Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia. Although persistent striatal induction of some genes has already been associated with such pathologic profiles in hemiparkinsonian rats, molecular and cellular mechanisms underlying such long-term adaptations remain to be elucidated. In this study, using a rat model of L-Dopa-induced dyskinesia, we report that activity regulated cytoskeletal (Arc)-associated protein is strongly upregulated in the lesioned striatum and that the extent of its induction further varies according to the occurrence or absence of locomotor sensitization. Moreover, Arc is preferentially induced, along with FosB, nur77, and homer-1a, in striatonigral neurons, which express mRNA encoding the precursor of dynorphin. Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa.

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Background-Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan

Previous studies have shown that activation of the 5-HT_1A receptor subtype enhances rat plasma ACTH concentration. Such receptors have been suggested to be located on CRH neuronal cell bodies in the paraventricular nuclei of the hypothalamus (PVN). In this report, microinjection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT_1A agonist, into the PVN increased rat plasma ACTH concentration in a dose-related manner. Similar responses were observed when two other 5-HT_1A agonists, buspirone and gepirone, were used. (± )-Pindolol, known to have 5-HT_1A antagonist properties, blocked the effect induced by an optimal dose of 8-OH-DPAT after injection into the PVN. This same dose of 8-OH-DPAT also induced a decrease of hypothalamic CRH concentration, which was completely antagonized as well by pretreatment injection of ( ± )-pindolol into the PVN. A significant inverse correlation was found between hypothalamic CRH and plasma ACTH levels. These results confirm that elevation of the plasma ACTH concentration induced by 5-HT_1A receptor subtype activation is mediated by the release of CRH from the paraventricular nuclei of the hypothalamus in rats, but do not exclude other mechanisms.

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The hypothermia produced by 5-HT 1A 1A receptors are located both on the cell body of 5-HT neurons and on postsynaptic neurons throughout the central nervous system. On 5-HT neurons, 5-HT 1A receptors mediate a negative feedback influence on firing activity. When overactivated by an excess amount of 5-HT, or by an exogenous agonist, they slow down the pacemaker activity leading to a decreased firing rate of 5-HT neurons (Aghajanian and Lakoski 1984;Blier and de Montigny 1987). As 5-HT release is proportional to firing rate, the excess activation of these 5-HT 1A autoreceptors generally results in a decrease of 5-HT release in projecting structures (see Rueter et al. Gainesville, FL 32610, Tel.: 352-392-3681, Fax : 352-392-2579, E-mail : blier@psych.med.ufl.edu Received May 11, 2001 revised January 16, 2002; accepted February 20, 2002. Online publication: 2/27/02 at www.acnp.org/citations/ Npp022702253. 302 P. Blier et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 2 1997). The postsynaptic 5-HT 1A receptors, particularly abundant in the limbic system, commonly exert an inhibitory function on neuronal activity as well. Therefore, the net effect of the systemic administration of a 5-HT 1A receptor agonist on 5-HT 1A signal transfer in postsynaptic areas represents a composite of decreased 5-HT release, resulting from 5-HT 1A autoreceptor activation, and direct occupation of the postsynaptic 5-HT 1A receptors.Although it is well established that neuroendocrine responses, such as growth hormone and adenocorticotropic hormone release, produced by systemic administration of 5-HT 1A agonists are mediated by postsynaptic 5-HT 1A receptors (Van de Kar et al. 1985;Gilbert et al. 1988;Pan and Gilbert 1992), there has been controversy with respect to the hypothermia resulting from this pharmacological challenge. The very first study examining the pre-versus postsynaptic mediation of the hypothermia clearly indicated that this response was produced by postsynaptic 5-HT 1A receptors (Hjörth 1985). Indeed, this initial study clearly showed that the hypothermic response to the prototypical 5-HT 1A agonist 8-OH-DPAT was not attenuated, but even enhanced in rats pretreated daily for 3 days with the 5-HT synthesis inhibitor parachlorophenylalanine (PCPA). Subsequently, identical results were obtained by another group of investigators using 2-day injections of a higher dose of PCPA (Goodwin et al. 1987). When their PCPA treatment was prolonged, however, for 14 days, despite producing its maximal effect on 5-HT levels after the first 3 days, the 8-OH-DPATinduced hypothermia was dampened and the conclusion of a presynaptic mediation of this phenomenon was made. From then on, several studies carried out in laboratory animals and humans used the 5-HT 1A -induced hypothermia to assess the responsiveness of the 5-HT 1A autoreceptor in different disease states and following administration of various types of psychotropic drugs. Although the majority of studies (Hutson et al. 1987;O'Connell et al. 1992;Hillegaart 1991;Mill...

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We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopainduced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282-288, 2006). In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking placed in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudateputamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a nonhuman primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.