A trans-diagnostic perspective on obsessive-compulsive disorder

© Cambridge University Press 2017. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Progress in understanding the underlying neurobiology of obsessive-compulsive disorder (OCD) has stalled in part because of the considerable problem of heterogeneity within this diagnostic category, and homogeneity across other putatively discrete, diagnostic categories. As psychiatry begins to recognize the shortcomings of a purely symptom-based psychiatric nosology, new data-driven approaches have begun to be utilized with the goal of solving these problems: specifically, identifying trans-diagnostic aspects of clinical phenomenology based on their association with neurobiological processes. In this review, we describe key methodological approaches to understanding OCD from this perspective and highlight the candidate traits that have already been identified as a result of these early endeavours. We discuss how important inferences can be made from pre-existing case-control studies as well as showcasing newer methods that rely on large general population datasets to refine and validate psychiatric phenotypes. As exemplars, we take 'compulsivity' and 'anxiety', putatively trans-diagnostic symptom dimensions that are linked to well-defined neurobiological mechanisms, goal-directed learning and error-related negativity, respectively. We argue that the identification of biologically valid, more homogeneous, dimensions such as these provides renewed optimism for identifying reliable genetic contributions to OCD and other disorders, improving animal models and critically, provides a path towards a future of more targeted psychiatric treatments.Peer reviewedFinal Published versio

Indiviididevahelised erinevused rottide afektiivses käitumises: neurokeemilised uuringud

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Erinevate neurokeemiliste, näiteks monoamiinsete, süsteemide normaalse funktsioneerimise tasakaalu muutumine võib viia mitmete meeleolu- ja sõltuvushäirete tekkimiseni. Depressiooniga seotud häirete uurimisel kasutatakse sageli uudistaval käitumisel põhinevaid teste. Lisaks on leitud, et nii uudistavad kui ka sõltuvusega seotud käitumise regulatsioonis omavad rolli just monoamiinsed neurotransmitterid, mille süsteemide mõjutamine toob kaasa ka erinevused loomade käitumises. Eelnevalt oleme leidnud, et uudiskasti meetodil määratud indiviididevahelised erinevused uudistamisaktiivsuses on ajas püsivad ning neid indiviididevahelisi erinevusi on ka neurotransmitterite regulatsioonis. Mikrodialüüsi katsed näitasid, et serotonergiline süsteem on eri ajupiirkondades erinevalt reguleeritud. Väheuudistavatel (LE) rottidel on frontaalkoores kõrgemad rakuvälised serotoniini sisaldused kõrgemad peale serotoniini transpordi inhibeerimist tsitalopraamiga. Vastupidised tulemused ilmnesid hipokampuses, kus kõrgemad serotoniini tasemed olid just paljuuudistavatel (HE) rottidel. Kuna hiljutised uuringud on näidanud, et monoamiinide kõrval võib ka glutamaadi süsteemil olla oluline roll depressiooni kujunemisel, siis uuriti ka glutamaadi sisaldusi erineva uudistamisaktiivsusega rottidel. Leiti, et võrreldes väheuudistavate rottidega, on paljuuudistavatel rottidel kõrgemad glutamaadi sisaldused peale glutamaadi transpordi inhibeerimist juttkehas, kuid mitte hipokampuses. Sellest järeldub, et indiviididevahelised erinevused uudistavas käitumises võivad olla seotud lisaks serotonergilisele ka glutamatergilise närviülekandega. Uudistav käitumine on suurel määral sõltuv sinava tuuma (locus coeruleus) noradrenaliini projektsioonidest. Rotid, kellel on antud süsteemi kahjustus, käituvad uudiskasti testis nagu LE-fenotüüp, mida on seostatud madalama dopaminergilise neurotransmissiooni efektiivsusega. uuriti, kas sinava tuuma projektsioonid on olulised dopaminergilisele süsteemile toimivatele psühhostimulantide efektidele. Leiti, et ulatuslik sinava tuuma projektsioonide kahjustus närvitoksiiniga DSP-4 [N-(2-kloroetüül-N-etüül-2-bromobensüülamiin] vähendas psühhostimulandi kokaiini poolt stimuleeritud kohaeelistust ja liikumisaktiivsust. Kuna elusündmused varajases elustaadiumis võivad samuti omada mõju neurokeemilistele süsteemidele, siis uuriti kas alkoholist tingitud efektid monoamiini süsteemidele on sõltuvad varajasest elukeskkonnast. Leiti, et erinevused serotonergilises süsteemis olid just alkoholi eelistavatel loomadel, kes olid noores eas emast kõige kauem eraldatud. Siit järeldub, et varajases eas toimuvatel sündmustel on oluline mõju alkoholi tarbimisele ning serotonergilise süsteemi toimimisele. Leiti, et nendel alkoholi eelistavatel loomadel, kes olid noores east emast kaua eraldatud, olid serotoniini tasemed madalamad just mandelkehas, mida seostakse enim just sõltuvushäirete tekkimisega. Siit järeldub, et varajases eas toimuvatel sündmustel on oluline mõju alkoholi tarbimisele ning serotonergilise süsteemi toimimisele. Viimastel aastatel on negatiivsete afektiivsete seisundite kõrval hakatud rohkem uurima positiivse emotsionaalsuse võimaliku rolli üle depressiooni kujunemisel. Positiivset emotsionaalsust on võimalik uurida mõõtes rottide ultraheli-häälitsusi. Nüüdseks on leitud, et rottidel on püsivad indiviidivahelised erinevused nende 50-kHz ultraheli häälitsustes, mida seostatakse rottide positiivse emotsionaalsusega. Antud töös leiti, et stressi tingimustes on vähepiuksuvatel rottidel kõrgemad serotoniini tasemed peale serotoniini transpordi tagasihaarde inhibeerimist. Lisaks on samadel rottidel kõrgemad kortikosterooni tasemed. Antud tulemustest järeldub, et madalama positiivse emotsionaalsusega rotid on stressile vastuvõtlikumad. Võttesse arvesse neurotransmitterite erinevat regulatsiooni rottide käitumise kujunemisel võib jõuda depressiooniga seotud seisundite uudsete farmakoloogiliste ravimeetoditeni.Inter-individual differences, that are probably caused by variations in the regulation of neurochemical pathways, exist between organisms, and are likely to be significant in the pathogenesis of affective disorders. Depression is a highly prevalent psychopathological condition. In order to investigate depression the tests based on exploratory behaviour of rats are mostly used. Studies in the present dissertation indicate that rats with different exploratory phenotype differ, in addition to catecholaminergic mechanisms, also with regard to regulation of serotonergic and glutamatergic systems. Serotonergic neurotransmission in hippocampus and prefrontal cortex was found to be regionally differentially regulated in low exploring (LE) and high exploring (HE) rats. In prefrontal cortex, the LE-rats had higher extracellular serotonin levels induced by citalopram and higher levels of serotonin transporter binding. In dentate gyrus, contrary, the HE-rats had higher levels of extracellular serotonin. Additionally, HE-rats had increased levels of glutamate after blockade of glutamate transporter in striatum. Exploratory behaviour is very much dependent on the function of the noradrenergic projections of the locus coeruleus. All rats with near complete denervation of these projections behave in the exploration box test like the spontaneous LE-phenotype that has been associated with less efficient dopaminergic neurotransmission. It appeared that extensive denervation of the noradrenergic projections from locus coeruleus indeed reduced the effect of cocaine-induced place preference and locomotor activation. Early life experiences may also affect neurochemical mechanisms and thereby influence the behavioural pattern later in life. Thus, the effect of maternal separation (as the early life stress) on alcohol consumption was studied. It appeared that animals that experienced long maternal separation had low serotonin levels in amygdala and responded with an increase in serotonin after ethanol intake, which is a key area in addiction processes. Predisposition to express positive affect at low levels had previously been linked to vulnerability to depression. We could confirm the higher sensitivity of the LC-rats that produce less 50-kHz vocalizations to chronic stress: they gained weight more slowly and had higher corticosterone levels measured from full blood after stress. LC-rats have also differences in serotonergic mechanisms after chronic stress was supported by the finding that stressed LC-rats had higher extracellular serotonin levels induced by citalopram in hippocampus, where serotonergic system has been known to mediate response to anxious stimuli. These findings support the notion that male rats with low 50-kHz USVs response to tickling, having lower positive emotionality, are behaviourally more vulnerable to stress. Taken together, the consideration of these neurobiological differences between individuals could lead to novel approaches to more personalized medical treatment of depression-related states

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

Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations

Glucocorticoid hormones (GCs) released from the fetal/maternal glands during late gestation are required for normal development of mammalian organs and tissues. Accordingly, synthetic glucocorticoids have proven to be invaluable in perinatal medicine where they are widely used to accelerate fetal lung maturation when there is risk of pre-term birth and to promote infant survival. However, clinical and pre-clinical studies have demonstrated that inappropriate exposure of the developing brain to elevated levels of GCs, either as a result of clinical over-use or after stress-induced activation of the fetal/maternal adrenal cortex, is linked with significant effects on brain structure, neurological function and behaviour in later life. In order to understand the underlying neural processes, particular interest has focused on the midbrain dopaminergic systems, which are critical regulators of normal adaptive behaviours, cognitive and sensorimotor functions. Specifically, using a rodent model of GC exposure in late gestation (approximating human brain development at late second/early third trimester), we demonstrated enduring effects on the shape and volume of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (origins of the mesocorticolimbic and nigrostriatal dopaminergic pathways) on the topographical organisation and size of the dopaminergic neuronal populations and astrocytes within these nuclei and on target innervation density and neurochemical markers of dopaminergic transmission (receptors, transporters, basal and amphetamine-stimulated dopamine release at striatal and prefrontal cortical sites) that impact on the adult brain. The effects of antenatal GC treatment (AGT) were both profound and sexually-dimorphic, not only in terms of quantitative change but also qualitatively, with several parameters affected in the opposite direction in males and females. Although such substantial neurobiological changes might presage marked behavioural effects, in utero GC exposure had only a modest or no effect, depending on sex, on a range of conditioned and unconditioned behaviours known to depend on midbrain dopaminergic transmission. Collectively, these findings suggest that apparent behavioural normality in certain tests, but not others, arises from AGT-induced adaptations or compensatory mechanisms within the midbrain dopaminergic systems, which preserve some, but not all functions. Furthermore, the capacities for molecular adaptations to early environmental challenge are different, even opponent, in males and females, which may account for their differential resilience or failure to perform adequately in behavioural tests. Behavioural “normality” is thus achieved by the midbrain dopaminergic network operating outside its normal limits (in a state of allostasis), rendering it at greater risk to malfunction when challenged in later life. Sex-specific neurobiological programming of midbrain dopaminergic systems may, therefore, have psychopathological relevance for the sex bias commonly found in brain disorders associated with these systems, and which have a neurodevelopmental component, including schizophrenia, ADHD (attention/deficit hyperactivity disorders), autism, depression and substance abuse

Behavioural addiction-A rising tide?

The term 'addiction' was traditionally used in relation to centrally active substances, such as cocaine, alcohol, or nicotine. Addiction is not a unitary construct but rather incorporates a number of features, such as repetitive engagement in behaviours that are rewarding (at least initially), loss of control (spiralling engagement over time), persistence despite untoward functional consequences, and physical dependence (evidenced by withdrawal symptoms when intake of the substance diminishes). It has been suggested that certain psychiatric disorders characterized by maladaptive, repetitive behaviours share parallels with substance addiction and therefore represent 'behavioural addictions'. This perspective has influenced the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which now has a category 'Substance Related and Addictive Disorders', including gambling disorder. Could other disorders characterised by repetitive behaviours, besides gambling disorder, also be considered 'addictions'? Potential examples include kleptomania, compulsive sexual behaviour, 'Internet addiction', trichotillomania (hair pulling disorder), and skin-picking disorder. This paper seeks to define what is meant by 'behavioural addiction', and critically considers the evidence for and against this conceptualisation in respect of the above conditions, from perspectives of aetiology, phenomenology, co-morbidity, neurobiology, and treatment. Research in this area has important implications for future diagnostic classification systems, neurobiological models, and novel treatment directions.This research was supported by a Grant from the Academy of Medical Sciences (UK) to Dr Chamberlain. Dr Chamberlain consults for Cambridge Cognition. Dr Grant has received research Grants from the National Center for Responsible Gaming, and Forest and Roche Pharmaceuticals. Dr Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies and has received royalties from Oxford University Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill. Dr. Goudriaan was supported by an innovative scheme Grant of the Dutch Scientific Association (ZonMw VIDI Grant no. 016.136.354) and received support from the European Association for Alcohol Research, the National Center for Responsible Gaming and has consulted for TüV Germany. The other authors report no potential conflicts of interest or funding declarationsThis is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.08.01

Lateral habenula regulates temporal pattern organization of rat exploratory behavior and acute nicotine-induced anxiety in hole board

Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems worldwide, and is the first preventable cause of death. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here we have focused on nicotine-induced anxiety-like behavior in unlesioned and lesioned lateral habenula (LHb) rats. Firstly, we showed that acute nicotine induces anxiogenic effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.) as measured by the hole-board apparatus, and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the LHb induced a significant anxiogenic effect, reduced the mean occurrences of T-patterns detected, and strikingly reverted the nicotine-induced anxiety to an anxiolytic effect. We suggest that LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulating serotonergic/dopaminergic nuclei.peer-reviewe