The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4–7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

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The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely, low frequency oscillatory activity and synchronization seem to be more important in PD because they are not influenced by prolonged L-DOPA administration.

1 Imidazoline binding sites have been reported to be present in the locus coeruleus (LC). To investigate the role of these sites in the control of LC neuron activity, we studied the eect of imidazolines using in vivo and in vitro single-unit extracellular recording techniques. 2 In anaesthetized rats, local (27 pmoles) and systemic (1 mg kg 71 , i.v.) administrations of 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a selective I-imidazoline receptor ligand, increased the ®ring rate of LC cells (maximal increase: 22+5%, P50.001 and 16+7%, P50.001 respectively). Chronic pretreatment with the irreversible monoamine oxidase inhibitor clorgyline (3 mg kg 71 , i.p., every 12 h for 14 days) abolished this eect. 3 In rat midpontine brain slices containing the LC, bath application (1 mM) of the imidazolines 2-BFI, 2-(4,5-dihydroimidaz-2-yl)-quinoline (BU224), idazoxan, efaroxan, phentolamine and (2-2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX821002) reversibly stimulated LC cells. The maximal eect was *90% except for RX821002 and efaroxan which induced smaller maximal eects (*58% and *35% respectively). Simultaneous application of idazoxan and 2BFI did not lead to additive eects. 4 Bath application of the a 2 -adrenoceptor antagonists, yohimbine (1 ± 10 mM) and N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (10 mM), failed to modify LC activity. The irreversible blockade of a 2 -adrenoceptors with EEDQ (10 mM) did not alter the eect of idazoxan or that of efaroxan. Previous application of clorgyline (10 mM) did not modify the excitatory eect of 2-BFI or efaroxan. 5 Changes in the pH of the bathing solution (6.84 ± 7.84) did not in¯uence the eect caused by idazoxan. Bath application of 2-BFI (1 mM) reversed the inhibition induced by diazoxide (300 mM), an ATP-sensitive K + channel opener, whereas application of glibenclamide (3 mM), an ATP-sensitive K + channel blocker, partially blocked the eect of 2-BFI. 6 This study shows that imidazoline compounds stimulate the ®ring rate of LC neurons. This eect is not mediated by a 2 -adrenoceptors nor by I 1 or I 2 -imidazoline receptors but involves a dierent subtype of imidazoline receptor. Our results indicate that this receptor is located extracellularly and modulates ATP-sensitive K + channels.

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The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity.

Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.