Extrapyramidal Function Research Articles

Presbyvestibulopathie

ZusammenfassungIn dieser Publikation werden die Diagnosekriterien für Presbyvestibulopathie (PVP) durch das Klassifikationskomitee der Bárány-Gesellschaft beschrieben. PVP ist als ein chronisches vestibuläres Syndrom definiert, das durch Gangunsicherheit, Gangstörungen und/oder wiederholte Stürze bei leichten bilateralen vestibulären Defiziten gekennzeichnet ist, mit Labortestbefunden, die zwischen Normalwerten und Schwellenwerten für die bilaterale Vestibulopathie liegen.Die Diagnose von PVP basiert auf der Anamnese des Patienten, der körperlichen Untersuchung des Patienten und der Auswertung von Untersuchungen des Gleichgewichtssystems. Die Diagnose von PVP setzt eine bilateral verminderte Funktion des vestibulookulären Reflexes (VOR) voraus. Dies kann für den Hochfrequenzbereich des VOR mit dem Video-Kopf-Impuls-Test (vKIT), für den mittleren Frequenzbereich mit dem Drehstuhltest und für den Niederfrequenzbereich mit der kalorischen Prüfung diagnostiziert werden.Für die Diagnose von PVP sollte der horizontale anguläre VOR-Verstärkungsfaktor (Gain) auf beiden Seiten < 0,8 und > 0,6 betragen, und/oder die Summe der maximalen Spitzengeschwindigkeiten in der langsamen Phase des kalorisch induzierten Nystagmus sollte bei der Stimulation mit warmem und kaltem Wasser auf jeder Seite < 25°/s und > 6°/s betragen, und/oder der horizontale anguläre VOR-Gain sollte bei Drehstuhlpendelung > 0,1 und < 0,3 betragen.PVP tritt typischerweise zusammen mit anderen altersbedingten Defiziten des Sehvermögens, der Propriozeption und/oder der kortikalen, zerebellären und extrapyramidalen Funktion auf, die ebenfalls zur Manifestation der Symptome von Gangunsicherheit, Gangstörungen und Stürzen beitragen und diese möglicherweise erst auftreten lassen. Die hier beschriebenen Kriterien berücksichtigen lediglich das Vorhandensein dieser Symptome zusammen mit einer dokumentierten Beeinträchtigung der vestibulären Funktion bei älteren Erwachsenen.

SUN-520 Brain Calcinosis Syndrome Manifesting as Cerebellar Ataxia in a Chronic Hypoparathyroid Patient

BACKGROUND Chronic hypoparathyroidism in adults is usually secondary to previous thyroid surgery and is characterized by low calcuim and inappropriately low circulating PTH levels. The clinical presentation of hypoparathyroidism can vary with the serum calcium levels and chronicity of hypocalcemia. Hypoparathyroidism can cause intracranial calcifications but extensive intracranial calcifications are rare. Brain calcinosis syndrome is defined as bilateral calcium accumulation in the brain parenchyma, most often within the basal ganglia. Such intracranial calcifications occur in 0.3-1.5% of patients with hypoparathyroidism, often detected incidentally. The mechanism of intracranial calcification is not completely understood. Its occurrence with hypocalcemia suggests that increased calcium-phosphorus complex formation plays a role. THE CASE A 63-year old female was admitted due to dizziness. She had a fall prior confinement due to loss of consciousness lasting for less than 5 minutes, however, recovered afterwards. No head injury was detected at the referring hospital. She is hypertensive with good BP control on Amlodipine 2.5 mg and Losartan 50 mg taken once daily. She had total thyroidectomy for colloid adenoma 20 years ago, prescribed with Levothyroxine 100 mcg once daily but taken with poor compliance. She had episodes of cold intolerance, hoarseness, and weight gain. On examination, she was conscious and coherent. Blood pressure was 95/60 mm Hg, heart rate of 67 beats per minute. A midline neck scar from previous surgery was visible, no palpable neck mass or lymph nodes. Notable on the neurological examination were positive Rhomberg test and dysmetria evaluated by finger-to-nose test. Chvostek’s and Trosseau’s signs were negative. Motor, sensory and cranial nerve functions were intact. Plain cranial CT scan showed extensive cranial calcifications on both basal ganglia, corona radiata, brainstem and cerebellum. Blood tests revealed low levels of ionized calcium (0.91 mmol/L; N 1.12-1.32 mmol/L)), intact PTH (0.51 pg/ml; N 15-65 pg/ml), and FT4 (5.54 pmol/L; N 12-22 pmol/L). TSH was elevated (32.85 uIU/ml; N 0.27- 4.2 uIU/ml). Calcium with active vitamin D and levothyroxine were given. Physical rehabilitation initiated. Patient was eventually discharged improved, with decreased dizziness. CONCLUSION Basal ganglia calcifications present with diverse manifestations and include seizures, mental deterioration and disorders of the cerebellar or extrapyramidal function. Treatment usually involves calcium and vitamin D supplementation. Marked clinical improvement usually results from treatment of hypoparathyroidism. Measurement and monitoring of serum calcium, phosphorus and intact PTH is warranted. REFERENCE: Ramen C. Basak. A Case Report of Basal Ganglia Calcification - A Rare Finding of Hypoparathyroidism. Oman Med J. 2009 Jul; 24(3): 220-222.

The development of antipsychotic drugs.

Antipsychotic drugs revolutionised psychiatric practice and provided a range of tools for exploring brain function in health and disease. Their development and introduction were largely empirical but based on long and honourable scientific credentials and remarkable powers of clinical observation. The class shares a common core action of attenuating central dopamine transmission, which underlies the major limitation to their use – high liability to disrupt extrapyramidal function – and also the most durable hypothesis of the basis of psychotic disorders, especially schizophrenia. However, the Dopamine Hypothesis, which has driven drug development for almost half a century, has become a straight-jacket, stifling innovation, resulting in a class of compounds that are largely derivative. Recent efforts only cemented this tendency as no clinical evidence supports the notion that newer compounds, modelled on clozapine, share that drug’s unique neurological tolerability and can be considered ‘atypical’. Patients and doctors alike must await a more profound understanding of central dopamine homeostasis and novel methods of maintaining it before they can again experience the intoxicating promise antipsychotics once held.

Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia.

This article provides an overview of the clinical features, neuropathologic findings, diagnostic criteria, and management of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), together known as the Lewy body dementias. DLB and PDD are common, clinically similar syndromes that share characteristic neuropathologic changes, including deposition of α-synuclein in Lewy bodies and neurites and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations, often with a variable degree of coexisting Alzheimer pathology. The clinical constellations of DLB and PDD include progressive cognitive impairment associated with parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. Current clinical diagnostic criteria emphasize these features and also weigh evidence for dopamine cell loss measured with single-photon emission computed tomography (SPECT) imaging and for rapid eye movement (REM) sleep behavior disorder, a risk factor for the synucleinopathies. The timing of dementia relative to parkinsonism is the major clinical distinction between DLB and PDD, with dementia arising in the setting of well-established idiopathic Parkinson disease (after at least 1 year of motor symptoms) denoting PDD, while earlier cognitive impairment relative to parkinsonism denotes DLB. The distinction between these syndromes continues to be an active research question. Treatment for these illnesses remains symptomatic and relies on both pharmacologic and nonpharmacologic strategies. DLB and PDD are important and common dementia syndromes that overlap in their clinical features, neuropathology, and management. They are believed to exist on a spectrum of Lewy body disease, and some controversy persists in their differentiation. Given the need to optimize cognition, extrapyramidal function, and psychiatric health, management can be complex and should be systematic.

Dose-related effects of clozapine and risperidone on pattern of brain regional serotonin and dopamine metabolism and on extrapyramidal functions in rats

Dose-related effects of clozapine and risperidone on pattern of brain regional serotonin and dopamine metabolism and on extrapyramidal functions in rats

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats

The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

Developments in understanding the physiology and pharmacology of parkinsonism.

While the era of major advances in understanding and treating parkinsonism seems to be over, steady progress is being made in elucidating physiological and pharmacological aspects of extrapyramidal function. The dramatic impact of levodopa therapy has been followed by the recognition of serious limitations to its long-term use, which provides a continuing stimulus for efforts to analyze the physiological and pharmacological properties of the basal ganglia and substantia nigra. There are reasonable grounds for the hope that this research will lead to significant developments in therapy.

Amisulpride plus valproate vs haloperidol plus valproate in the treatment of acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial

The primary objective of this study was to compare the effectiveness of combination treatment of valproate and amisulpride with that of valproate and haloperidol in bipolar I disorder. Adult inpatients with a current manic episode fulfilling DSM-IV-TR diagnostic criteria for bipolar type I disorder were included. Patients were randomized to amisulpride (400-800 mg/day) or haloperidol (5-15 mg/day) for 3 months and all received valproate. The primary effectiveness criterion was the percentage of responders (defined by a decrease of >/=50% of the Y-MRS) in patients completing the study. Safety was evaluated by adverse event reporting, determination of extrapyramidal function and clinical examination. Sixty-two patients were randomized to receive valproate-amisulpride, and 61 to receive valproate-haloperidol. At study end, responder rates were 72.6% in the amisulpride group and 65.5% in the haloperidol group. Remission rates were 83.9% and 89.7%, respectively. At study end, neither response rates nor remission rates differed significantly between groups. Treatment-emergent adverse events occurred significantly (p = 0.009) more frequently in the haloperidol group (86.4%) than in the amisulpride group (66.1%). In conclusion, the valproate-amisulpride combination was as effective as the valproate - haloperidol combination in bipolar I patients, with a better safety profile.

A double-blind randomised comparative trial of amisulpride versus olanzapine for 2 months in the treatment of subjects with schizophrenia and comorbid depression

Purpose To compare the efficacy and safety of amisulpride and olanzapine in subjects with schizophrenia and comorbid depression in a randomised double-blind trial. Patients Eighty-five adult patients fulfilling DSM-IV criteria for schizophrenia and presenting a depressive episode were randomised to amisulpride (200–600 mg/day) or olanzapine (5–15 mg/day) for 8 weeks. Primary efficacy variables were change in Calgary Depression Scale (CDS) score and Clinical Global Impression (CGI) of Change. Safety was monitored by adverse event reporting and determination of extrapyramidal function and metabolic variables. Results The mean change from baseline of CDS score was –6.84 in the amisulpride group and –7.36 in the olanzapine group. 65.9% and 61.5% of subjects, respectively, were considered “much” or “very much” improved. No significant inter-group difference in effect size was observed. The frequency of adverse events was low and emergence of extrapyramidal symptoms was not seen. Four patients in the olanzapine group developed abnormal triglyceride levels. Mean weight gain was 1.45 and 0.5 kg, respectively, in the olanzapine and amisulpride groups. Conclusion Amisulpride and olanzapine are effective in patients with schizophrenia and comorbid depression. Tolerance of both drugs was acceptable, although use of olanzapine was associated with a trend toward greater metabolic side-effects [19].

Apparent Transient Effects of Recent ???Ecstasy??? Use on Cognitive Performance and Extrapyramidal Signs in Human Subjects

Our purpose is to investigate cognitive performance and extrapyramidal function early after ecstasy use. Ecstasy, containing 3,4 methylenedioxymethamphetamine, has shown evidence of causing cognitive deficits and parkinsonian signs. Previous research has examined cognitive performance after a period of prolonged abstinence, but research assessing the early effects of ecstasy after recent use is limited despite temporal neurochemical differences demonstrated in nonhuman models. This study compared task performance between 13 ecstasy users (10 to 15 h postdrug use) and a control group on a battery of neuropsychologic assessments while matching for education level, sleep deprivation, and premorbid IQ. The groups were also compared on measures relating to parkinsonian signs. The ecstasy subjects showed impairments on measures of executive function as evaluated by Raven's Standard Progressive Matrices (SPM) and the Wisconsin Card Sorting Task (WCST). Short-delay free recall memory was also impaired in ecstasy subjects on the California Verbal Learning Test (CVLT-II). No extrapyramidal motor impairments were detected. These deficits resemble deficits previously reported in chronic ecstasy use but also seem to reveal transient impairments in executive function. Future research is needed to better understand the neurologic and neuropsychologic implications of ecstasy use across time and extent of use.

Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully?

Many older adults walk with a cautious and impaired gait of unknown origin, however, the relationship between fear of falling and the observed gait changes is not well understood. To better understand the "cautious" gait of the elderly, we tested the hypothesis that temporal gait variability, putatively a marker of intrinsic walking unsteadiness, is increased among older adults with a cautious gait and a higher-level gait disorder (HLGD), an altered gait that cannot be attributed to a well-defined cause. Twenty-five older adults (mean age: 78 years) with a HLGD were compared to healthy controls of similar age and sex (n=28). The clinical characteristics (e.g., neurological status, fear of falling), the magnitude of the stride-to-stride variations in gait cycle timing (a measure of temporal gait variability), and a fractal index of gait (a measure of the stride dynamics independent of the magnitude of the variability) were studied in both groups. Gait variability was significantly increased (P<0.0001) in HLGD subjects (52+/-26 ms) compared to controls (27+/-9 ms). Changes in frontal lobe and extra-pyramidal function were also found in the patient group. Among HLGD subjects, gait variability was not associated (P>0.05) with age, gender, MMSE score, muscle strength, # of co-morbidities, balance, cerebellar signs, or pyramidal signs, but was significantly associated with scores on the Geriatric Depression Scale (r=0.46, P<0.02) and fear of falling (r=0.69, P<0.0001). Among HLGD subjects, only a fractal index was significantly different in fallers and non-fallers. These findings underscore the idea that the gait changes in older adults who walk with fear may be an appropriate response to unsteadiness, are likely a marker of underlying pathology, and are not simply a physiological or psychological consequence of normal aging.

Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease.

The effects of serotonin (5-HT) in the CNS are mediated through receptor subtypes distinguished by seven major families. The 5-HT6 receptor gene maps to the human chromosome region 1p35-p36 and a polymorphism (C267T) of the 5-HT6 gene has been associated with the risk of developing schizophrenia.1 Unlike most 5-HT receptors, the 5-HT6 receptor is highly expressed in the striatum,2 suggesting a possible involvement of this receptor in the extrapyramidal function. In this study, we investigated whether the allelic variant C267T of the 5-HT6 gene could contribute to the risk for developing PD. Patients diagnosed with sporadic PD (n = 243) and control subjects (n = 234) were included in our study. Patients with PD were consecutively selected starting in March 1999 until December 2000 from the outpatients attending the Institute of Neurology of the University of Catanzaro, Italy. PD was defined by the presence of at least two of four cardinal signs (bradykinesia, rigidity, rest tremor, and postural instability). Only cases with idiopathic PD responsive to levodopa were included. No patient had …

Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform.

Retinoid X receptors RXRalpha, beta and gamma exert multiple functions in the genetic regulation of mammalian signalling systems by forming heterodimeric complexes with several nuclear ligand receptors. In contrast to the widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is restricted to particular tissues in which RXRgamma1 is the major isoform expressed in the mouse corpus striatum. To investigate the function of this particular isoform RXRgamma1, we generated RXRgamma1 gene-knockout mice by homologous recombination in ES cells. Both heterozygous and homozygous mice showed severe runting after birth, which often resulted in the early death of mice of the 129/C57BL-6 genetic background. Independent of genetic background, however, the expression of choline acetyltransferase (ChAT) in the cholinergic interneurones in the striatum (caudal putamen) was markedly reduced in the RXRgamma1 gene-null mice. Furthermore, the mutant exhibited an altered response to the administration of dopamine receptor antagonists, haloperidol and chlorpromazine, which normally induce catalepsy in mice. These results strongly suggest that RXRgamma1 plays an important role in either the development or activation of cholinergic neurones in nigrostriatal extrapyramidal pathways.

Loss of cannabinoid receptor binding and messenger RNA levels and cannabinoid agonist-stimulated [ 35s]guanylyl- 5′- O-(thio)-triphosphate binding in the basal ganglia of aged rats

Recent reports have demonstrated that cannabinoid receptor binding decreases in several neurodegenerative diseases related to extrapyramidal function. However, there is little evidence with regard to potential changes of these receptors during senescence. The present study was designed to determine the possible existence of ageing-induced changes in cannabinoid receptor binding and gene expression in extrapyramidal areas. To this end, we analysed cannabinoid receptor binding and basal and cannabinoid receptor agonist-stimulated [ 35S]guanylyl-5′- O-(γ-thio)-triphosphate binding, by using autoradiography and cannabinoid receptor messenger RNA levels, by using in situ hybridization, in slide-mounted brain sections obtained from young (three-month-old) and aged (>two-year-old) rats. Results were as follows. Aged rats exhibited a marked decrease in cannabinoid receptor binding in most of the basal ganglia, excepting the globus pallidus which had similar binding levels in both young and aged rats. The highest decreases were in the entopeduncular nucleus (−49.6%) and substantia nigra pars reticulata (−45.2%), whereas more moderate decreases were found in the lateral caudate-putamen (−29%) and only a decremental trend in the medial caudate-putamen (−13.1%). These decreases in cannabinoid receptor binding were paralleled by less marked increases in WIN 55212-2-stimulated [ 35S]guanylyl-5′- O-(γ-thio)-triphosphate binding in these structures in aged rats (% of agonist stimulation: 189% in the substantia nigra; 29.4% in the lateral caudate-putamen) as compared to young rats (296% and 53.2%, respectively). Contrarily, the percentage of agonist stimulation was similar in the globus pallidus, an area where cannabinoid receptor binding did not change during ageing, of aged (205.5%) and young (215.5%) rats. In addition, aged rats also exhibited significant reductions in the cannabinoid receptor messenger RNA levels in the medial (−14.3%) and, in particular, in the lateral (−29.4%) caudateputamen, the area where the cell bodies of cannabinoid receptor-containing neurons, projecting to the substantia nigra, entopeduncular nucleus and globus pallidus, are located. In summary, the synthesis and binding levels of cannabinoid receptors markedly dropped in different structures of the extrapyramidal system of aged rats. Since these receptors, located in the basal ganglia, seem to play a role in motor control, this loss of cannabinoid receptors might be related to the motor impairment which progressively appears during senescence.

Adverse effects of antipsychotic agents. Do newer agents offer advantages?

Although antipsychotic drugs are effective in treating the so-called positive features of schizophrenia, between one-quarter and one-third of patients respond poorly. Furthermore, the incidence of adverse effects is high, especially those reflecting disruption of extrapyramidal function, and is a major source of non-compliance. There is a clear need for new compounds that are more efficacious and/or better tolerated. Until recently, the classical dopamine hypothesis, with its emphasis on D2 blockade as the key mechanism of antipsychotic action, dominated drug development, though the emphasis is now shifting. Three 'new' antipsychotics have reached the international market in the past 5 years-the newly rehabilitated clozapine and the genuinely new remoxipride and risperidone. Claims of enhanced tolerability have been made for each of these, but as none is free from adverse effects, their place in treatment can only be meaningfully established in relation to the efficacy of each in different clinical situations. Clozapine has an extensive profile of general, nonhaematological adverse effects which is slightly different in emphasis from, but comparable in incidence to, that of chlorpromazine. There is a 0.8% risk of agranulocytosis in the first year of exposure, which can be fatal, though the boundary separating it from other (especially phenothiazine) antipsychotics in this regard is becoming increasingly blurred. It has a clearly diminished liability to cause extrapyramidal adverse effects. Its proven efficacy in operationally defined treatment-resistant schizophrenia and in patients intolerant to the extrapyramidal adverse effects of standard drugs establishes its credentials for advantage in these groups. There is on present evidence, however, only a hint of enhanced efficacy in acute schizophrenia: this requires further investigation. Open maintenance studies provide impressive data on long term outcome, especially in terms of quality-of-life parameters, but this issue requires to be addressed in blind, randomised trials. Until such additional information is forthcoming the risks and consequent costs would not justify extension of its use. The evidence to date is that reported benefits in so-called negative features probably reflect its favourable neurological profile. While the advantages of clozapine are undoubted, they remain as yet restricted to selected patient groups. Remoxipride has a good general tolerability profile, its special strength being its low sedative effect. However, its reported association with aplastic anaemia has severely restricted its use, and regular haematological monitoring is required. Although remoxipride appears to have a lower liability to produce extrapyramidal adverse effects than the high potency haloperidol, its benefits relative to other low potency compounds in this regard remain unproven. The only obvious situation in which its risks and consequent costs would be justified would seem to be patients with established compliance problems as a result of intrusive sedation with standard drugs. The position of other benzamides such as raclopride and amisulpride remains to be established. Risperidone, perhaps from its antiadrenergic actions, has more in the way of cardiovascular adverse effects than haloperidol, though these can be obviated by graded early exposure. It may also be associated with greater weight gain. Otherwise it appears to be well tolerated. In comparison with haloperidol, it appears to be associated with a lower prevalence of acute extrapyramidal adverse effects in dosages < or = 10 mg/day, the most potentially important component of which is its reportedly insignificant likelihood of promoting akathisia. These conclusions emerge from comparisons with haloperidol in doses many might consider somewhat high. The question of the advantage of risperidone over low or milligram-equivalent haloperidol regimens remains open.(ABSTRACT TRUNCATED)

Heart rate variability in schizophrenic patients: Effect of clozapine

The outcome of treatment in schizophrenia is best considered as a multidimensional construct. This report lists thirteen categories of outcome measures that have been studied in schizophrenia research, among the most important of which are psychopathology, cognitive function, interpersonal social function, quality of life, extrapyramidal function, the suicide tendeccy and the need for hospitalisation. Clozapine is effective in achieving improved outcome in all these measures in a high percentage of neuroleptic-resistant patients. Ninety-two of 180 (51.1%) clozapine-treated neuroleptic-resistant patients achieved a decrease of 20% in Brief Psychiatric Rating Scale total scores at six weeks using the 0–6 scaling system. Cognitive function contributes importantly to overall function for schizophrenia. Clozapine has been shown to improve some types of cognition in schizophrenia, especially semantic memory and some tests of executive function. Clozapine has also been shown to decrease the incidence of suicide and hospitalisation. The task of deciding which therapies to use in schizophrenia should encompass the spectrum of benefits of each therapy, their risks and costs, in relation to all alternatives.

Time-course of the effects of anandamide, the putative endogenous cannabinoid receptor ligand, on extrapyramidal function

We have recently described the dose-response effect of anandamide (AEA), the N-amide derivative of arachidonic acid that acts as an endogenous ligand for the cannabinoid receptor, on extrapyramidal function. The present study has been designed to examine the time-course of this effect. To this end, adult male rats were submitted to an acute i.p. injection of AEA, Δ 9-tetrahydrocannabinol (THC) or vehicle and examined at different times after drug administration. Animals were tested in an open-field test, then sacrificed and their striata used for analyses of dopaminergic indices. Results were as follows. The administration of AEA or THC produced the expected inhibition of motor behavior. Thus, the administration of AEA decreased the ambulation and the frequency of stereotypic movements (in particular, the number of rears) and increased the time spent by the rats in inactivity. These effects were evident at 10 and 30 min after the administration of the cannabinoid agonist, but mostly disappeared at 60 min. Interestingly, motor inhibition was observed again around 2 or 3 h after the administration of AEA. This was a small but persistent effect (decreased ambulation followed by increased inactivity), because it was observed until at least 6 h after AEA administration. The other cannabimimetic, THC, was always able of decreasing the ambulation and the frequency of rearing and grooming behavior, and of increasing the time spent in inactivity. This effect was usually something more marked than the effect of AEA, but the most characteristic fact was its persistence at all times studies, even at 6 h after administration. These motor disturbances were accompanied by changes in the activity of nigrostriatal dopaminergic neurons. Thus, the administration of AEA decreased the activity of tyrosine hydroxylase (TH) in the striatum at 10 and 30 min after treatment, suggesting a decreased nigrostriatal activity parallel to the motor deficit observed at these times. This was followed by an increase in TH activity and dopamine and l-3,4-dihydroxyphenylacetic acid contents at 60 min after treatment, which would likely reflect a compensatory stimulation of these neurons, whereas restoration of control values was found at 180 min after AEA administration, suggesting that the motor deficit observed at this time was not dependent on dopaminergic influence. Paradoxically, the administration of THC only produced changes in dopaminergic activity at 60 min after treatment, similar to those seen with AEA, but was ineffective at the other times. In summary, AEA inhibits motor behavior in parallel to reductions in the activity of nigrostriatal dopaminergic neurons. However, this effect was of short duration, disappearing at 60 min after treatment, as compared with the inhibitory effect of THC on motor behavior which was observed at all times studied. Interestingly, a new AEA-induced inhibition of motor behavior, which was not accompanied by dopaminergic changes, appeared at longer times although its meaning remains to be determined.

The CB1 cannabinoid receptor antagonist SR 141716A affects A9 dopamine neuronal activity in the rat.

CB1 receptors and their putative natural ligand anandamide, have been tentatively involved in the control of midbrain extrapyramidal function. Electrophysiological activity of dopamine neurones was measured after acute and repeated administration of the CB1 receptor antagonist SR 141716A (0.3-3 mg kg-1) in rats. Acute SR 141716A increased A9, but not A10 cell population response without affecting either their spontaneous firing rate or apomorphine-induced rate inhibition and prevented amphetamine-induced inhibition of A9, but not of A10 cell firing. After repeated administration SR 141716A (1 or 5 mg kg-1) decreased population response of A9 cells, which was reversed by apomorphine. These results suggest that CB1 receptor blockade by SR 141716A interrupts a cannabinoid-like endogenous tone controlling extrapyramidal function.

Multiple-outcome criteria in schizophrenia: an overview of outcome with clozapine

The outcome of treatment in schizophrenia is best considered as a multidimensional construct. This report lists thirteen categories of outcome measures that have been studied in schizophrenia research, among the most important of which are psychopathology, cognitive function, interpersonal social function, quality of life, extrapyramidal function, the suicide tendeccy and the need for hospitalisation. Clozapine is effective in achieving improved outcome in all these measures in a high percentage of neuroleptic-resistant patients. Ninety-two of 180 (51.1%) clozapine-treated neuroleptic-resistant patients achieved a decrease of 20% in Brief Psychiatric Rating Scale total scores at six weeks using the 0-6 scaling system. Cognitive function contributes importantly to overall function for schizophrenia. Clozapine has been shown to improve some types of cognition in schizophrenia, especially semantic memory and some tests of executive function. Clozapine has also been shown to decrease the incidence of suicide and hospitalisation. The task of deciding which therapies to use in schizophrenia should encompass the spectrum of benefits of each therapy, their risks and costs, in relation to all alternatives.

Neuropeptide levels in discrete brain regions in the iminodipropionitrile-induced persistent dyskinesia rat model

To clarify the role of neuropeptides in dyskinesia induced by iminodipropionitrile (IDPN), the levels of five representative neuropeptides were examined in discrete regions of the rat brain 4 weeks after intraperitoneal injection of IDPN. The five neuropeptides examined were methionine-enkephalin (Met-Enk), substance P (SP) and somatostatin, which are closely related to extrapyramidal function, and thyrotropin-releasing hormone (TRH) and cholecystokinin octapeptide (CCK-8), which are closely related to the neural mechanism of the dopamine system. IDPN pretreatment significantly increased Met-Enk in the basal ganglia but not SP or somatostatin; however, all three neuropeptide levels were increased in the hindbrain. In IDPN-treated rats, TRH and CCK-8 levels were increased in the nucleus accumbens, and the frontal cortical CCK-8 level was extremely increased. These findings, together with previous reports, suggest that neuropeptides in the basal ganglia, hindbrain and cerebral cortex play important roles in the manifestation of dyskinetic symptoms.