Régis Bordet

Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.

Involvement of the direct striatonigral pathway in levodopa‐induced sensitization in 6‐hydroxydopamine‐lesioned rats

Induction of dopamine D3 receptor gene expression in 6‐hydroxydopamine‐lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3 receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P‐expressing neurons of the direct striatonigral pathway. In agreement, induction of D3 receptor binding sites was evidenced, using 7‐[3H]hydroxy‐N,N‐di‐propyl‐2‐aminotetralin ([3H]7‐OH‐DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway. Changes in D3 receptor binding and behavioural sensitization during intermittent administration of levodopa paralleled changes in prodynorphin/preprotachykinin rather than preproenkephalin/prodynorphin and preproenkephalin/preprotachykinin mRNA ratios. Behavioural sensitization, induction of D3 receptor binding and changes in prodynorphin/preprotachykinin ratio were all prevented together when levodopa was continuously delivered or intermittently delivered in combination with r‐(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine (SCH 23390), a selective D1 receptor antagonist. Our results indicate that functional changes of the direct striatal output pathway, possibly through an interaction between D1 and D3 receptors at the level of terminals in the substantia nigra pars reticulata, are important for the development of behavioural sensitization.

PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus.

Epidemiological data suggest that omega-3 polyunsaturated fatty acids (PUFA) consumption may be inversely correlated to the prevalence and severity of depression but little is known about the underlying mechanisms. In this study, we experimentally investigated whether a chronic supplementation with PUFA may induce antidepressant-like effects in mice in parallel to brain structural and molecular changes. Six weeks feeding with a PUFA-enriched diet induced behavioral changes in the Forced Swim Test (FST), the Tail Suspension Test and the Novelty-Suppressed Feeding Test. Moreover, more than 5 weeks supplementation with a PUFA blend containing 70% alpha-linolenic acid induced antidepressant-like effects in the FST with an increase in both swimming and climbing behaviors. The combination of a shorter duration of PUFA supplementation with a low dose of imipramine also induced an additive effect in the FST. Finally, PUFA supplementation was associated with an increase in the hippocampal volume, an over-expression of both synaptophysin and BDNF, and a raise in the number of newborn cells. Besides the possible modulation of brain plasticity, present results highlight the effectiveness of PUFA given alone or in combination with antidepressant drug as potential treatment of depressive disorders.

Beneficial effect of pharmacological mobilization of bone marrow in experimental cerebral ischemia

Bone marrow stem cells are able to differentiate into nervous and endothelial cells. In our study, we found that administration of a bone marrow-stimulating factor (granulocyte colony-stimulating factor; G-CSF 50 microg/kg) decrease the brain infarct volume and enhance survival rate in a model of cerebral ischemia. Taken together, these data suggest a beneficial effect of a pharmacological endogenous bone marrow mobilization in the course of cerebral ischemia and open a new direction for cellular therapy strategy in stroke.

Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson’s disease

Background: Therapeutic management of gait disorders in patients with advanced Parkinson’s disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb-related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology. Aim: To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters. Methods: Efficacy was blindly assessed on video for 17 patients in the absence of l-dopa and again after acute administration of the drug, both before and after a 3-month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale. Results: An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l-dopa after 3 months of taking MPD. The l-dopa-induced improvement in these various scores was also stronger after the 3-month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found. Interpretation: Chronic, high doses of MPD improved gait and motor symptoms in the absence of l-dopa and increased the intensity of response of these symptoms to l-dopa in a population with advanced PD.

Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia

Background and purpose:u2002 Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t‐PA) during the acute phase of cerebral ischaemia.

The dopamine D3 receptor and drug addiction

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of nucleus accumbens, a brain region in which neurons co-express the D1 (D1R) and D3 (D3R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D3R, through a cross-talk with the D1R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitization, a cardinal feature of addiction arises from repeated administration of drugs of abuse is thought to play a role in intensification of reinforcing efficacy of these drugs observed under certain conditions. Stimulation of the D3R also appears to enhance the reinforcing effect of cocaine in rats. By interacting with these processes, D3R agents have potential therapeutic applications for treating drug addiction. BP 897 (N-[4-(4-(2-methoxyphenyl) piperazin-1-yl) butyl] naphtalen 2-carboxamide dichlorhydrate), a partial and highly selective D3R agonistin vitro, behaves as an agonist or an antagonistin vivo depending on the response considered. BP 897 has the unprecedented property to reduce cocaine-seeking behavior induced by presentation of a cocaine-associated cue, without having any intrinsic reinforcing effect. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, D3R agents like BP 897 may represent new medications for drug addiction, with minimal liability to maintaining dependence.

Anticonvulsant effects of linolenic acid are unrelated to brain phospholipid cell membrane compositions

Purpose:u2002 Recent studies have revealed that polyunsaturated fatty acids (PUFAs) have anticonvulsive properties. Clinical trials using PUFAs reported conflicting results. It was suggested that PUFAs have anticonvulsant effects via modifications of brain phospholipids. Moreover, some authors suggested that the effect of the ketogenic diet (KD) leads to a high PUFA content. The aim of the study was to evaluate the anticonvulsant properties of a mixture containing α‐linolenic acid (ALA) and linolenic acid (LA).

Longitudinal reproducibility of default-mode network connectivity in healthy elderly participants: A multicentric resting-state fMRI study.

To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test-retest reproducibility in the consortium was high (ICC=0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test-retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈4% test-retest error, ICC=0.85), the medial frontal cortex the least reliable (≈12%, ICC=0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.

Effects of the PPAR-α Agonist Fenofibrate on Acute and Short-Term Consequences of Brain Ischemia

In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR-α generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR-α agonists could check the key points of a potential disease-modifying effect in stroke.