Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson's disease.

Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias.

Pramipexole induced place preference after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications.

RATIONALE: Impulsive-compulsive disorders (ICD) in patients with Parkinson's disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT). OBJECTIVES: A remaining challenge is to understand the neuroadaptations leading to reward bias in PD patients under DRT. METHODS: To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model. RESULTS: Association of progressive nigral loss and chronic L-dopa was required to observe a pramipexole-induced place preference. This behavioral outcome was inhibited by metabotropic glutamate receptor 5 (mGluR5) antagonism while transcriptional profiling highlighted regulations potentially related to the context of psychostimulant addiction. CONCLUSION: This study provides evidences strongly suggesting that PD-like lesion and L-dopa therapy were concomitant factors involved in striatal remodeling underlying the pramipexole-induced place preference. Molecular and pharmacological data suggest a key involvement of the glutamatergic pathway in this behavioral outcome.

Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats.

The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating.

Does the olfactory cue activate the same brain network during aging in the rat after taste potentiated odor aversion retrieval?

Depending on the brain networks involved, aging is not accompanied by a general decrease in learning and memory capabilities. We demonstrated previously that learning and retrieval of taste potentiated odor aversion (TPOA) is preserved, and even slightly improved, in senescent rats showing some memory deficiencies in cognitive tasks (Dardou, Datiche, & Cattarelli, 2008). TPOA is a particular behavior in which the simultaneous presentation of odor and taste cues followed by a delayed visceral illness leads to a robust aversion towards both conditioned stimuli, which permits diet selection and animal survival. The present experiment was performed in order to investigate the stability or the evolution of the brain network underlying TPOA retrieval during aging. By using immunocytochemical detection of Fos and Egr1 proteins we mapped the cerebral activation induced by TPOA retrieval elicited by the odor presentation in the young, the adult and the senescent rats. The pattern of brain activation changed and the number of activated areas decreased with age. Nevertheless, the piriform cortex and the basolateral amygdala nucleus were always activated and seemed essential for TPOA retrieval. The hippocampus and the neocortical areas could have different implications in TPOA memory in relation to age. The patterns of expression of Fos and Egr1 were different, suggesting their differential involvement in TPOA retrieval. Data are discussed according to the possible roles of the brain areas studied and a model of schematic brain network subtending TPOA retrieval induced by the odor cue is proposed.

Memory is differently impaired during aging according to the learning tasks in the rat.

The aim of the present study was to determine the impact of aging on learning and retrieval of taste-potentiated odor aversion (TPOA). TPOA, which involves processing of odor, gustatory, and visceral cues, is a particular form of learning important to food selection. The experiment was carried out on young (1.5 month), adult (12 months), and old (20-24 months) rats. To determine whether the possible effects of aging on TPOA were related or not to general memory alterations, mnesic abilities of the rats were previously evaluated by submitting the animals to object recognition, olfactory discrimination, and spatial homing task. It was noted that the young, the adult, and the old rats were able to learn and to retrieve TPOA whatever the stimulus - either odor or taste - used to elicit retrieval. Interestingly, it can be underlined that the rejection of the odor stimulus only was even slightly increasing with the rat age. Thus, TPOA which is important in food selection and in animal survival is spared during aging while mnesic deficits were observed in the other behavioral tasks tested according to the task requirement.

Does taste or odor activate the same brain networks after retrieval of taste potentiated odor aversion?

When simultaneous presentation of odor and taste cues precedes illness, rats acquire robust aversion to both conditioned stimuli. Such a phenomenon referred to as taste-potentiated odor aversion (TPOA) requires information processing from two sensory modalities. Whether similar or different brain networks are activated when TPOA memory is retrieved by either the odor or the taste presentation remains an unsolved question. By means of Fos mapping, we investigated the neuronal substrate underlying TPOA retrieval elicited by either the odor or the taste conditioned stimulus. Whatever the sensory modality used to reactivate TPOA memory, a significant change in Fos expression was observed in the hippocampus, the basolateral nucleus of amygdala and the medial and the orbito-frontal cortices. Moreover, only the odor presentation elicited a significantly higher Fos immunoreactivity in the piriform cortex, the entorhinal cortex and the insular cortex. Lastly, according to the stimulus tested to induce TPOA retrieval, the BLA was differentially activated and a higher Fos expression was induced by the odor than by the taste in this nucleus. The present study indicates that even if they share some brain regions, the cerebral patterns induced by either the odor or the taste are different. Data are discussed in view of the relevance of each conditioned stimulus to reactivate TPOA memory and of the involvement of the different labeled brain areas in information processing and TPOA retrieval.

Fos and Egr1 expression in the rat brain in response to olfactory cue after taste-potentiated odor aversion retrieval.

When an odor is paired with a delayed illness, rats acquire a relatively weak odor aversion. In contrast, rats develop a strong aversion to an olfactory cue paired with delayed illness if it is presented simultaneously with a gustatory cue. Such a conditioning effect has been referred to as taste-potentiated odor aversion learning (TPOA). TPOA is an interesting model for studying neural mechanisms of plasticity because of its robustness and rapid acquisition. However, the neural substrate involved in TPOA retrieval has not been well characterized. To address this question, we used immunocytochemical detection of inducible transcription factors encoded by the immediate-early genes Fos and Egr1. Thirsty male rats were conditioned to TPOA learning, and they were submitted to retrieval in the presence of the learned odor 3 d later. Significant increases in both Fos and Egr1 expressions were observed in basolateral amygdala, insular cortex, and hippocampus in aversive rats in comparison with the all the control groups. The pattern of neuronal activity seemed unlikely to be related to the sole LiCl injection. Lastly, opposite patterns of Fos and Egr1 were noted in the entorhinal cortex and the central nucleus of amygdala, suggesting a differential involvement of these markers in retrieval of TPOA.