5 research outputs found
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-naĂŻve 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
Le rôle de la neurotensine dans l’expression de la sensibilisation dopaminergique induite par un traitement continu aux antipsychotiques
Les médicaments antipsychotiques améliorent les symptômes de la schizophrénie, mais peuvent perdre leur efficacité à long terme en sensibilisant le système dopaminergique. Les mécanismes sous-tendant cette sensibilisation ne sont pas connus. Le neuropeptide neurotensine module le système dopaminergique et est régulé par les antipsychotiques dans le noyau accumbens. Dans cette région, la neurotensine peut avoir des effets anti- et pro-dopaminergiques via les récepteurs NTS1. Nous avions pour hypothèse que la neurotensine du noyau accumbens module l’expression de la sensibilisation dopaminergique induite par les antipsychotiques. Ainsi, nous avons traité par intermittence ou continuellement des rats à l’antipsychotique halopéridol. Seule l’administration continue sensibilise le système dopaminergique et donc sensibilise aux effets locomoteurs de l’amphétamine. Des microinjections de neurotensine dans le noyau accumbens ont diminué l’hyperlocomotion induite par l’amphétamine chez les rats témoins et ceux traités par intermittence aux antipsychotiques. Au contraire, la sensibilisation dopaminergique induite par un traitement continu serait liée à une augmentation des effets pro-dopaminergiques de la neurotensine. Ceci est indépendant d’un changement de densité des récepteurs NTS1 dans le noyau accumbens. Un traitement intermittent n’a pas d’effet sur cette mesure également. De plus, autant un traitement antipsychotique continu qu’intermittent augmentent la transcription de proneurotensine. Donc, seule l’altération de la fonction de la neurotensine du noyau accumbens corrèle avec la sensibilisation dopaminergique. En parallèle, dans le caudé-putamen, un traitement continu augmente la transcription de proneurotensine et un traitement intermittent augmente la densité des récepteurs NTS1. En somme, la neurotensine du noyau accumbens module la sensibilisation dopaminergique induite par les antipsychotiques.Antipsychotic medications improve schizophrenia symptoms, but they can also sensitize the dopamine system over time, consequently leading to impaired treatment efficacy. The mechanisms underlying antipsychotic-evoked dopamine supersensitivity are not known. The neuropeptide neurotensin regulates the dopamine system and can be modulated by antipsychotics, particularly in the nucleus accumbens. In this area, neurotensin has both anti- and pro-dopaminergic effects via an interaction with NTS1 receptors. In the present study, we hypothesized that neurotensin in the nucleus accumbens can modulate the expression of dopamine supersensitivity-evoked by an antipsychotic treatment. We treated rats with the antipsychotic haloperidol administered either intermittently or continuously. Continuous, but not intermittent, haloperidol treatment induces dopamine supersensitivity as shown by an increased locomotor activity induced by amphetamine. Microinjections of neurotensin in the nucleus accumbens diminish amphetamine-induced locomotion in control and intermittently antipsychotic-treated rats. Dopamine supersensitivity-evoked by a continuous antipsychotic treatment is linked to a potential enhancement of the pro-dopaminergic effects of neurotensin. This is not caused by any change in NTS1 receptor levels in the nucleus accumbens. An intermittent treatment did not alter NTS1 receptor levels as well in this area. Also, both continuous and intermittent treatment increased neurotensin transcription in the nucleus accumbens. Thus, only neurotensin altered function correlates with dopamine supersensitivity. In the caudate-putamen, continuous antipsychotic treatment increased neurotensin transcription, whereas intermittent treatment increased NTS1 receptor levels. In summary, neurotensin in the nucleus accumbens can modulate the expression of dopamine supersensitivity-evoked by antipsychotics
Metabotropic group II glutamate receptors in the basolateral amygdala mediate cue-triggered increases in incentive motivation
Rationale: Reward-associated cues can trigger incentive motivation for reward and invigorate reward-seeking behaviour via Pavlovian-to-instrumental transfer (PIT). Glutamate signaling within the basolateral amygdala (BLA) modulates cue-triggered increases in incentive motivation. However, the role of BLA metabotropic group II glutamate (mGlu2/3) receptors is largely unknown.
Objectives: In Experiment 1, we characterized cue-triggered increases in incentive motivation for water reward using the PIT paradigm. In Experiment 2, we assessed the influence of intra-BLA microinjections of the mGlu2/3 receptor agonist LY379268 on this effect.
Methods: Water-restricted male Sprague-Dawley rats learned to press a lever for water. Separately, they learned to associate one of two auditory cues with free water. On test days, rats could lever press under extinction conditions (no water), with intermittent, non-contingent CS+ and CS- presentations. In Experiment 1, rats were tested under baseline conditions. In Experiment 2, rats received intra-BLA microinjections of LY379268 (0, 3 and 6 [Formula: see text]g/hemisphere) before testing.
Results: Across experiments, CS+, but not CS-, presentations increased water-associated lever pressing during testing, even though responding was reinforced neither by water nor the CS+. Intra-BLA LY379268 abolished both CS+ potentiated pressing on the water-associated lever and CS+ evoked conditioned approach to the site of water delivery. LY379268 did not influence locomotion or instrumental and Pavlovian response rates during intervals between CS presentations or during the CS-, indicating no motor effects.
Conclusions: mGlu2/3 receptor activity in the BLA mediates cue-triggered potentiation of incentive motivation for reward, suppressing both cue-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour
Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats
Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity
The conditioning and extinction of fear in youths: What's sex got to do with it?
a b s t r a c t Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses