What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease?

In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD-related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD.

Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits.

In addition to the classical motor symptoms, motivational and affective deficits are core impairments of Parkinson's disease (PD). We recently demonstrated, by lesional approaches in rats, that degeneration of the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is likely to have a crucial role in the development of these neuropsychiatry symptoms. We have also shown that, as in clinical investigations, chronic treatment with levodopa or the DA D2/D3 receptor (D2/D3R) agonist ropinirole specifically reverses these PD-related motivational deficits. The roles of specific DA receptor subtypes in such reversal effects remain, however, unknown. We therefore investigated here the precise involvement of D1, D2 and D3R in the reversal of the motivational and affective deficits related to SNc DA neuronal loss. Three weeks after bilateral and partial 6-hydroxydopamine (6-OHDA) SNc lesions, rats received 14 daily intraperitoneal administrations of the selective D1R agonist SKF-38393 (2.5 or 3.5 mg kg(-1)), the selective D2R agonist sumanirole (0.1 or 0.15 mg kg(-1)), or the preferring D3R gonist PD-128907 (0.1 or 0.15 mg kg(-1)). Anxiety-, depressive-like and motivated behaviors were assessed in an elevated-plus maze, a forced-swim test, and an operant sucrose self-administration procedure, respectively. All DA agonists attenuated anxiety- and depressive-like behaviors. However, only PD-128907 reversed the motivational deficits induced by 6-OHDA SNc lesions. This effect was blocked by a selective D3R (SB-277011A, 10 mg kg(-1)), but not D2R (L-741,626, 1.5 mg kg(-1)), antagonist. These data provide strong evidence for the role of D3R in motivational processes and identify this receptor as a potentially valuable target for the treatment of PD-related neuropsychiatric symptoms.

Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson's disease.

Parkinson's disease (PD) involves the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that is thought to cause the classical motor symptoms of this disease. However, motivational and affective impairments are also often observed in PD patients. These are usually attributed to a psychological reaction to the general motor impairment and to a loss of some of the neurons within the ventral tegmental area (VTA). We induced selective lesions of the VTA and SNc DA neurons that did not provoke motor deficits, and showed that bilateral dopamine loss within the SNc, but not within the VTA, induces motivational deficits and affective impairments that mimicked the symptoms of PD patients. Thus, motivational and affective deficits are a core impairment of PD, as they stem from the loss of the major group of neurons that degenerates in this disease (DA SNc neurons) and are independent of motor deficits.

Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson's disease.

Striatal dopaminergic denervation leads to a change in afferent activity within the basal ganglia. Coupled with the effect of local dopaminergic denervation in the subthalamic nucleus, this is likely to affect the responsiveness of subthalamic neurons to their hyperdirect inputs in Parkinson's disease. Therefore, in this report, we investigated subthalamic nucleus responses to visual stimuli relayed by one such input - the superior colliculus - in 6-hydroxydopamine (6-OHDA)-lesioned rats. We used a protocol where the superior colliculus was selectively unlocked from the inhibitory effect of anesthesia with an injection of bicuculline, attenuating GABAergic inhibition in the colliculus, which arises predominantly from the substantia nigra pars reticulata. We found that visual responses in the superior colliculus were facilitated by partial or total lesions of dopaminergic neurons in the substantia nigra pars compacta, once the colliculus was disinhibited by bicuculline. Responses were faster, larger in amplitude and lasted longer compared to those in control rats. In the subthalamic nucleus, visual responses were also increased in amplitude and magnitude in partial or total lesioned groups. A classic hypothesis in Parkinson's disease suggests that following dopaminergic denervation, the discharge of cells in the substantia nigra pars reticulata increases, thereby intensifying the inhibitory influence that this structure exerts on its targets in the thalamus and brainstem. Our results suggest that neuroadaptations may have taken place within the superior colliculus in order to maintain normal function in the face of increased inhibitory tone coming from the substantia nigra pars reticulata, which once reduced, gave rise to facilitated responding. This facilitated responding in the superior colliculus then appears to lead to facilitated responding in the subthalamic nucleus.

Incidence of neoplastic disease following lung transplantation: a 17-year single-center experience.

OBJECTIVE: Chronic immunosuppressive therapy following solid organ transplantation has been correlated with an increased risk of posttransplantation neoplastic disease (PTND). In this study we evaluated PTND incidence and outcome at our institution over a 17-year period among patients receiving lung transplantation. MATERIALS AND METHODS: Between February 1992 and December 2008, we performed 290 lung transplantations in 280 patients, including 139 single (48% with 5 retransplantations), and 151 double lung transplantations (52% with 5 retransplantations). Among the 280 patients, 2 had undergone previous double lung transplantation in other hospitals. Follow-up of transplant recipients was performed up to December 2009. RESULTS: Forty-two patients died in the hospital, producing a cumulative early (30-day) mortality rate of 15%. Among the 238 patients discharged from the hospital who entered our follow-up program, 36 (15%) experienced PTND. The mean time between transplantation and diagnosis was 47 ± 42 months, and patients' mean age at time of diagnosis was 55 ± 14 years. Overall freedom from PTND was 97%, 84%, and 73% at 1, 5, and 10 years, respectively. PTND was considered to be the direct cause of death in 11 patients (30%). Overall survival of patients with PTND at five years (45%) did not differ from the remainder of the transplanted population (46%). However, PTND became a relevant cause of death in the long-term (>5 years) follow-up. CONCLUSION: Our experience confirms that PTND was frequently diagnosed following lung transplantation. Even if PTND did not seem to significantly affect the survival of patients undergoing lung transplantation, it may become a significant cause of death among those surviving beyond 5 years.

Resection and end-to-end anastomosis for ascending aortic aneurysm: surgical technique.

Treatment of ascending aortic aneurysm, without involvement of aortic sinuses of Valsalva, is usually treated by tube graft interposition. Nowadays, many alternative techniques were described. The technique of resection and end-to-end anastomosis has been already described both by our group and by other authors as well. This report will focus on some surgical details of this technique based on a ten-year-experience. The preoperative study of candidates amenable to undergo this technique has to be completed by a computed tomography-scan of thoracic aorta. The ideal candidate has an elongated aorta in the antero-lateral wall. As a consequence, the heart is usually displaced inferiorly and toward a more horizontal plane. The aortotomy is done circumferentially one and half cm above the aortic commissures. A wide wedge resection of the aortic wall is performed. The resected aortic wall is wider in the anterior part than in the posterior. A very accurate hemostasis of the fat tissue close to the pulmonary artery is achieved by diathermy. The amount of wedge resection is mainly dictated by the elongation of the aortic wall. In authors' experience it usually ranges between 4 and 6 cm anteriorly and 1 cm posteriorly. The suture of the two stumps is performed by a running suture. The technique described has extensively been used; up today 136 patients undergo. According to authors' opinion this technique can be a useful alternative to the tube graft interposition in selected patients.

Chronic transverse sternal fracture. Role of CT scan and repair by an alternative use of the Synthes-Titanium Sternal Fixation System.

Chest wall fractures, including injuries of the sternum, usually heal spontaneously without specific treatment. However sometimes, they need surgical treatment. To treat these patients the selection criteria often are subjective in spite of many surgical devices for sternal osteosynthesis are available nowadays. One of the most recent device is the Synthes-Titanium Sternal Fixing System, usually used to treat post-sternotomy dehiscence. We describe the case of a 67-year-old man with previous history of chest trauma presenting to our institution with chronic transverse sternal fracture. We describe the pre-operative study, stressing the particular role of the CT scan and a surgical approach by an alternative use of the Synthes.

Surgical treatment of pericardial cyst through median sternotomy.

Pericardial cysts are an uncommon benign congenital anomaly in the middle mediastinum. They are thought to result from failure of fusion of one of the mesenchymal lacunae that form the pericardial sac. The authors present the case of a 77-year-old-man with a large pericardial cyst, treated by surgical resection trough a median sternotomy. They analyze the different diagnostic alternatives and the various management options in this pathology. In the reported case the authors used a surgical resection trough a median sternotomy, to facilitate the exposure of all of the cyst, extending around the great vessels area, and on the other side of the chest.

Assessment of metabolic changes in the striatum of a rat model of parkinsonism: an in vivo (1)H MRS study.

Degeneration of the dopaminergic neurons of the substantia nigra pars compacta in Parkinson's disease induces an abnormal activation of the glutamatergic neurotransmission system within the basal ganglia network and related structures. The aim of this study was to use proton MRS to show metabolic changes in the striatum of 6-hydroxydopamine-lesioned rats, a rodent animal model of Parkinson's disease. Animals were examined before and after extensive lesioning of the nigral dopaminergic neurons and after acute administration of L-3,4-dihydroxyphenylalanine. No significant alterations in glutamate concentrations, assessed by the MR signal dominated by glutamate with minor contributions from glutamine and gamma-aminobutyric acid, could be measured. The total choline/total creatine ratio was found to be reduced in the striatum of the ipsilateral hemisphere.

Na+ channel-mediated Ca2+ entry leads to glutamate secretion in mouse neocortical preplate.

Before synaptogenesis, early excitability implicating voltage-dependent and transmitter-activated channels is known to be crucial for neuronal development. We previously showed that preplate (PP) neurons of the mouse neocortex express functional Na(+) channels as early as embryonic day 12. In this study, we investigated the role of these Na(+) channels in signaling during early development. In the neocortex of embryonic-day-13 mice, activation of Na(+) channels with veratridine induced a large Ca(2+) response throughout the neocortex, even in cell populations that lack the Na(+) channel. This Na(+)-dependent Ca(2+) activity requires external Ca(2+) and is completely blocked by inhibitors of Na(+)/Ca(2+) exchangers. Moreover, veratridine-induced Ca(2+) increase coincides with a burst of exocytosis in the PP. In parallel, we show that Na(+) channel stimulation enhances glutamate secretion in the neocortical wall. Released glutamate triggers further Ca(2+) response in PP and ventricular zone, as indicated by the decreased response to veratridine in the presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NMDA-receptor inhibitors. Therefore, the combined activation of the Na(+) channel and the Na(+)/Ca(2+) exchanger triggers Ca(2+) signaling in the PP neurons, leading to glutamate secretion, which amplifies the signal and serves as an autocrine/paracrine transmitter before functional synapses are formed in the neocortex. Membrane depolarization induced by glycine receptors activation could be one physiological activator of this Na(+) channel-dependent pathway.

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

Increased extracellular DA and normal evoked DA release in the rat striatum after a partial lesion of the substantia nigra.

After injection of 6-hydroxydopamine into the lateral part of the rat substantia nigra, tissue dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced in the corresponding lateral part of the ipsilateral caudate/putamen (CP) complex (13, 40 and 56% of controls, respectively). In this region, tyrosine hydroxylase (TH, the rate limiting enzyme of the DA synthesis) immunoautoradiography decreased by more than 80% as was the case for the binding of tritiated GBR12935 (a specific marker of the DA-carrier protein). In the medial region of the CP, only very moderate reductions of DA, DOPAC and HVA (77, 76 and 84% of controls, respectively) were observed. In this region, TH immunoautoradiography and GBR12935 binding were only reduced by about 20% reflecting weak DA denervation. However, using in vivo voltammetry, extracellular basal DA levels were found to be particularly high in the medial region of CP complex when compared to unoperated animals (up to 235%). In the medial region, TH activity was also significantly increased (161%) but the electrical stimulation of DA fibers produced the same DA overflow in control and lesioned animals. From these results, it may be concluded that elevated basal DA levels in this region cannot be attributed to the reduced DA uptake and/or to an increased ability of DA neurons to release DA in response to impulse flow.

High frequency stimulation of the subthalamic nucleus increases the extracellular contents of striatal dopamine in normal and partially dopaminergic denervated rats.

The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats.

[Amyotrophic lateral sclerosis and animal models]. / Sclérose latérale amyotrophique et modèles animaux.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which affects cortical, bulbar and spinal motoneurones. The cause of the disease, probably due to several factors, is still unknown and the survival delay of patients with ALS generally does not exceed 3-5 years. Animals models provide a unique opportunity to study pathological features and to evaluate potential therapeutic effects of news treatments. Natural disease models, neurotoxins or viral-induced models and more recently transgenic models with genetic anomalies mimicking those found in ALS patients have been extensively studied. This review summarizes the most relevant clinical and pathological advances issuing from these animal studies.

Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat.

High frequency stimulation (130 Hz) of the subthalamic nucleus has dramatic beneficial motor effects in severe parkinsonian patients. However, the mechanisms underlying these clinical results remain obscure. The objective of the present work was to study the neurochemical changes induced in rats by high frequency stimulation of the subthalamic nucleus by using intracerebral microdialysis within its target structures. Our results show that high frequency stimulation of the subthalamic nucleus induces a significant increase of extracellular glutamate levels in the ipsilateral globus pallidus and substantia nigra while GABA was augmented only in the substantia nigra. These data suggest that functional effects induced by high frequency stimulation of the subthalamic nucleus might imply distal mechanisms involving the synaptic relationships with the subthalamic efferences. They question the current view that the direct inhibition of the subthalamic neurons is induced by high frequency stimulation.

Unrelated course of subthalamic nucleus and globus pallidus neuronal activities across vigilance states in the rat.

The pallido-subthalamic pathway powerfully controls the output of the basal ganglia circuitry and has been implicated in movement disorders observed in Parkinson's disease (PD). To investigate the normal functioning of this pathway across the sleep-wake cycle, single-unit activities of subthalamic nucleus (STN) and globus pallidus (GP) neurons were examined, together with cortical electroencephalogram and nuchal muscular activity, in non-anaesthetized head-restrained rats. STN neurons shifted from a random discharge in wakefulness (W) to a bursting pattern in slow wave sleep (SWS), without any change in their mean firing rate. This burst discharge occurred in the 1-2 Hz range, but was not correlated with cortical slow wave activity. In contrast, GP neurons, with a mean firing rate higher in W than in SWS, exhibited a relatively regular discharge whatever the state of vigilance. During paradoxical sleep, both STN and GP neurons increased markedly their mean firing rate relative to W and SWS. Our results are not in agreement with the classical 'direct/indirect' model of the basal ganglia organization, as an inverse relationship between STN and GP activities is not observed under normal physiological conditions. Actually, because the STN discharge pattern appears dependent on coincident cortical activity, this nucleus can hardly be viewed as a relay along the indirect pathway, but might rather be considered as an input stage conveying corticothalamic information to the basal ganglia.

DA uptake sites, D1 and D2 receptors, D2 and preproenkephalin mRNAs and Fos immunoreactivity in rat striatal subregions after partial dopaminergic degeneration.

Stereotaxic injection of a limited amount of 6-hydroxydopamine in the lateral part of the rat substantia nigra induces a partial degeneration of the nigrostriatal dopaminergic system. This animal model in which the destruction of the dopaminergic nigral cell population reaches approximately 50% could be considered as a preclinical Parkinson's model. Autoradiography of dopaminergic uptake sites performed with a specific marker ([3H]GBR 12935) allowed the precise determination of dopaminergic denervated and non-denervated areas in the striatum 1 month after partial lesion of the substantia nigra pars compacta. In both striatal areas, dopaminergic D1 and D2 receptor densities and dopaminergic D2 and preproenkephalin mRNAs levels were measured by autoradiography and in situ hybridization coupled to an image analysis system. Our results show that in the denervated striatal subregion, none of the dopaminergic targets were modified, contrary to the observations made after complete lesion of the nigrostriatal DA system at the same post-lesion delay. However, striatal Fos activation induced by amphetamine (5 mg/kg i.p., 2 h before killing) revealed that the number of Fos-positive cells detected in the denervated striatal subregion was lower than that observed in the non-denervated one. These data argue in favour of the existence of compensatory mechanisms different from the up-regulation of DA receptor densities, thereby allowing the maintenance of striatal dopaminergic transmission. Such mechanisms could contribute to the delay of the appearance of neurological symptoms (which are reported to be clinically apparent only when depletion of striatal dopamine levels reaches near 80%) in Parkinsonian patients.

Effects of long-term hypoxia on tyrosine hydroxylase protein content in catecholaminergic rat brainstem areas: a quantitative autoradiographic study.

The nucleus tractus solitarius (NTS), the ventrolateral medulla (VLM), the dorsal motor vagus nucleus (DMnX) and the locus coeruleus (LC) are catecholaminergic brainstem areas involved in ventilatory and cardiovascular responses to hypoxia and tyrosine hydroxylation is the rate limiting step of cathecholamine biosynthesis in the central nervous system. The aim of this study was to evaluate the effects of long-term hypoxia on tyrosine hydroxylase (TH) content in these different areas using a quantitative autoradiographic technique. Two experimental groups of rats were studied: Group I (9 males, 8 females) was submitted to normobaric hypoxia (10% O2-90% N2) for 21 days and compared to 12 (6 males, 6 females) normoxic control rats (Group II). Coronal tissue sections from fresh-frozen rat brains, obtained along the caudo-rostral axis, were incubated in the presence of a TH monoclonal antibody, and the reaction was revealed by a 35S-labelled secondary antibody. TH levels were quantified in the NTS, VLM, DMnX and LC by measuring optical density on autoradiographic films using an automatic image analyser system. Regional antigen quantification was assessed by computer-assisted image analysis. Chronic hypoxia led to body weight decrease until day 5, haematocrit increase (65 +/- 2% vs. 44 +/- 2%, P < 0.01) and right ventricle hypertrophy (35 +/- 0.5% vs. 23 +/- 0.1% of the weight of the two ventricles, P < 0.01). TH protein contents expressed as percentage of controls were as follows. In males, in the rostral part of the NTS 132 +/- 9% (P < 0.02), in the caudal part of the NTS, 117 +/- 5% (P < 0.04). In female rats, the TH quantity reached a value of 124 +/- 4% (P < 0.01) in the rostral part and 126 +/- 6% (P < 0.01) in the caudal part of the NTS. In females, TH content was significantly increased in the VLM, 124 +/- 6%, P = 0.01, whereas in males there was only a non-significant trend to increase, 122 +/- 11%. In females, there was a significant increase in the DMnX, 127 +/- 9%, P = 0.05, whereas in males there was only a trend to increase, 120 +/- 5%. This study shows that long-term hypoxia induces a persistent increase in TH protein content both in the caudal and rostral part of the NTS, which are known to receive respectively chemo- and barosensory inputs, and in other catecholaminergic areas involved in baroreflex activity. Our data clearly demonstrate the implication of neurochemical mechanisms in the central relationship between chemo- and baroreflex which are responsible for changes in systemic arterial pressure and oxygen partial pressure as required for maintaining an adequate oxygen supply to the tissues.

Regional study of spinal alpha 2-adrenoceptor densities after intraspinal noradrenergic-rich implants on adult rats bearing complete spinal cord transection or selective chemical noradrenergic denervation.

One of the challenges of restorative neuronal transplantation in the CNS of mammals is the appropriate integration of grafted cells in the host circuitry. One key parameter is the specific influence of grafted cells upon corresponding receptors. In order to test this issue on the lesioned spinal cord of adult rats, two models of spinal cord denervation were used: the first one consisted of a complete transection 1 week prior to an intraspinal transplantation of embryonic locus coeruleus (LC) primordia cell suspension; the second one was a chemical destruction of the spinal noradrenergic (NA) system 1 month prior to a similar transplantation. Five weeks after transplantation, spinal sections were processed for autoradiographic quantification of alpha 2-adrenoceptor binding sites densities. In most regions, alpha 2-adrenoceptor densities remained comparable or higher than before graft; interestingly, in lumbar dorsal horn, lumbar intermediate zone and sacral distal dorsal horn of transected-grafted rats, they returned to control level. Results are discussed in relation to the parallel study performed concerning alpha 1-adrenoceptors.