Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs

Etude in vivo du contrôle inhibiteur tonique et phasique exercé par les récepteurs sérotoninergiques de type 5-HT2c sur l'activité des voies dopaminergiques nigrostriée et mésoaccumbale chez le rat

Ce travail, portant sur le récepteur sérotoninergique 2C (5-HT2c), a eu pour but d'approfondir la nature du contrôle tonique et phasique inhibiteur exercé par ce récepteur sur la libération de DA mesurée par microdyalyse intracérébrale dans le noyau accumbens (NAc) et le striatum chez le rat anestrhésié à l'halothane. A l'aide d'outils pharmacologiques appropriés (agoniste, agoniste inverse et antagoniste des récepteurs 5-HT2c), nous avons évalué 1) la participation de l'activité constitutive des récepteurs 5-HT2c in vivo 2) l'importance du niveau d'activité des neurones DA ascendants, et 3) l'existence de contrôles région-dépendants sur la voie DA mésolimbique. Dans les deux régions d'intérêt, l'effet excitateur de l'agoniste inverse 5 HT2c le SB 206553 sur la libération de DA est bloqué par l'antagoniste 5-HT2c le SB 242084 mais pas modifié par une réduction du tonus 5-HT central. Le SB 206553, sans effet sur la libération de DA induite par la clozapine, potentialise celle induite par l'halopéridol, alors que le SB 242084, sans effet sur l'halopéridol, bloque de façon dose-dépendante l'effet de la clozapine. Ces deux ligands 5-HT2c potentialisent la libération de DA évoquée par la cocaine alors que l'agoniste 5-HT2c le Ro 60-0175 ne la modifie pas, mais réduit celle induite par l'halopéridol. Enfin, l'application locale d'antagonistes 5-HT2c dans l'aire tegmentale ventrale (ATV) et le NAc bloque la diminution de la libération accumbale de DA induite par l'administration systémique du Ro 60-0175. Nos données montrent que 1) l'activité constitutive des récepteurs 5-HT2c participe au contrôle tonique inhibiteur exercé sur les neurones DA mésoaccumbaux et nigrostriés in vivo en conditions basales et activées ; 2) les récepteurs 5-HT2c modulent l'exocytose de DA de façon dépendante du degré d'activation des neurones DA ; 3) le contrôle inhibiteur de la voie DA mésolimbique implique, au moins en partie, les récepteurs 5-HT2c de l'ATV et du NAc. Ce travail ouvre des perspectives tant physiologiques que thérapeutiques quant au rôle des récepteurs 5-HT2c au sein des ganglions de la base.This study, concerning the serotonergic 2C (5-HT2c) receptor, was aimed to go deeper into the mechanisms of the tonic and phasic inhibitory control exerted by this receptor on DA release measured by intracerebral microdialysis in the halothane-anesthetized rat nucleus accumbens (NAc) and striatum. By using appropriate pharmacological tools (agonist, inverse agonist, antagonist of 5-HT2c receptors), we explored 1) the participation of the constitutive activity of 5-HT2c receptors in vivo 2) the relevance of the degree of activity of mesolimbic and nigrostriatal DA neurons, and 3) the existence of region-dependant controls of the mesolimbic DA pathway. In both brain regions, the excitatory effect of the 5-HT2c inverse agonist SB 206553 on DA release is blocked by the 5-HT2c antahonist SB 242084 but not modified by the reduction of the central 5-HT tone. SB 206553, without effect on clozapine-stimulated DA release, potentiates haloperidol-induced DA release, whereas SB 242084, without effect on haloperidol, dose-dependently blocks the DA effect of clozapine. Both 5-HT2c ligands potentiate cocaine-stimulated DA release while the 5-HT2c agonist Ro 60-0175 does not affect the DA effect of cocaine but reduces that of haloperidol. Finally, the local application of 5-HT2c antagonists in the ventral tegmental area (VTA) and the NAc blocks the inhibition of accumbal DA release induced by the systemic administration of Ro 60-0175. These findings show that 1) the constititive activity of 5-HT2c receptors participates in the tonic inhibitory control of mesoaccumbal and nigrostriatal DA neurons in vivo ; 2) 5-HT2c receptors modulate DA exocytosis in a manner that is dependent of the degree of activation of ascending DA neurons ; 3) the 5-HT2c-dependent inhibitory control of the mesolimbic DA pathway is mediated, at least in part, by 5-HT2c receptors located in the VTA and the NAc. This work brings up new physiological and therapeutical perspectivesconcerning the role of 5-HT2c receptors in the basal ganglia.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Expression of Glucocorticoid Receptor and Early Growth Response Gene 1 during Postnatal Development of Two Inbred Strains of Mice Exposed to Early Life Stress

Early life stress can elicit profound changes in adult gene expression and behavior. One consequence of early life stress is a decreased expression of glucocorticoid receptors (GRs) in the frontal cortex and hippocampus. However, neither the time of onset nor the mechanism(s) leading to decreased GR expression during postnatal development are known. The present study used two inbred strains of mice that differ in their behavioral responsiveness to stress (Balb/c and C57Bl/6), exposed them to an established paradigm of early life stress (infant maternal separation), and measured their expression of frontal cortical and hippocampal GRs and the putative transcriptional activator of the GR gene, early growth response gene (egr)-1, at defined stages of postnatal development. In both strains, real-time RT-PCR experiments revealed that decreased expression of GR in adolescence and adulthood is, in fact, preceded by increased GR expression during early life stress exposure. Thus, the early life stress-induced disruption of the normal stress-hyporesponsive period during infancy is accompanied by increased GR expression. Moreover, chronic treatment with the antidepressant drug fluoxetine during adolescence or adulthood reversed the effect of early life stress on adult GR mRNA expression. In contrast to the strain-independent effect of early life stress on GR expression, however, changes in egr-1 expression occurred only in Balb/c mice, and unlike the biphasic developmental changes in GR mRNA expression, egr-1 mRNA was decreased throughout postnatal development. Moreover, there was no consistent overlap of anatomic regions affected by decreased GR and egr-1 protein expression. Thus, in Balb/c mice, changes in GR and egr-1 expression can independently contribute to the phenotypes resulting from early life stress exposure. These findings illustrate that the impact of early life stress on gene expression changes is modulated by the genetic background and that the persistent changes in GR and egr-1 expression that arise early during postnatal developmental are reversible by chronic fluoxetine treatment during adolescence and adulthood

Predicting Dopaminergic Effects of L-DOPA in the Treatment for Parkinson's Disease

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Coordinated Recruitment of Cortical–Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats

International audiencePeople with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical–striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking

Serotonin2c receptor constitutive activity: in vivo direct and indirect evidence and functional significance.

International audienceSerotonin2c (5-HT2c) receptors are widely expressed in the central nervous system where they play a pivotal role in the regulation of neuronal network excitability. Along with this fundamental physiological function, 5-HT2c receptors are thought to be implicated in the pathophysiology of several neuropsychiatric disorders and have become a major pharmacological target for the development of improved treatments of these disorders. In the past decade, many studies have focused on the constitutive activity of 5-HT2c receptors and the therapeutic potential of drugs acting as inverse agonists. Although the constitutive activity of the 5-HT2c receptor has been clearly described in vitro, the transposition of this concept to living animals is often difficult to ascertain. Nevertheless, cumulating evidence has demonstrated the functional relevance of such property in regulating physiological systems in vivo both at the level of the central and peripheral nervous systems. The present review provides an update of the growing number of studies that show, by means of pharmacological tools, the participation of the constitutive activity of 5-HT2c receptors in the control of various biochemical and behavioural functions in vivo and emphasizes the functional organization of this constitutive control together with the phasic and tonic (involving the spontaneous release of 5-HT) modalities of the 5-HT2c receptor in the brain

Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease.

International audienceThe therapeutic benefit of L-DOPA is commonly attributed to restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. However, the loss of efficacy of L-DOPA after chronic use is paradoxically associated with a similar or enhanced striatal DA response. Release of L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant neurochemical responses beyond the striatum. Using multi-site intracerebral microdialysis in a rat model of Parkinson's disease, we showed that chronic L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously reduced basal 5-HT release and metabolism. These effects were paralleled by a decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment severely altered the brain pattern of 5-HT and DA release responses to L-DOPA (3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release. Our data demonstrate for the first time in vivo that the impairment of 5-HT neuronal function induced by chronic L-DOPA alters in a region-dependent manner L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the brain may favour the occurrence of both motor and non-motor side effects

L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson's disease.

International audienceL-DOPA is the gold standard medication of Parkinson's disease, a neurological disorder consequent upon the degeneration of mesencephalic dopaminergic neurons. The therapeutic efficacy of L-DOPA has been related to its ability to restore dopamine (DA) extracellular levels in the Parkinsonian brain. The origin of the L-DOPA-induced rise in DA has been the object of numerous studies and controversies but the data collectively point to serotonergic (5-HT) neurons as being most significant in the release. Here, we review biochemical and behavioral evidence supporting serotonergic neurons as playing the main role in the actions of L-DOPA, considered from two points of view. The main aspect concerns the biochemical demonstration that 5-HT neurons are almost solely implicated in the release of DA induced by L-DOPA. The mechanism of action of L-DOPA inside 5-HT neurons will be thoroughly dissected on the basis of L-DOPA effects on extracellular versus tissue DA levels. The unique contribution of 5-HT neurons in mediating the release of newly synthesised DA from L-DOPA will be discussed in parallel with DA-dependent behaviors induced by L-DOPA. The other, and neglected, aspect concerns the possible deleterious impact of the presence of L-DOPA inside 5-HT neurons on 5-HT neuronal function. Overall, the fact that 5-HT neurons release the newly synthesised DA from L-DOPA in multiple brain regions beyond the striatum gives new insight into the large impact of L-DOPA in the Parkinsonian brain and strengthens therapeutic perspectives targeting the 5-HT system to reduce both motor and non-motor complications of L-DOPA medication

A tobacco extract containing alkaloids induces distinct effects compared to pure nicotine on dopamine release in the rat

International audienceIt has been suggested that minor alkaloids in plants play a role in the biological and neuronal actions of nicotine. We hypothesized that these molecules modulate the effect of nicotine on the activity of central dopamine (DA) neurons, one of the main cellular targets in addiction to drugs. In this study the effect of a single intraperitoneal injection of either nicotine or an alkaloid extract of the tobacco plant (0.5 mg/kg) on the efflux of DA were investigated. DA was measured in vivo by intracerebral microdialysis in the nucleus accumbens and the striatum of freely-moving rats. Results show that nicotine enhanced accumbal and striatal DA extracellular levels (+47 and 20% above baseline, respectively). The extract also evoked a significant increase in DA extracellular levels in both regions (+33 and +38% above baseline). However, this effect was significantly higher compared to nicotine in the striatum only. In conclusion, the tobacco extract enhanced the neurochemical effect of nicotine alone in the striatum, a response that could underlie the higher propensity of developing addictive-like behavior using nicotine with tobacco alkaloids