Dopamine metabolism increases in post-mortem schizophrenic basal ganglia

Summary The dopamine-rich regions of post-mortem brains from 6 schizophrenics and 7 controls were analyzed. There were no significant changes in dopamine concentrations in basal ganglia and nucleus accumbens of schizophrenics compared with controls. Schizophrenic basal ganglia (putamen and caudate) showed significantly higher levels of homovanillic acid, and tyrosine hydroxylase activity. Among the schizophrenic patients, markedly high activity of tyrosine hydroxylase was measured in a patient diagnosed as catatonic type. He had not taken antipsychotic drugs for 3 months prior to death. In his relatives, three other schizophrenics were found to the second degree. A remarkable low level of dopamine and a high level of homovanillic acid measured indicate this case would have had an increased turnover rate of dopamine in the dopaminergic nerve terminals. Among the schizophrenic patients, there might be one group whose enzyme activity of dopamine synthesis in the brain is exceptionally high.A part of this study was presented at the 3rd World Congress of Biological Psychiatry, Stockholm, 1981 and at the Satellite Symposium of 8th International Congress of Pharmacology on Psychobiology of Schizophrenia, Gifu, 1981.     

Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson's disease: clinical score and internal globus pallidus activity

Summary We analysed the firing activity of internal globus pallidus cells in two Parkinson's disease patients undergoing stereotaxic surgery. Both patients showed an advanced rigid-akinetic syndrome with disabling levodopa induced dyskinesias. Apomorphine, intraoperatively administered at doses (1–2 mg) inducing a short but clear clinical improvement without involuntary movements, reduced the pallidal discharge rate by >50% in both patients. An higher apomorphine dose (2.5 mg), tested in one hemisphere, blocked the firing activity with a time course independent from the occurrence of dyskinesias. These finding suggest that the reduction of internal pallidus excitability is one of the mechanisms underlying the efficacy of dopaminergic therapy, but also that changes in other basal ganglia stations are likely to be involved in dyskinesias.     

Differential Localization of AMPA Glutamate Receptor Subunits in the Two Segments of the Globus Pallidus and the Substantia Nigra Pars Reticulata in the Squirrel Monkey

The subthalamic nucleus has long been known as the main source of glutamatergic afferents to the pallidum and the substantia nigra in primates. Recent findings showed that the excitatory effects induced by the subthalamic nucleus in pallidal cells are mediated through the activation of non-NMDA receptors in the rat. The objective of the present study was to analyse the distribution of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptor subunits in the external pallidum (GPe), the internal pallidum (GPi) and the substantia nigra pars reticulata (SNr) in squirrel monkeys ( Saimiri sciureus ). This was achieved by means of immunohistochemistry using antibodies raised against the GluR1 and the GluR2/3 subunits of the AMPA receptor. Our results show that all neuronal perikarya in GPe and GPi display immunoreactivity for GluR2/3 subunits whereas GluR1 is confined exclusively to cells in the GPe. The proportion of GluR1-immunoreactive neurons is not uniform throughout the rostrocaudal extent of GPe; in the rostral third all GPe cells display GluR1 immunoreactivity, whereas in the caudal third the proportion of GluR1-positive cells decreases to 50%. The intensity of GluR1 immunostaining associated with GPe cells is lower than that associated with neighbouring large-sized neurons in the nucleus basalis of Meynert. In contrast to GPi cells, the neurons in the SNr display immunoreactivity for both GluR1 and GluR2/3 subunits. In conclusion, our results provide the first evidence for a different distribution of the GluR1 subunit of the AMPA receptors in the two segments of the globus pallidus in monkeys. These findings imply that the control of the basal activity of GPe and GPi cells by the subthalamic nucleus is exerted via the activation of AMPA receptors composed of different subunits. These data reinforce the view that the two segments of the globus pallidus are different entities that possess their own functional characteristics in primates.     

Distribution of neuropeptide Y immunoreactivity in the basal forebrain and upper brainstem of the squirrel monkey (Saimiri sciureus)

The distribution of neuropeptide Y (NPY) immunoreactivity in the brain of the squirrel monkey (Saimiri sciureus) was studied by means of the indirect immunofluorescence, peroxidase-antiperoxidase, and avidin-biotin-complex methods. The antiserum used was raised in rabbits and did not show any significant crossreactivity with related peptides including peptide YY and avian pancreatic polypeptide. In the upper brainstem of the squirrel monkey a dense NPY-immunoreactive terminal field is seen in lateral parabrachial area, locus coeruleus, and interpeduncular nucleus. A small group of NPY-immunoreactive cell bodies is present in the lateral habenula and a moderate number of NPY-immunoreactive fibers occurs in periaqueductal gray and nucleus raphe pallidus. The substantia nigra (SN) appears mostly devoid of NPY immunoreactivity whereas the ventral tegmental area contains a few reactive fibers. In the hypothalamus the medial preoptic area as well as the arcuate and paraventricular nuclei receive a strikingly dense NPY innervation. In addition, numerous NPY-positive cell bodies are found within the dorsomedial half of the supraoptic nucleus but very few are seen in paraventricular nucleus. A large number of NPY-immunoreactive cell bodies is also present in arcuate nucleus. In the basal telencephalon NPY-immunoreactive cells abound mostly in striatum, but some are also found in the amygdala (particularly basal, central, and lateral amygdaloid nuclei), the claustrum, and in the bed nucleus of the stria terminalis. Intensely reactive network of NPY-immunoreactive fibers is also present in all of these structures. In striatum, the numerous, fine and non-varicose NPY-immunoreactive fibers, as well as the NPY-positive cell bodies, are slightly more abundant in caudate nucleus than in putamen. The globus pallidus (GP) is mostly devoid of NPY-immunoreactive fibers and terminals. The fact that the two major recipient structures of striatal outflow (SN and GP) do not receive significant NPY input suggests that the striatal NPY-containing neurons are intrinsically organized.     

Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats

It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation.     

Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus

The subthalamic nucleus (STN) has been argued to be an important component of reward‐sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task‐related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision‐making processes.     

Subcortical overactivation in untreated schizophrenic patients: a functional magnetic resonance image finger-tapping study

Functional magnetic resonance imaging (fMRI) is a well established, non-invasive technique for mapping the working brain. Yet imaging of subcortical regions has proven to be difficult. We studied 40 subjects performing an unilateral self-paced finger-tapping task. Patients with schizophrenia according to DSM-IV treated with olanzapine (n =10) or haloperidol (n=10) were compared to healthy controls (n =10) and untreated patients (n=10). Brainvoyager software was used for data-analyzing. All subjects showed highly significant activation in the contralateral sensorimotor area, the supplementary motor area and the ipsilateral cerebellum. In every investigated subject contralateral subcortical regions were also significantly activated (P < 0.001). Activation in ipsilateral pallidum was significantly higher in untreated patients compared with the other groups indicating an increase in subcortical coactivation. In addition, significant correlations were revealed within groups. This study emphasizes the possibility of investigating subcortical brain activation in patients with schizophrenia. The results of the present study outline the importance of further fMRI studies to investigate interindividual activation differences under different conditions especially focusing on basal ganglia.     

Shell and core in monkey and human nucleus accumbens identified with antibodies to calbindin-D28k

The neurochemical division of the rodent nucleus accumbens into shell and core is now a widely accepted concept. However, such divisions in the primate nucleus accumbens have yet to be fully clarified and described. In the present study, the forebrains of three primates—marmoset, rhesus monkey, and human—and a Wistar rat, were immunoreacted with antibodies directed against calbindin-D_28k. The patterns of immunoreactivity in the primates' ventral striatum were mapped and compared to that of rat. Calbindin staining was uneven in all species and there was no evidence of a bicompartmental organization, i.e., striosome/patch and matrix, in central parts of the nucleus. Nucleus accumbens in primates, as in rat, could be divided immunohistochemically into a crescent-shaped outer shell—medially, ventrally and laterally—and an inner core. In general, medial parts of the shell stained less intensely for calbindin than did lateral parts. However, interspecific variation in the intensity of the immunoreactive staining and the mediolateral extent of the shell was obvious. The core, which immunostained unevenly, was consistently more intensely immunoreactive than either medial or lateral shell in all species except the marmoset. These results suggest that the neurochemical subdivisions of shell and core established for nucleus accumbens of rodents are also present in primates. However, further work is needed to establish whether these territories are homologous and, if so, the full extent of that homology. © 1996 Wiley-Liss, Inc.     

Spatial distribution of thalamic projections to the supplementary motor area and the primary motor cortex: A retrograde multiple labeling study in the macaque monkey

The exact knowledge on spatial organization of information sources from the thalamus to the supplementary motor area (SMA) and to the primary motor cortex (MI) has not been established. We investigated the distribution of thalamocortical neurons projecting to forelimb representations of the SMA and the MI using a multiple retrograde labeling technique in the monkey. The forelimb area of the SMA, and the distal and proximal forelimb areas of the MI were identified by electrophysiological techniques of intracortical microstimulation and single neuron recording. Injections were made into these three representations with three different dyes in the same animal (horseradish peroxidase conjugated to wheat germ agglutinin, diamidino yellow, and fast blue), and the thalamic neurons were retrogradely labeled. Injections into the SMA densely labeled thalamic neurons in nuclei ventralis lateralis pars oralis (VLo), ventralis lateralis pars medialis (VLm) and ventralis lateralis pars caudalis (VLc), but not in nucleus ventralis posterior lateralis pars oralis (VPLo). Injections into the MI labeled thalamic neurons primarily in VLo, VLc, and VPLo. We found that the distribution of projection neurons to the three areas was largely separate in the thalamus. However, in the middle part of VLo, and in a limited portion of VLc, thalamic neurons projecting to the SMA partially overlapped with those to the distal forelimb area of the MI. They overlapped little with those to the proximal forelimb area of the MI. We noted no overlap between the distributions of thalamic projection neurons to the distal and proximal forelimb areas of the MI. These findings suggest that the SMA and MI receive separate information from the thalamus, while sharing minor sources of common inputs. © 1995 Wiley-Liss, Inc.     

Striatal lesions change the behavioral effects of morphine in cats

Cats injected with a relatively low single dose of morphine sulfate (0.5–3.0 mg/kg i.p.) exhibit a long-lasting group of behaviors which we quantified via a time-sampling video technique. The dominant events are complex head movements accompanied by discrete paw, ear and body movements with the animal in a quiet posture, all of which appeared to be visually mediated. Cats with extensive lesions of the caudate nuclei do not show this profile; instead they show unspecific locomotor activity proportional to the size of the ablation and to the dose of morphine. These effects are blocked by naloxone in both intact and lesioned animals. The robustness of these results indicate that (i) the striatum is involved in the behavioral effects of morphine, and (ii) that the cat is a useful, sensitive model for the study of the behavioral effects of opiates.     

Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.     

Distribution and ultrastructural features of the serotonin innervation in rat and squirrel monkey subthalamic nucleus

The main purpose of this light and electron microscopic immunocytochemical study was to characterize and compare the serotonin (5‐HT) innervation of the subthalamic nucleus (STN) in rats and squirrel monkeys (Saimiri sciureus) following labeling with an antibody against the 5‐HT transporter (SERT). Unbiased counts of SERT+ axon varicosities revealed an average density of 5‐HT innervation higher in monkeys (1.52 × 10⁶ varicosities/mm³) than rats (1.17 × 10⁶), particularly in the anterior half of the nucleus (1.70 × 10⁶). As measured by electron microscopy, SERT+ axon varicosity profiles in the STN of both species were smaller than unlabeled profiles. The number of SERT+ profiles displaying a synaptic junction indicated that, in both rat and monkey STN, approximately half of 5‐HT axon varicosities were asynaptic. In monkeys, all synaptic junctions made by SERT+ varicosities were asymmetrical, as opposed to only 77% in rats. Despite the higher density of 5‐HT innervation in the anterior half of monkey STN, the ultrastructural features of its SERT+ varicosities, including synaptic incidence, did not significantly differ from those in its posterior half. These findings suggest that, throughout the rat and monkey STN, 5‐HT afferents may exert their influence via both synaptic delivery and diffusion of 5‐HT, and that an ambient level of 5‐HT maintained in STN by these two modes of transmission might also modulate neuronal activity and influence motor behavior. A better understanding of the factors governing the complex interplay between these signaling processes would greatly improve our knowledge of the physiopathology of the STN.     

Quantitative and ultrastructural study of serotonin innervation of the globus pallidus in squirrel monkeys

The present immunohistochemical study was aimed at characterizing the serotonin (5‐HT) innervation of the internal (GPi) and external (GPe) pallidal segments in the squirrel monkey (Saimiri sciureus) with an antibody against the 5‐HT transporter (SERT). At the light microscopic level, unbiased counts of SERT+ axon varicosities showed that the density of innervation is similar in the GPi (0.57 ± 0.03 × 10⁶ varicosities/mm³ of tissue) and the GPe (0.60 ± 0.04 × 10⁶), with the anterior half of both segments being more densely innervated than the posterior half. Dorsoventral and mediolateral decreasing gradients of SERT varicosities occur in both pallidal segments, but are statistically significant only in the GPi. The neuronal density being significantly greater in the GPe (3.41 ± 0.23 × 10³ neurons/mm³) than in the GPi (2.90 ± 0.11 × 103), the number of 5‐HT axon varicosities per pallidal neuron was found to be superior in the GPi (201 ± 27) than in the GPe (156 ± 26). At the electron microscopic level, SERT+ axon varicosities are comparable in size and vesicular content in GPi and GPe, where they establish mainly asynaptic contacts with unlabeled profiles. Less than 25% of SERT+ varicosities display a synaptic specialization, which is of the symmetrical or asymmetrical type and occurs exclusively on pallidal dendrites. No SERT+ axo‐axonic synapses are present, suggesting that 5‐HT exerts its well‐established modulatory action upon various pallidal afferents mainly through diffuse transmission, whereas its direct control of pallidal neurons results from both volumic and synaptic release of the transmitter.     

Pallidotomy suppresses beta power in the subthalamic nucleus of Parkinson's disease patients

Parkinsonian patients, who have had a unilateral pallidotomy, may require bilateral deep brain stimulation of the subthalamic nucleus (STN), due to disease progression. The current model of the basal ganglia circuitry does not predict a direct effect of pallidotomy on the neuronal activity of the ipsilateral STN. To date, only three studies have investigated the effect of pallidotomy on overall activity of the STN or neuronal firing rate, but not on the spectral content of the neuronal oscillatory activity. Moreover, none of these studies attempted to differentiate the effects on the dorsal (sensory-motor) and ventral (associative-limbic) parts of the STN. We studied the effect of pallidotomy on spectral power in six frequency bands in the STN ipsilateral and contralateral to pallidotomy from seven patients and in 60 control nuclei of patients without prior functional neurosurgery, and investigated whether this effect is different on the dorsal and ventral STN. The data show that pallidotomy suppresses beta power (13-30 Hz) in the ipsilateral STN. This effect tends predominantly to be present in the dorsal part of the STN. In addition, spectral power in the frequency range 3-30 Hz is significantly higher in the dorsal part than in the ventral part. The effect of pallidotomy on STN neural activity is difficult to explain with the current model of basal ganglia circuitry and should be envisaged in the context of complex modulatory interactions in the basal ganglia.     

Glycine receptors in the striatum, globus pallidus, and substantia nigra of the human brain: an immunohistochemical study

Glycine receptors (GlyRs) are heteropentameric chloride ion channels that facilitate fast-response, inhibitory neurotransmission in the mammalian spinal cord and brain. GlyRs have four functional subunits, alpha1-3 and beta, which likely exist in heteromeric alphabeta combinations. Mutations in GlyR alpha1 and beta subunits are well known for their involvement in hyperekplexia, a paroxysmal motor disorder. In this study we present the first detailed immunohistochemical investigation at the regional, cellular, and subcellular levels of GlyRs in the human basal ganglia. The results show that GlyRs are present at the regional level in low concentrations in the striatum and globus pallidus and are present in the highest concentrations in the substantia nigra. At the cellular level, GlyRs are present only in discrete populations of neurons immunoreactive for choline acetyltransferase (ChAT), parvalbumin, and calretinin in the human striatum, on a subpopulation of parvalbumin- and calretinin-positive neurons in the globus pallidus, and in the substantia nigra GlyRs are present on approximately three-fourths of all pars compacta and one-third of all pars reticulata neurons. They also form a distinct band of immunoreactive neurons in the intermedullary layers of the globus pallidus. At the subcellular level in the substantia nigra pars reticulata (SNr), GlyRs show a localized distribution on the soma and dendrites that partially complements but does not overlap with the distribution of gamma-aminobutyric acid (GABA)A receptors. Our results demonstrate the precise cellular and subcellular localization of GlyRs in the human basal ganglia and suggest that glycinergic receptors may play an important complementary role to other inhibitory receptors in modulating cholinergic, dopaminergic, and GABAergic neuronal pathways in the basal ganglia.     

Neuroleptics: effects on neuropsychological function in chronic schizophrenic patients

We have reviewed the literature from the 1950's to the present on the effects of neuroleptics on perceptual and neuropsychological function in chronic schizophrenic patients. In contrast to previous reviews, we have delineated the acute and chronic effects of neuroleptics on individual cognitive and motor tasks by drug, dose, and length of administration. To date, studies have shown that acute administration of neuroleptics impairs performance on some, but not all, tasks requiring vigilance and attention, and on some tasks requiring motor behavior. Chronic administration of neuroleptics, however, improves performance on some tasks requiring sustained attention and visuomotor problem-solving skills depending on dose and length of administration. Moreover, there is consistent evidence to suggest that chronic administration of neuroleptics in this patient population does not impair neuropsychological function independent of motor function. These findings have direct implications regarding the risk/benefit ratio and legal ramifications for the use of neuroleptics in chronic schizophrenic patients.     

综合性心理行为干预对慢性精神分裂症的康复效果

目的　探讨综合性心理行为干预对慢性精神分裂症的康复效果。方法　 6 4例慢性精神分裂症患者根据其意愿被分为对照组和研究组。在精神药物剂量不变的情况下 ,对照组结合简单娱乐活动及支持性心理治疗 ,研究组结合综合性心理行为干预 ,疗程 12周。结果　疗程结束后 ,研究组有效率 6 4.5 % ,而对照组 2 1.2 % ;研究组简明精神病评定量表 (BPRS)、阴性症状量表 (SANS)、社会功能评定量表 (DAS)和生活质量量表 (QOL)评分优于对照组 (P <0 .0 5或 0 .0 1)。结论　综合性心理行为干预能提高临床疗效 ,改善慢性精神分裂症的阴性症状、社会功能及生活质量。     

基底节区脑脓肿并发脑疝手术治疗的方法及预后

目的:探讨基底节区脑脓肿并发脑疝手术治疗的方法及预后。方法:回顾性分析2002年1月至2007年6月收治的11例基底节区脑脓肿并发脑疝患者的手术方法及其预后。结果:11例基底节区脑脓肿并发脑疝患者接受开颅去骨瓣减压加脓肿穿刺抽出术,其中10例治愈,且肢体功能都恢复正常;1例基底节区脑脓肿并发脑疝同时破入脑室患者,行开颅去骨瓣减压加脓肿穿刺抽出术的同时行脑室外引流术,术后10d死亡。结论:去骨瓣减压加脓肿穿刺抽出术是治疗基底节区脑脓肿并发脑疝有效的方法,且避免了基底节区重要结构(如内囊)的损伤。一旦脓肿破入脑室,则预后较差。     

Clinical and biochemical effects of nicergoline in chronic schizophrenic patients

To investigate the potential effect of Nicergoline, an alpha-adrenolytic drug, on negative symptoms in patients suffering from chronic schizophrenia, we administered this compound to 20 male chronic schizophrenics. Patients were previously maintained on long-term neuroleptic (NL) medication. Neuroleptic treatment was discontinued for 12 days, patients were then treated with 30 mg Nicergoline per day. Under NL (A), after 12 days NL-withdrawal (B), after 15 (C) and 30 (D) days Nicergoline treatment clinical ratings (BPRS and AMDP) and stimulation with clonidine (0.002 micrograms/kg body weight) were carried out. Norepinephrine (NE), epinephrine (E), and human growth hormone (HGH) were measured before and after application. Seventeen patients finished the study, 3 dropped out. Some ratings on the AMDP and BPRS scales showed an improvement. However, this improvement was only weak and accompanied by a worsening in other subscores. The withdrawal-induced decrease in NE serum levels continued after 15 days NIC, followed by an increase after 30 days. HGH response to clonidine stimulation was only attenuated after 30 days NIC. Epinephrine, blood pressure and heart rate showed no significant changes throughout the entire study. Our data suggest that NIC in the dosage applied shows no clear and pronounced alpha-2-adrenolytic effects and no specific clinical benefits for chronic schizophrenics. Further investigations are required to evaluate its effect on alpha-1-adrenoceptors.