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Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD.

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age-dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13-15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements.

Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction.

Introduction The major substrate underlying amphetamine (AMPH)-induced locomotor activity is associated with dopamine forebrain circuits. Brain regions associated with AMPH-induced locomotor activity express high levels of retinoid receptors. However, the role of these transcription factors in dopamine-mediated effects remains poorly understood. Two nuclear receptor families, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR), transduce retinoic acid signal. RARs are specifically involved in retinoid signaling, whereas RXRs also participate in other signaling pathways as partners for other nuclear receptors such as Nur77, an orphan member of the nuclear receptor family expresses in dopamine system. Materials and methods To explore the role of retinoid receptors and Nur77 in AMPH-induced locomotor activity, we administered selective retinoid receptor drugs in combination with AMPH in adult wild-type and Nur77-deficient mice. At a low dose, AMPH similarly increased ambulatory activity in wild-type and Nur77-deficient mice, while it did not alter non-ambulatory activity. Results and discussion At a high dose, AMPH did not alter ambulatory activity anymore, while non-ambulatory activity strongly increased in wild-type mice. Nur77-deficient mice still displayed a higher ambulatory activity with no change in non-ambulatory activity. HX531, a synthetic RXR antagonist, blocks AMPH-induced ambulatory activity, whereas RAR drugs tested remained without effect. Interestingly, the effect of HX531 was abolished in Nur77-deficient mice, suggesting that this orphan nuclear receptor is essential for the action of the RXR drug. Conclusion This study shows that RXR and Nur77 participate in AMPH-induced locomotor activity and prompts for further investigations on the role of Nur77 and RXR in addiction and reward-related behaviors.

The dopamine system is the main target of antipsychotic and psychostimulant drugs. These drugs induce intracellular events that culminate in the transcription of immediate early genes, such as c-fos. Another class of transcription factors, namely, the nuclear receptor subgroup called Nurs (Nur77, Nurr1 and Nor-1), has recently been associated with behavioral and biochemical effects mediated by dopamine. However, the signaling cascade leading to modulation of Nur mRNA levels in the brain has never been investigated. In the present study, we explore in vivo using specific kinase inhibitors the role of mitogen-associated and extracellular signal-regulated kinases (MEK) and protein kinase C (PKC) in the modulation of Nur expression induced by dopamine receptor drugs. Modulation of Nur77 expression by a dopamine D(2) receptor antagonist is associated with MEK and PKC activities, whereas only the PKC activity participates in the modulation of Nor-1 expression. Both MEK and PKC activities also participate in the modulation of Nur77 mRNA levels induced by dopamine receptor agonists, whereas a selective MEK activity is associated with the modulation of Nor-1 mRNA levels. Interestingly, modulation of dopamine drug-induced locomotor activities by kinase inhibitors is in accordance with the effects on Nur77, but not Nor-1, expression. Taken together, the results indicate that signaling events leading to modulation of Nur77 and Nor-1 expression following dopamine receptor interacting drugs are distinct. Considering that orphan nuclear receptors of the Nur subgroup display an important ligand-independent constitutive activity, characterization of the signaling cascades involved in the regulation of their expression represents an important step for understanding their role in dopamine system physiology and pathophysiology.

Key points In the hippocampus, calcium‐permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood.In the present study, we looked for calcium‐permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses.Computer modelling predicted (and experiments verified) that fast calcium‐permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity.The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium‐permeable AMPA receptors. Abstract AMPA‐type glutamate receptors (AMPARs) lacking an edited GluA2 subunit are calcium‐permeable (CP) and contribute to synaptic plasticity in several hippocampal interneuron types, although their precise role in the neocortex is not well described. We explored the presence of CP‐AMPARs at pyramidal cell (PC) inputs to Martinotti cells (MCs) and basket cells (BCs) in layer 5 of the developing mouse visual cortex (postnatal days 12–21). GluA2 immunolabelling was stronger in MCs than in BCs. A differential presence of CP‐AMPARs at PC‐BC and PC‐MC synapses was confirmed electrophysiologically, based on measures of spermine‐dependent rectification and CP‐AMPAR blockade by 1‐naphtyl acetyl spermine using recordings from synaptically connected cell pairs, NPEC‐AMPA uncaging and miniature current recordings. In addition, CP‐AMPAR expression in BCs was correlated with rapidly decaying synaptic currents. Computer modelling predicted that this reduces spike latencies and sharpens suprathreshold responses in BCs, which we verified experimentally using the dynamic clamp technique. Thus, the synapse‐specific expression of CP‐AMPARs may critically influence both plasticity and information processing in neocortical microcircuits., Key points In the hippocampus, calcium‐permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood.In the present study, we looked for calcium‐permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses.Computer modelling predicted (and experiments verified) that fast calcium‐permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity.The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium‐permeable AMPA receptors.

Dopamine D(2) receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D(2) antagonist in the striatum. First, we investigated D(2) antagonist-induced Nur77 mRNA in D(2L) receptor knockout mice. Surprisingly, deletion of the D(2L) receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A(2A) receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D(2) receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D(2) receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D(2) heteroreceptors and support a prominent role of glutamate in the effect of D(2) antagonists.

Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT(1A) and 5-HT(2A/2C), and α₁- and α₂-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT(2A/2C) agonist, MDL11939, a 5-HT(2A) antagonist, 8-OH-DPAT, a 5-HT(1A) agonist, prazosin, an α₁-adrenergic antagonist and idazoxan, an α₂-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT(2A/2C) agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α₂ antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α₁ antagonist) remained without effect. Taken together, these results show the ability of a 5-HT(1A) agonist or a 5-HT(2A) antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs.

Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.

Monitoring gene expression has been intensively used to identify neurobiological and neuroanatomical substrates associated with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently associated with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calculate an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by anti-psychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine 2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addition to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacological effects.