criteria does not appear to adequately identify individuals who will benefit from such treatments. Mismatch negativity (MMN) may be a suitable biomarker of NMDAr function, to help clarify the neurobiological relationship between pharmacological intervention and clinical treatment efficacy. MMN is an auditory event-related potential elicited following the presentation of a deviant stimulus, when it violates an established sequence stored in echoic memory. MMN is a robust deficit in schizophrenia and is categorised as a physiological element in the Cognitive Systems domain of the Research Domain Criteria framework. However, few studies have examined direct pharmacological modulation of MMN in schizophrenia patients. The aim of this thesis was to determine the nature of the relationship between MMN and NMDAr function, to inform the relative utility of MMN as a biomarker of NMDAr-mediated improvements in clinical symptoms in schizophrenia. To achieve this aim, three separate empirical studies were performed..

Neural substrates mediating the behavioural effects of antipsychotic medications and pavlovian cues : importance for maladaptive processes in psychiatric disorders

Les antipsychotiques sont administrés chroniquement pour prévenir de nouveaux épisodes psychotiques dans la schizophrénie. Ces médicaments diminuent l’activité des récepteurs dopaminergiques de type 2. Diminuer chroniquement la transmission dopaminergique induit des compensations pouvant mener à une sensibilisation du système dopaminergique. Cette sensibilisation pourrait diminuer l’efficacité des antipsychotiques et exacerber la psychose. Chez le rat, la sensibilisation dopaminergique induite par les antipsychotiques augmente les effets psychomoteurs et motivationnels des agonistes dopaminergiques. Le premier objectif de la présente thèse était de caractériser les substrats neuronaux régulant l’expression de la sensibilisation dopaminergique évoquée par les antipsychotiques. Ceci est important afin d’améliorer le traitement à long terme de la schizophrénie. Pour ce faire, des rats ont reçu un traitement cliniquement pertinent à l’antipsychotique halopéridol. Ce traitement sensibilise aux effets psychomoteurs de l’agoniste dopaminergique d-amphétamine. Cet indice comportemental de sensibilisation dopaminergique a été utilisé pour déterminer les contributions spécifiques du système dopaminergique et l’implication des effets centraux de la d-amphétamine. Puisqu’il y a une relation étroite entre le stress et l’activité dopaminergique, les réponses liées au stress ont également été mesurées. Ceci est important, puisque le stress exacerbe la psychose. La présente thèse démontre que les récepteurs dopaminergiques régulent de manière distincte la sensibilisation dopaminergique. En effet, la transmission via les récepteurs de type 2 exacerbe cette sensibilisation, alors que la transmission via les récepteurs de type 1 la tempère. Également, la présente thèse suggère que des processus périphériques sont nécessaires à l’expression de la sensibilisation dopaminergique. De plus, la sensibilisation pourrait augmenter les réponses au stress. En effet, cette sensibilisation est renversée lorsque la synthèse de l’hormone de stress corticostérone est inhibée, en plus d’être associée à certains comportements suggérant un stress augmenté. Chez le rat, la sensibilisation dopaminergique évoquée par les antipsychotiques potentialise également les effets motivationnels des stimuli conditionnés prédisant des récompenses. Lorsque ces stimuli acquièrent trop de valeur motivationnelle, ils peuvent motiver des comportements pathologiques. Ainsi, une potentialisation de la valeur motivationnelle des stimuli conditionnés provoquée par les antipsychotiques pourrait avoir des implications importantes dans des processus motivationnels anormaux dans la schizophrénie, tels que la psychose et la forte prévalence de toxicomanie. Ainsi, le deuxième objectif de la présente thèse était d’étudier les mécanismes neurobiologiques régulant les effets comportementaux des stimuli conditionnés, particulièrement le rôle du noyau basolatéral de l’amygdale. Ici, le rôle de ce noyau a été étudié chez des animaux non traités aux antipsychotiques, puisque sa contribution reste incomprise. Ce travail pourrait révéler des mécanismes neurobiologiques potentiellement impliqués dans la sensibilisation dopaminergique évoquée par les antipsychotiques. La présente thèse démontre que l’activation optogénétique de l’amygdale basolatérale potentialise les effets comportementaux des stimuli conditionnés, en augmentant leur valeur motivationnelle et leur capacité à guider le comportement vers des récompenses imminentes. Ainsi, une activité excessive de l’amygdale basolatérale pourrait attribuer trop de pouvoir aux stimuli conditionnés, et ceci pourrait jouer un rôle dans l’état motivationnel anormal provoqué par les antipsychotiques. La présente thèse identifie de nouveaux mécanismes par lesquels les antipsychotiques et les stimuli conditionnés favorisent des réponses pathologiques.Schizophrenia requires long-term antipsychotic treatment to prevent psychosis relapse. Antipsychotic drugs temper psychotic symptoms by reducing dopamine D2 receptor-mediated signalling. Chronically decreasing dopamine transmission produces neuronal compensation leading to supersensitivity to dopamine stimulation. In patients, this dopamine supersensitivity would compromise antipsychotic efficacy and exacerbate psychotic symptoms. In laboratory animals, antipsychotic-evoked dopamine supersensitivity enhances the psychomotor and reward-enhancing effects of dopamine agonists. The first objective of the present thesis was to characterize the biological substrates mediating the expression of antipsychotic-evoked dopamine supersensitivity, a necessary work for developing better long-term treatment strategies. To do so, rats were chronically exposed to a clinically relevant antipsychotic treatment regimen, using the drug haloperidol. Haloperidol produces dopamine supersensitivity, as indicated by an exaggerated psychomotor response to the dopamine agonist d-amphetamine. This behavioural index of supersensitivity was used to examine the specific contributions of the dopamine system and the central effects of d-amphetamine. Given that there is a close relationship between stress and dopamine activity, it was also determined whether antipsychotic-evoked dopamine supersensitivity alters stress-like responses. This is important to consider because stress is a contributing factor to psychosis relapse. The present thesis first reveals that D1- and D2-mediated transmissions contribute distinctively to the expression of antipsychotic-evoked dopamine supersensitivity, with D2 transmission promoting this supersensitivity and D1 transmission tempering it. The present thesis also provides evidence that peripheral processes play a necessary role in dopamine supersensitivity. Additionally, antipsychotic-evoked dopamine supersensitivity could potentiate stress-like responses. Indeed, the expression of supersensitivity is reversed by inhibition of the synthesis of the stress hormone corticosterone and is linked with some signs of heightened stress-related behaviours. In rats, antipsychotic-evoked dopamine supersensitivity potentiates the incentive motivational effects of reward-predictive conditioned stimuli. When these stimuli acquire too much motivational value, they motivate maladaptive responses. Hence, the increased motivational value of conditioned stimuli elicited by antipsychotic exposure could be involved in impaired motivational processes found in schizophrenia, such as psychosis and the greater vulnerability to drug addiction. Thereby, the last goal of the present thesis was to investigate the neurobiological substrates mediating the behavioural effects of reward-predictive stimuli, with a special focus on the role of the basolateral nucleus of the amygdala. This was investigated in antipsychotic-naïve rats because there are important caveats in our current understanding of the functional role of the basolateral amygdala. Such investigation could give novel insights on the neurobiological effects of antipsychotic-evoked dopamine supersensitivity. Here it is shown that optogenetic stimulation of basolateral amygdala neurons potentiates the behavioural effects of conditioned stimuli, by increasing their motivational value and their ability to guide behaviour toward impending rewards. The implication for this is that excessive activity in the basolateral amygdala could attribute too much motivational power to conditioned stimuli, and this could be involved in the abnormal motivational state produced by antipsychotic drugs. Taken together, the present thesis provides novel mechanisms by which antipsychotic drugs and reward-predictive stimuli promote maladaptive responses

Antipsychotic-induced sensitization and tolerance: Behavioral characteristics, developmental impacts, and neurobiological mechanisms

Antipsychotic sensitization and tolerance refer to the increased and decreased drug effects due to past drug use, respectively. Both effects reflect the long-term impacts of antipsychotic treatment on the brain and result from the brain’s adaptive response to the foreign property of the drug. In this review, clinical evidence of the behavioral aspect of antipsychotic sensitization and tolerance is selectively reviewed, followed by an overview of preclinical literature that examines these behavioral characteristics and the related pharmacological and nonpharmacological factors. Next, recent work on the developmental impacts of adolescent antipsychotic sensitization and tolerance is presented and recent research that delineates the neurobiological mechanisms of antipsychotic sensitization and tolerance is summarized. A theoretical framework based on “drug learning and memory” principles is proposed to account for the phenomena of antipsychotic sensitization and tolerance. It is maintained that antipsychotic sensitization and tolerance follow basic principles of learning or acquisition (“induction”) and memory (“expression”). The induction and expression of both effects reflect the consequences of associative and nonassociative processing and are strongly influenced by various pharmacological, environmental, and behavioral factors. Drug-induced neuroplasticity, such as functional changes of striatal dopamine D2 and prefrontal serotonin (5-HT)2A receptors and their mediated signaling pathways, in principle, is responsible for antipsychotic sensitization and tolerance. Understanding the behavioral characteristics and neurobiological underpinnings of antipsychotic sensitization and tolerance has greatly enhanced our understanding of mechanisms of antipsychotic action, and may have important implications for future drug discovery and clinical practice

Typical and atypical neuroleptic drug effects on dopamine and other neurotransmitter functions in rodents

The antischizophrenic effect of neuroleptic drugs probably arises from blockade of central dopamine receptors which also leads to extrapyramidal side effects (EPSEs). The aim of the work described in this thesis was to elucidate how some drugs, the so-called atypical neuroleptics, alleviate the symptoms of schizophrenia without producing marked EPSEs. An intracerebral microdialysis system was developed and used to monitor the acute effects of neuroleptic drugs on dopamine release and metabolism in the caudate putamen (CP), nucleus accumbens (NAc) and medial prefrontal cortex (MPFC) of halothane-anaesthetised rats. Dopamine and its metabolites DOPAC and HVA were estimated in brain dialysates by HPLC with electrochemical detection. In other studies extracellular recording techniques were used to assess the effects of neuroleptics and dopamine agonists on the spontaneous activity of neurons in the CP and MPFC. Both haloperidol (typical neuroleptic) and clozapine (atypical) elevated the efflux of dopamine metabolites in the CP, NAc and MPFC although only clozapine significantly facilitated dopamine efflux and this was restricted to the MPFC. Neither neuroleptic showed any consistent effects on neuronal activity in the CP, however, unlike haloperidol, but similar to the dopamine agonist apomorphine, clozapine both stimulated and inhibited neuronal activity in the MPFC. The ability of these agents to antagonise the effects of apomorphine was also evaluated. Apomorphine produced a dose-dependent inhibition of neuronal activity and efflux of dopamine and metabolites in both the CP and the MPFC. Although fewer cells in the MPFC showed any response to apomorphine compared with those in the CP, those that did, were markedly more sensitive to the inhibitory effects of this agent. The effects of apomorphine were reversed by haloperidol but only partially reduced by clozapine. Since clozapine did not alter the time course of apomorphine appearance in CP dialysates and haloperidol only reduced the appearance at one dose level, it was concluded that the antagonism of apomorphine's actions in the CP and MPFC were directly mediated. The differential effects of haloperidol and clozapine on dopamine function in the CP and MPFC are discussed in respect of their typical and atypical profiles. The weak dopamine (apomorphine) antagonism shown by clozapine in the CP would account for the low incidence of EPSEs seen with this compound although its relatively weak action in the MPFC implies that its antischizophrenic action must stem, at least in part, from other actions. The ability of clozapine to enhance the efflux (release?) of dopamine in the MPFC could explain its efficacy against the negative symptoms of schizophrenia. A possible mechanism to account for the ability of clozapine to alleviate the positive aspects of this disorder (despite weak dopamine receptor antagonism) is also discussed. In other experiments designed to reveal the nature of clozapine's atypical action its effects on 5-HT3 mediated release of dopamine in the NAc as well as on the contraction of guinea-pig ileum in-vitro were studied. It was also compared with other atypical and typical neuroleptics on muscarinic, a-adrenergic and tachykinin receptors in the guinea- pig ileum and rat vas-deferens. The effects of typical and atypical neuroleptics in all these preparations is discussed in an attempt to explain their differential clinical effects

Regulation of Akt and Wnt signalling by the dopamine D2 receptor and metabotropic glutamate receptor 2/3

Akt and the Wnt pathway, two cascades that regulate GSK-3, have been implicated in schizophrenia and antipsychotic drug action. Although it is known that antipsychotic drugs alleviate psychosis by blocking the dopamine D2 receptor (D2DR) and that metabotropic glutamate receptor 2/3 (mGluR2/3) agonists may improve some of the symptoms of schizophrenia, it is unclear if both classes of drugs exert their effects through Akt, GSK-3 and/or the Wnt pathway or if changes in these pathways are mediated through the D2DR and mGluR2/3 respectively. In addition to antipsychotics, mood stabilizers and antidepressants also target GSK-3, suggesting that there must be something unique in the way GSK-3 is targeted by antipsychotics since neither mood stabilizers nor antidepressants alleviate psychosis. The current study examined whether Akt and the Wnt pathway are regulated by the D2DR and mGluR2/3 and investigated the role of Akt and Dvl-3, a key activator in the Wnt pathway, in regulating GSK-3 in the rat brain. The study also compared the effects of antipsychotic, mood stabilizers and antidepressants on Akt and Wnt pathway proteins to determine if antipsychotics have unique effects on these signalling proteins. Results showed that raclopride (D2DR antagonist) regulated Akt and the Wnt pathway via Dvl-3 and the response was identical to antipsychotic treatment. Administration of the mGluR2/3 agonist, LY379268 also targeted Akt and the Wnt pathway and induced a similar response as antipsychotics. In addition, repeated amphetamine treatment, an established animal model for the positive symptoms of schizophrenia, quinpirole (D2DR agonist) and LY341495 (mGluR2/3 antagonist) induced similar changes in Akt and Wnt signalling that parallel alterations reported in schizophrenia. Furthermore, systemic inhibition of GSK-3 was able to attenuate the increase in locomotion induced by LY341495, a behavioural measure that models the positive symptoms of schizophrenia. The study also showed that clozapine and haloperidol (antipsychotics) induced a common Wnt response that was not mimicked by the mood stabilizers or antidepressants tested but that all neuropsychiatric drugs tested induced changes in Akt. Collectively the data shows that the Wnt pathway is regulated specifically by drugs with antipsychotic properties and may represent a novel target for pharmaceutical intervention

Could dopamine agonists aid in drug development for anorexia nervosa?

Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways

Antipsychotic-induced sensitization and tolerance: Behavioral characteristics, developmental impacts, and neurobiological mechanisms

Antipsychotic sensitization and tolerance refer to the increased and decreased drug effects due to past drug use, respectively. Both effects reflect the long-term impacts of antipsychotic treatment on the brain and result from the brain’s adaptive response to the foreign property of the drug. In this review, clinical evidence of the behavioral aspect of antipsychotic sensitization and tolerance is selectively reviewed, followed by an overview of preclinical literature that examines these behavioral characteristics and the related pharmacological and nonpharmacological factors. Next, recent work on the developmental impacts of adolescent antipsychotic sensitization and tolerance is presented and recent research that delineates the neurobiological mechanisms of antipsychotic sensitization and tolerance is summarized. A theoretical framework based on “drug learning and memory” principles is proposed to account for the phenomena of antipsychotic sensitization and tolerance. It is maintained that antipsychotic sensitization and tolerance follow basic principles of learning or acquisition (“induction”) and memory (“expression”). The induction and expression of both effects reflect the consequences of associative and nonassociative processing and are strongly influenced by various pharmacological, environmental, and behavioral factors. Drug-induced neuroplasticity, such as functional changes of striatal dopamine D2 and prefrontal serotonin (5-HT)2A receptors and their mediated signaling pathways, in principle, is responsible for antipsychotic sensitization and tolerance. Understanding the behavioral characteristics and neurobiological underpinnings of antipsychotic sensitization and tolerance has greatly enhanced our understanding of mechanisms of antipsychotic action, and may have important implications for future drug discovery and clinical practice

The role of dopamine, 5-hydroxytryptamine, sigma and NMDA receptors in the action of antipsychotic drugs

http://www.ester.ee/record=b1053244~S1*es