Low frequency deep brain stimulation in the inferior colliculus ameliorates haloperidol-induced catalepsy and reduces anxiety in rats.

Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600µA, pulse width 100µs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.

Cyclosomatostatin- and haloperidol-induced catalepsy in Wistar rats: Differential responsiveness to sleep deprivation.

Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, p > 0.05). By contrast, 3-h SD suppressed (p < 0.01) cSST-induced catalepsy, however, enhanced (p < 0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions.

Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20-180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.

Awakenings in rats by ultrasounds: A new animal model for paradoxical kinesia.

Paradoxical kinesia refers to a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. The mechanisms underlying this phenomenon are unknown due a paucity of valid animal models that faithfully reproduce paradoxical kinesia. Here, in a first experiment, we present a new method to study paradoxical kinesia by "awakening" cataleptic rats through presenting appetitive 50-kHz ultrasonic vocalizations (USV), which are typical for social situations with positive valence, like juvenile play or sexual encounters ("rat laughter"). Rats received systemic haloperidol to induce catalepsy, which was assessed by means of the bar test. During that test, 50-kHz USV, time- and amplitude-matched white noise (NOISE), or background noise (BACKGROUND) were played back and compared to SILENCE. Every animal was exposed to all four acoustic stimuli in random order, with four independent groups of rats being tested. Only when exposed to playback of appetitive 50-kHz USV, the otherwise akinetic rats rapidly started to move efficiently. The acoustic control stimuli, in contrast, did not release rats from catalepsy, despite eliciting the auditory pinna reflex and head movements towards the sound source. Moreover, in a second experiment, playback of aversive 22-kHz USV and relevant acoustic control stimuli did also not significantly affect catalepsy time. Together, our animal model provides a completely new approach to study mechanisms of paradoxical kinesia, which might help to improve behavioral therapies for Parkinson's disease and other disorders, where akinetic or cataleptic states occur.

Exposure to an enriched environment facilitates motor recovery and prevents short-term memory impairment and reduction of striatal BDNF in a progressive pharmacological model of parkinsonism in mice.

Previous studies showed that the repeated administration with a low dose of reserpine (RES) induces a gradual appearance of motor signs and cognitive deficits compatible with parkinsonism in rodents. Environmental stimulation has neuroprotective effects in animal models of neurodegenerative damage, including acutely induced parkinsonism. We investigated the effects of exposure to an enriched environment (EE) on motor, cognitive and neuronal (levels of tyrosine hydroxylase, TH and brain derived neurotrophic factor, BDNF) deficits induced by a progressive model of Parkinson's disease (PD) in mice. Male mice were repeatedly treated with vehicle or 0.1mg/kg of RES (s.c) and kept under two housing conditions: standard environment (SE) and EE. In animals kept in SE, the treatment with RES induced deficits in motor function (catalepsy test, open field and oral movements), in novel object recognition (NOR) and plus-maze discriminative avoidance tasks. The environmental stimulation facilitated the recovery of motor deficits assessed by the catalepsy test after the end of treatment. Additionally, exposure to EE prevented the memory deficit in the NOR task. Treatment with RES induced a reduction in the number of TH positive cells in SNpc and VTA, which recovered 30days after the end of treatment. Finally, RES reduced the levels of BDNF in the striatum and the exposure to the EE prevented this effect. These results suggest that plastic brain changes induced by EE promote beneficial effects on the progression of neuronal impairment related to PD.

[Narcolepsy in childhood and adolescence: symptoms, diagnosis, and therapy. A case report]. / Narkolepsie im Kindes- und Jugendalter: Symptome, Diagnostik und Therapie. Ein Fallbericht.

Narcolepsy is a rare, multifactorial disease of the hypothalamus characterized by its leading symptoms of excessive daytime sleepiness and cataplexy. Sleep-EEG and a HLA-DR-genotype serve to secure the diagnosis. We report here on a 14-year-old girl suffering from anxieties, depression, school refusal, social withdrawal as well as very frequent attacks of sleep during the day and cataplexy. Currently, there is no approved drug for children and adolescents suffering from narcolepsy. Our patient benefited significantly and quickly from an off-label treatment with methylphenidate in combination with psychoeducation, cognitive behavioral therapy, and family therapy. Narcolepsy is a very rare but probably underestimated differential diagnosis applied to unclear daytime sleepiness, anxieties, or depression in childhood and adolescence. Both the key symptoms and the comorbid symptoms improve significantly under treatment with stimulants, albeit at a higher dosage.

The combined depletion of monoamines alters the effectiveness of subthalamic deep brain stimulation.

Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN-DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild "depressive-like" behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated "depressive-like" behavior. STN-DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN-DBS. Furthermore, our results showed that acute STN-DBS improved "depressive-like" disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN-DBS upon the motor and anxiety disorders in the context of Parkinson's disease.

Regenerative effects of umbilical cord matrix cells (UCMCs) in a rodent model of rotenone neurotoxicity.

Rotenone is one of the pesticides thought to have neurotoxic effect that could potentially play a role in the development of Parkinson's disease (PD). The neurotoxic effects of rotenone have been used to induce PD model in animals that can help in testing suggested therapies. Cell replacement therapies are suggested as new promising approach for treating PD. This study was done to evaluate the regenerative effect of intrathecal administered umbilical cord matrix cells in a rotenone model of PD in mice. Thirty, male BALB/c mice were used and divided into 3 equal groups. The control group (G.1) received only carboxymethyl cellulose orally once daily at a volume of 10ml/kg. The second group was given a daily rotenone oral dose of 30mg/kg for 28days. The third group received rotenone (30mg/(kgday) orally for 28days) and in the 15th day 1×10(5) of UCMCs were given intrathecally and then they completed the rotenone course. At the 23rd day all the animals were evaluated regarding locomotor incoordination through behavioral tests for monitoring PD development. At the end of the 28days all animals were sacrificed by overdose of phenobarbital and their brain were subjected to immunohistochemical analysis for dopaminergic neurons staining for anti TH antibodies. Intrathecal UCMCs revealed regenerative effects in SNpc as evidenced by immunohistochemical staining; this was in parallel with better performance in behavioral tests. In conclusion, the results of this study revealed the regenerative capacities of UCMCs against rotenone neurotoxicity in mice.

Hexokinase II gene transfer protects against neurodegeneration in the rotenone and MPTP mouse models of Parkinson's disease.

A typical feature of Parkinson's disease is the progressive loss of dopaminergic neurons in the substantia nigra, in which inhibition of mitochondrial complex I activity may play an important role. Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibit the mitochondrial complex I and they cause the death of substantia nigra dopaminergic neurons, thereby providing acute murine models of Parkinson's disease. We have found that increasing mitochondrial hexokinase II activity can prevent cell death in neuronal cultures treated with rotenone. As a result, we have studied the effects of hexokinase II gene transfer in vivo using a herpes simplex virus type 1 (HSV-1) amplicon vector. The placHK2 amplicon vector was injected into substantia nigra of mice that were subsequently administered rotenone or MPTP. Overexpression of hexokinase II prevented both rotenone and MPTP-induced dopaminergic neuronal cell death, as well as reducing the associated motor defects. Our results provide the first proof-of-principle that hexokinase II protects against dopaminergic neurodegeneration in vivo, emphasizing the role of this enzyme in promoting neuronal survival. Thus, the increase of hexokinase II expression by gene transfer or other means represents a promising approach to treat Parkinson's and other neurodegenerative diseases.

Narcolepsy in childhood.

Narcolepsy is a chronic disease commonly diagnosed in middle adulthood. However, the first symptoms often appear in childhood and/or adolescence. Pediatric cases of narcolepsy are among the most often underrecognised and underdiagnosed diseases. This fact raises questions about the reasons for such diagnostic delay from the clinical point of view, and what kind of help can be expected from auxiliary diagnostic examinations. The aim of the review is to stress some specific features of the clinical picture in children, to discuss the role of auxiliary examinations at the onset of the disease including sleep studies, tests for human leukocyte antigens (HLAs), and cerebrospinal fluid hypocretin (Hcrt) measurement, and to draw attention to the most common cases of pediatric misdiagnosis. Frequent cataplectic attacks at an early age should lead to detailed clinical, neuroimaging and genetic examinations to rule out a secondary etiology. Beside the typical symptoms (excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations), some additional features including obesity and nocturnal bulimia can appear. Also poor school performance and emotional disorder are common complaints. Treatment should start as early as possible to avoid the development of problems with progress at school, and close cooperation between school and family should be maintained.

Cortical effects of subthalamic stimulation correlate with behavioral recovery from dopamine antagonist induced akinesia.

High-frequency stimulation of around 130 Hz delivered to the subthalamic nucleus (STN-DBS [deep brain stimulation]) is an effective treatment of Parkinson's disease (PD), but the mechanisms of its therapeutic effect remain obscure. Recently, it has been shown in anaesthetized rats that STN-DBS antidromically activates cortical neurons with coincident reduction of the cortical slow wave oscillations that occur in this preparation. Here we extend this work; recording the effect of STN-DBS upon cortical EEG and akinesia, in unanesthetized rats rendered cataleptic by acute dopaminergic blockade. STN-DBS-like stimulation resulted in a short latency, presumed antidromic, evoked potential in the cortex. In cataleptic animals, there was a significant increase in the power of beta oscillations in the electroencephalography which was reversed by stimulation that evoked the cortical response. We also observed a significant rescue of motor function, with the level of akinesia (bar test score) being inversely correlated to the amplitude of the evoked potential (R2 = 0.84). These data confirm that (probably antidromic) short latency cortical responses occur in the awake animal and that these are associated with reductions in abnormal cortical oscillations characteristic of PD and with improvements in akinesia. Our results raise the possibility that STN-DBS reduces PD oscillations and symptoms through antidromic cortical activation.

High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy.

Deep brain stimulation (DBS) of the subthalamic nucleus has been used extensively in the treatment of Parkinson's disease. However, the efficacy of such treatments on bradykinesia/akinesia remains low. DBS of the posterior hypothalamic nucleus (PH) elicits spontaneous, non-stereotypical motor behaviours. We tested the hypothesis that PH stimulation could restore movement in animals made cataleptic by the D(2) receptor antagonist haloperidol. We further hypothesized that hippocampal-striatal neural synchrony may be important in the organization of motor behaviours. Animals chronically implanted with hippocampal and striatal recording electrodes and PH stimulating electrode were tested in open field, catalepsy and active avoidance paradigms. The degree of hippocampal-striatal theta (5-10 Hz) field coherence was assessed during baseline avoidance testing and following the administration of haloperidol. Haloperidol abolished movement in open field and active avoidance tasks and increased the latency to respond in the catalepsy test. Stimulation of the PH under haloperidol reversed catalepsy. Hippocampal-striatal theta coherence was high throughout the active avoidance task in control experiments but was greatly reduced under haloperidol. PH stimulation was able to reinstate the hippocampal-striatal theta coherence while restoring task-related behaviours. These results support the hypothesis that DBS of the PH could restore motor behaviours in rats made cataleptic with haloperidol, thus providing strong support for the PH as a promising candidate for DBS in the treatment of Parkinson's disease. Furthermore, the results support the view that hippocampal-striatal theta coherence may be important for the planning and execution of goal-oriented behaviors.

Catatonia complicated by pneumothorax successfully treated with electroconvulsive therapy.

We describe 2 patients with catatonia who developed the complication of pneumothorax, the accumulation of air in the pleural cavity leading to collapse of a lung. Electroconvulsive therapy was safely administered to resolve catatonia, with special attention to managing pneumothorax by insertion of a thoracostomy tube and careful management of ventilation.

Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) remarkably alleviates motor disorders in parkinsonian patients. The mechanisms by which STN HFS exerts its beneficial effects were investigated in anesthetized rats, using a model of acute interruption of dopaminergic transmission. Combined systemic injections of SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine] and raclopride, antagonists of the D1 and D2 classes of dopaminergic receptors, respectively, were performed, and the parameters of STN HFS that reversed the neuroleptic-induced catalepsy were determined in freely moving animals. The effects of neuroleptics and the impact of STN HFS applied at parameters alleviating neuroleptic-induced catalepsy were analyzed in the substantia nigra pars reticulata (SNR), a major basal ganglia output structure, by recording the neuronal firing pattern and the responses evoked by cortical stimulation. Neuroleptic injection altered the tonic and regular mode of discharge of SNR neurons, most of them becoming irregular with bursts of spikes and pauses. The inhibitory component of the cortically evoked response, which is attributable to the activation of the direct striatonigral circuit, was decreased, whereas the late excitatory response resulting from the indirect striato-pallido-subthalamo-nigral circuit was reinforced. During STN HFS, the spontaneous firing of SNR cells was either increased or decreased with a global enhancement of the firing rate in the overall population of SNR cells recorded. However, in all of the cases, SNR firing pattern was regularized, and the bias between the trans-striatal and trans-subthalamic circuits was reversed. By these effects, STN HFS restores the functional properties of the circuits by which basal ganglia contribute to motor activity.

Foxy methoxy: a new drug of abuse.

INTRODUCTION: In 1999, a new synthetic tryptamine, 5-MeO-DIPT, became known as a street drug, with the street name of "Foxy" or "Foxy Methoxy". By February 2003, the DEA reported law enforcement seizures and/or reports of abuse in 12 states. We report a case along with an analysis of poison center data on this new drug of abuse. CASE REPORT: A 19-year-old male was brought to the emergency department following ingestion of a larger than his usual dose of Foxy. Upon arrival, he had hallucinations, hypertension, tachycardia, mydriasis, and catalepsy. Symptoms resolved within two hours after administration of lorazepam and he recovered uneventfully. DISCUSSION: The AAPCC TESS database contained 41 exposures to "Foxy" between April, 2002 and June, 2003; 26 had moderate or major effects, indicating this drug has significant toxic potential. Given the expanding use of this and other club drugs, the spectrum of toxicity from this new agent will continue to be elucidated.

Effect of chronic thyroxine treatment on catalepsy in rats.

The effect of chronic thyroid hormone (thyroxine, T4) administration on the duration of cataleptic freezing was studied in males of random-bred Wistar and genetic cataleptic (GC) rat strains. It was found that thyroidectomy brought about a sharp increase in immobility time in Wistar rats. Replacement with 0.015 mg/kg per day of T4 for 30 days from the day after thyroidectomy prevented the development of predisposition to catalepsy, whereas the same dose of T4 failed to attenuate the predisposition to catalepsy in the case of a month delay between the thyroidectomy and the beginning of treatment. A chronic administration of T4 at a dose of 0.1 mg/kg per day clearly decreased the genetically determined high expression of cataleptic reaction in GC rats. The results are evidence of the involvement of T4 in the regulation of cataleptic freezing and suggest that predisposition to catalepsy may be caused or enhanced by a deficit of thyroid hormone.

Catatonia LSD induced?

The case of a patient who developed catatonia one week following Lysergic Acid Diethylamide (LSD) ingestion is presented. The psychosis developed two days after the intake. The catatonic syndrome resolved dramatically following one treatment of electroconvulsive therapy (ECT). This is perhaps the first case report of catatonia following the use of LSD. The need for a diagnostic category of organic catatonia is highlighted.

Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy.

A repeated testing paradigm was used to assess the efficacy for the management of daytime sleepiness in narcolepsy-cataplexy of single long, multiple short and no-nap sleep/wake schedule conditions, with total sleep per 24 hours held constant. Eight narcoleptic subjects participated and followed each experimental schedule for two consecutive days, the second of which served as a test day during which simultaneous electroencephalogram (EEG) polygraphic recordings were made. Performance tests reported here include a grammatical transformation test and a four-choice reaction time test. A single long nap placed 180 degrees out-of-phase with the nocturnal midsleep time improved sustained performance over the no-nap condition. Reaction time performance was significantly improved in the long nap condition over the no-nap condition. Time-of-day analyses found that the greatest improvement was in the afternoon and evening. By contrast, the grammatical transformation test results suffered under the napping compared to no-nap schedules, suggesting that continuity of wakefulness and/or a long nocturnal sleep period may be important for this test. In addition, unscheduled sleep episodes tended to occur earlier in the day than the period of maximum afternoon sleep tendency seen in normal subjects. Two napping strategies are suggested for further study.

Effects of age and isolation on the evolution of catalepsy during chronic haloperidol treatment

Sixteen young (5 months) and 16 old (20-24 months) male Wistar rats, housed together or in individual cages were observed for cataleptic behavior 10, 20 and 30 days after the beginning of chronic haloperidol treatment (1.0 mg/kg, twice daily, for 30 days). Catalepsy was measured by the bar test. Age increased the duration of haloperidol-induced catalepsy of isolated and group-housed rats in the three observation sessions (old-isolated = 7.4 ñ 0.2; old-group housed = 7.5 ñ 0.1; young-isolated =6.3 ñ 0.2; young-group housed = 6.8 ñ 0.2 In seconds in session 1, for example). Conversely, isolation did not modify the sensitivity to the sensitivity to the cataleptic effect of haloperidol. Even more important, no differences in duration of haloperidol-induced catalepsy were observed among the three sessions for each group. The resultss indicate that under the experimental conditions employed the animals did not develop tolerance nor sensitization to haloperidol-induced catalepsy. In addition, neither age nor isolation modified the absence of effects of repeated haloperidol treatment on the catalepsy behavior of rats