Clozapine and PD149163 elevate prepulse inhibition in Brown Norway rats.

Unmedicated schizophrenia patients exhibit deficits in prepulse inhibition (PPI) of the acoustic startle response. Similar deficits can be induced in rodents via a variety of manipulations and these deficits can be reversed by antipsychotics. Brown Norway (BN) rats exhibit natural PPI deficits under certain parametric conditions. We treated BN rats with haloperidol or clozapine to determine if the BN rat is a useful animal model with predictive validity for the effects of antipsychotics. In addition, we also tested PD149163, a neurotensin-1 receptor agonist, which has been shown to exhibit antipsychotic-like effects in several other animal models. BN rats received subcutaneous injections of either saline or one of two doses of haloperidol (0.5 mg/kg, 1.0 mg/kg), clozapine (7.5 mg/kg, 10 mg/kg) or PD149163 (1.0 mg/kg, 2.0 mg/kg). PPI was measured in startle chambers 30 min after injection. Systemic clozapine and PD149163 but not haloperidol facilitated PPI in BN rats (p     

Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment

Our previous studies demonstrated that huperzine A, a reversible and selective acetylcholinesterase inhibitor, exerts beneficial effects on memory deficits in various rodent models of amnesia. To extend the antiamnesic action of huperzine A to nonhuman primates, huperzine A was evaluated for its ability to reverse the deficits in spatial memory produced by scopolamine in young adult monkeys or those that are naturally occurring in aged monkeys using a delayed-response task. Scopolamine, a muscarinic receptor antagonist, dose dependently impaired performance with the highest dose (0.03 mg/kg, i.m.) producing a significant reduction in choice accuracy in young adult monkeys. The delayed performance changed from an average of 26.8/30 trials correct on saline control to an average of 20.2/30 trials correct after scopolamine administration. Huperzine A (0.01-0. 1 mg/kg, i.m.) significantly reversed deficits induced by scopolamine in young adult monkeys on a delayed-response task; performance after an optimal dose (0.1 mg/kg) averaged 25.0/30 correct. In four aged monkeys, huperzine A (0.001-0.01 mg/kg, i.m.) significantly increased choice accuracy from 20.5/30 on saline control to 25.2/30 at the optimal dose (0.001 mg/kg for two monkeys and 0.01 mg/kg for the other two monkeys). The beneficial effects of huperzine A on delayed-response performance were long lasting; monkeys remained improved for about 24 h after a single injection of huperzine A. This study extended the findings that huperzine A improves the mnemonic performance requiring working memory in monkeys, and suggests that huperzine A may be a promising agent for clinical therapy of cognitive impairments in patients with Alzheimer's disease.     

Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release

With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D4/D2), haloperidol (D2) and the selective D4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A10 and A9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D4 antagonist did not affect 5-HT release within either A10 or A9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D4 antagonist, PNU-101387G.     

Assessing patients'' priorities and perceptions of the quality of health care: the development of the QUOTE-Rheumatic-Patients instrument

BACKGROUND: Stress can exacerbate a number of psychiatric disorders, many of which are associated with prefrontal cortical (PFC) cognitive deficits. Biochemical studies demonstrate that mild stress preferentially increases dopamine turnover in the PFC. Our study examined the effects of acute, mild stress exposure on higher cognitive function in monkeys and the role of dopaminergic mechanisms in the stress response. METHODS: The effects of loud (105-dB) noise stress were examined on a spatial working memory task (delayed response) dependent on the PFC, and on a reference memory task with similar motor and motivational demands (visual pattern discrimination) dependent on the inferior temporal cortex. The role of dopamine mechanisms was tested by challenging the stress response with agents that decrease dopamine receptor stimulation. RESULTS: Exposure to noise stress significantly impaired delayed-response performance. Stress did not impair performance on "0-second" delay control trials and did not alter visual pattern discrimination performance, which is consistent with impaired PFC cognitive function rather than nonspecific changes in performance. Stress-induced deficits in delayed-response performance were ameliorated by pretreatment with drugs that block dopamine receptors (haloperidol, SCH 23390) or reduce stress-induced PFC dopamine turnover in rodents (clonidine, naloxone hydrochloride). CONCLUSIONS: These results indicate that stress impairs PFC cognitive function through a hyperdopaminergic mechanism. Stress may take the PFC "off-line" to allow more habitual responses mediated by posterior cortical and subcortical structures to regulate behavior. This mechanism may have survival value, but may often be maladaptive in human society, contributing to the vulnerability of the PFC in many neuropsychiatric disorders.     

Impairment in a discrimination reversal task after D1 receptor blockade in the pigeon "prefrontal cortex".

Dopamine (DA) is known to modulate cognitive functions of the prefrontal cortex (PFC) of mammals, especially via D1 receptor mechanisms. Like the PFC, the neostriatum caudolaterale (NCL) of birds is characterized by dopaminergic input, and NCL and PFC lesions cause similar deficits. The significance of DA it a color discrimination reversal was assessed by evaluating the effects of bilateral infusions of the D1 receptor antagonist SCH 23390 into the NCL of pigeons (Columba livia). Reversal deficits were qualitatively similar to those in mammals. At a low dose, perseveration occurred predominantly to the incorrect stimulus. Higher doses caused additional spatial perseveration. The data demonstrate, for the first time, that D1 receptor mechanisms in the NCL of pigeons contribute substantially to its function in cognitive processes. Thus, the avian NCL and mammalian PFC could represent functionally equivalent neural networks under control of the DA system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Dopamine agonist-induced inhibition of neurotransmitter release from the awake squirrel monkey putamen as measured by microdialysis

Male squirrel monkeys (Saimiri sciureus) were surgically prepared with cranial guide cannulae for acute microdialysis sampling of the putamen nucleus, a dopamine (DA)-rich brain region. On the day of an experiment an animal was placed in a Plexiglas restraining chair and a microdialysis probe was inserted through the guide into the putamen. Perfusates of artificial cerebrospinal fluid were collected every 20 min over several hours and analyzed via HPLC with electrochemical detection. DA D2/ D3 agonist drugs were administered either orally (p.o.) or subcutaneously (s.c.), and changes in levels of DA in the dialysates were measured. All of the drugs tested, i.e., quinpirole (0.5 mg/kg p.o.), talipexole (0.75 mg/kg p.o. or s.c.), and PD 135222 (7 mg/kg p.o.), decreased spontaneous DA overflow by approximately 40-50% during the first 2 h following dosing. In animals that routinely underwent the microdialysis procedure up to 23 times over a 2-year period, there was neither an appreciable change in basal DA overflow nor a significant change in the magnitude of drug response. These data suggest that DA D2/D3 agonists attenuate DA neuronal overflow in the primate brain, similar to effects seen in rodents. Furthermore, these results also demonstrate the utility of repeated intracerebral microdialysis as a tool to monitor dynamic changes in neurochemical activity in monkeys over a prolonged period of time.     

Effects of AF102B and tacrine on delayed match-to-sample in monkeys

1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders.     

Visual–spatial episodic memory in schizophrenia: A multiple systems framework.

Objective: Enhanced understanding of cognitive deficits, and the neurobiological abnormalities that mediate them, can be achieved through translational research that employs comparable experimental approaches across species. This study employed a multiple-systems framework derived from the rodent literature to investigate visual–spatial memory abilities associated with schizophrenia. Method: Using the bin task, a human analog of rodent maze tasks, everyday objects were hidden in visually identical bins. Following a 1-min filled delay, participants with schizophrenia-spectrum disorders (n = 30) and healthy community controls (n = 30) were asked to identify both the object hidden and bin used on the basis of its spatial location. Three dimensions of visual–spatial memory were contrasted: (a) memory for spatial locations versus memory for objects, (b) allocentric (viewpoint independent) versus egocentric (body-centered) spatial representations, and (c) event (working) memory versus reference memory. Results: Most pronounced was a differential deficit in memory for spatial locations under allocentric (p = .005, d = ?0.77) but not egocentric viewing conditions (p = .298, d = ?0.28) in the schizophrenia group relative to healthy controls. Similarly, schizophrenia-related spatial memory deficits were pronounced under demands for event memory (p = .004, d = ?0.77) but not reference memory (p = .171, d = ?0.33). Conclusions: These results support a heuristic of preferential deficits in hippocampal-mediated forms of memory in schizophrenia. Moreover, the task provides a useful paradigm for translational research and the pattern of deficits suggests that persons with schizophrenia may benefit from mnemonic approaches favoring egocentric representations and consistency when interacting with our visual–spatial world. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic, post-injury administration of D-cycloserine, an NMDA partial agonist, enhances cognitive performance following experimental brain injury

The purpose of this study was to determine the effect of augmenting NMDA receptor activation on cognitive deficits produced by traumatic brain injury (TBI). Specifically, D-cycloserine (DCS), a partial agonist of the NMDA-associated glycine site, was tested as a potential cognitive enhancer. Rats were injured using lateral fluid percussion TBI (2.8 +/- .10 atm). On days 1-15 post-injury, animals were injected (i.p.) with vehicle (n = 8), 10 mg/kg (n = 9), or 30 mg/kg (n = 8) of DCS. Sham-injured animals treated with either vehicle (n = 8) or 30 mg/kg of DCS (n = 8) were used for comparison. On days 11-15 post-injury, cognitive function was assessed using the Morris water maze (MWM). Results indicate that the 30 mg/kg dose of DCS significantly attenuated memory deficits as compared to injured vehicle-treated animals (P < 0.01). Analysis also revealed that performance of the injured-DCS (30 mg/kg) group was not significantly different from sham-injured animals treated with vehicle (P > 0.10). In contrast, the 10 mg/kg dose of DCS was ineffective in reducing injury-induced memory deficits. DCS (30 mg/kg) also significantly improved the spatial memory of sham-injured animals when compared with sham-injured animals treated with vehicle (P < 0.05). In conclusion, chronic, post-injury enhancement of the NMDA receptor is an effective strategy for ameliorating TBI-associated cognitive deficits.     

Demonstration of cytoplasmic CD32 (Fc gamma RII) within human lymphocytes following microwave treatment

The effects of a novel prolyl endopeptidase inhibitor (PEP), (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)- 1-pyrrolidinecar-boxamide (JTP-4819), on performance of the Morris water maze task and on central cholinergic function were investigated in aged rats. Spatial memory (escape latency, path length, and swimming speed to the platform) was impaired in aged rats performing the Morris water maze task when compared to young rats. Administration of JTP-4819 (1 mg/kg, p.o.) for 14 days improved this memory deficit in aged rats, as shown by the decrease in escape latency and path length. In addition, when JTP-4819 (at doses of 1 and 3 mg/kg, p.o.) was administered for 3 wk, it reversed the age-related increase of ChAT activity in the cerebral cortex and the decrease of 3H-choline uptake in the hippocampus. These data suggest that JTP-4819 ameliorates age-related impairment of spatial memory and partly reverses central cholinergic dysfunction, possibly due to the enhancement of neuropeptide function by inhibition of PEP mediated degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone.     

Contrasting effects of clonidine and diazepam on tests of working memory and planning

The alpha 2 adrenoceptor has recently been implicated in working memory (WM), a function dependent on the integrity of the prefrontal cortex. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 micrograms/kg and 2.5 micrograms/kg) of the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (CLO) on performance of various computerised tests of WM and planning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Administration of CLO resulted in impulsivity of responding in a planning task, as well as differential dose-dependent effects on two analogous tests of spatial and visual WM. The nature of these effects were suggestive of mnemonic, rather than executive, dysfunction. Conversely, DZP produced specific deficits on tests of spatial WM and planning very similar to those seen following lesions to the frontal lobes. Therefore, these two sedative drugs produce doubly dissociable, dose-dependent effects on different aspects of cognitive function.     

Lymphomas of the urinary tract

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.     

Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems

RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.     

Immunohistochemistry diagnosis of fungal infections

BACKGROUND: A potential beneficial outcome of treatment with certain of the atypical neuroleptics is the reduced risk of cognitive impairment, stemming from purported low affinity for cholinergic receptors. In vitro experiments have shown that clozapine is highly anticholinergic and risperidone is minimally so. In vivo tests of the anticholinergic burden imposed by these medications and its potential cognitive consequences are needed. This study examines anticholinergic burden in schizophrenia patients taking clozapine and risperidone and tests whether this burden is associated with cognitive deficits. METHOD: Serum anticholinergic levels were determined in a sample of 22 chronic schizophrenia patients using the radioreceptor assay method of Tune and Coyle (1980). Fifteen patients received clozapine; 7 received risperidone. Mean +/- SD age of the sample, comprising 12 men and 10 women (68% white), was 44.7 +/- 8.4 years. Mean +/- SD age at onset of schizophrenia illness was 23.5 +/- 7.4 years. Two anticholinergic assays based on blood samples collected 1 week apart were available on each patient. RESULTS: Data indicated that clozapine patients had significantly (p < .001) higher anticholinergic levels at both collection points, and levels for both drugs remained stable over time. The clozapine and risperidone patients had essentially equivalent scores on the cognitive measure. CONCLUSION: These data suggest that anticholinergicity distinguishes clozapine and risperidone in vivo but that this effect is not associated with differences in global cognitive functioning. Results suggest that clozapine, despite producing moderately high in vivo serum anticholinergic levels, still holds clinical advantage over standard neuroleptics in terms of cognitive side effects. Reasons for this lowered risk of cognitive impairment are discussed.     

The alpha-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys

Administration of either low or high doses of the alpha-2A adrenergic agonist guanfacine (GFC) to aged monkeys has been shown to improve performance of the delayed-response task, a task linked to the dorsolateral prefrontal cortex (dlPFC). Monkeys treated with higher guanfacine doses also appeared less disinhibited, suggesting enhanced ventromedial-orbital PFC (vmPFC) function. To test this hypothesis, the current study examined the effects of low versus high doses of GFC on reversal of a visual object discrimination task, a task particularly sensitive to vmPFC lesions. The results of this study showed that high (0.1 mg/kg) but not low (0.00001-0.001 mg/kg) doses of GFC significantly improved reversal performance in aged monkeys. These results may be relevant to GFC's calming effects in attention deficit hyperactivity disorder.     

Effects of CDP-choline treatment on neurobehavioral deficits after TBI and on hippocampal and neocortical acetylcholine release

The exogenous administration of cytidine-5'-diphosphate (CDP)-choline has been used extensively as a brain activator in different neurological disorders that are associated with memory deficits. A total of 50 rats were utilized to (a) determine whether exogenously administered CDP-choline could attenuate posttraumatic motor and spatial memory performance deficits and (b) determine whether intraperitoneal (i.p.) administration of CDP-choline increases acetylcholine (ACh) release in the dorsal hippocampus and neocortex. In the behavioral study, traumatic brain injury (TBI) was produced by lateral controlled cortical impact (2-mm deformation/6 m/sec) and administered CDP-choline (100 mg/kg) or saline daily for 18 days beginning 1 day postinjury. At 1 day postinjury, rats treated with CDP-choline 15 min prior to assessment performed significantly better than saline-treated rats. Between 14-18 days postinjury, CDP-choline-treated rats had significantly less cognitive (Morris water maze performance) deficits that injured saline-treated rats. CDP-choline treatment also attenuated the TBI-induced increased sensitivity to the memory-disrupting effects of scopolamine, a muscarinic antagonist. The microdialysis studies demonstrated for the first time that a single i.p. administration of CDP-choline can significantly increase extracellular levels of ACh in dorsal hippocampus and neocortex in normal, awake, freely moving rats. This article provides additional evidence that spatial memory performance deficits are, at least partially, associated with deficits in central cholinergic neurotransmission and that treatments that enhance ACh release in the chronic phase after TBI may attenuate cholinergic-dependent neurobehavioral deficits.     

The α-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys.

Administration of either low or high doses of the α-2A adrenergic agonist guanfacine (GFC) to aged monkeys has been shown to improve performance of the delayed-response task, a task linked to the dorsolateral prefrontal cortex (dlPFC). Monkeys treated with higher guanfacine doses also appeared less disinhibited, suggesting enhanced ventromedial-orbital PFC (vmPFC) function. To test this hypothesis, the current study examined the effects of low versus high doses of GFC on reversal of a visual object discrimination task, a task particularly sensitive to vmPFC lesions. The results of this study showed that high (0.1 mg/kg) but not low (0.00001-0.001 mg/kg) doses of GFC significantly improved reversal performance in aged monkeys. These results may be relevant to GFC's calming effects in attention deficit hyperactivity disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term cognitive impairment in MPTP-treated rhesus monkeys

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinson's patients, the MPTP-treated primates display spatial deficits.     

Emergency coronary artery surgery after failed PTCA: myocardial protection with continuous coronary perfusion of beta-blocker-enriched blood

MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate antagonist, induces dystonia in monkeys at doses of 0.08 mg/kg. This syndrome was tested with the dopamine D1 receptor antagonist NNC 756, the DA D2 receptor antagonist raclopride, the atypical antipsychotic clozapine, the dopamine D1 receptor agonist SKF 81297, the dopamine D2/D3 receptor agonist quinpirole, the anticholinergic biperiden, amphetamine, and the benzodiazepine midazolam in 7 Cebus apella monkeys previously treated with dopaminergic agents. NNC 756 (0.004 and 0.01 mg/kg), raclopride (0.004 and 0.01 mg/kg), SKF 81297 (0.3 and 0.6 mg/kg), quinpirole (0.1 and 0.2 mg/kg), amphetamine (0.25 and 0.5 mg/kg), and biperiden (0.125 and up to 1.0 mg/kg), had no significant effect on MK-801-induced dystonia. In contrast, both clozapine (2.0 mg/kg) and midazolam (0.4 and 1.0 mg/kg) reduced the dystonia caused by MK-801. Dystonia induced by dopamine D1 and D2 antagonists is easily antagonized by biperiden and dopamine agonists, whereas these drugs had no significant effect on MK-801-induced dystonia. It has been proposed that dystonia may be caused by a sudden drop in the output from the basal ganglia that is primarily GABAergic. Midazolam's enhancing effect on the GABAergic tone is consistent with this hypothesis. The effect of clozapine is more difficult to explain, but this drug has a rich pharmacology and suggests an agonistic glutamatergic effect.