bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complement peptides and neuronal dysfunction in the central nervous system: Specificity of receptor sites for anaphylatoxin C3a activity in the rat hypothalamus
Authors: Williams Curtis A. , Schupf Nicole , Reilly Christopher L. , Wagner Jolynn 
Published: January 2005

AbstractThe research described centers on the possible activities of complement in neural tissues. Activation of the complement cascade will generate the pharmacologically potent anaphylatoxins C3a and C5a, cleavage peptides of C3 and C5, respectively. Their actions depend on a carboxyterminal arginine, and they are inactivated by a carboxypeptidase in serum, yielding the desarginated derivatives C3ai and C5ai. Using well‐characterized eating and drinking responses to focal chemical stimulation of hypothalamic sites in the rat, we have shown that immune complex formation elicits consummatory behaviors which mimic the responses to norepinephrine (NE) and dopamine (DA). We have also shown these effects to be complement dependent. C5a was found to stimulate eating, similar to the effect of NE, and C3a was found to mimic the effect of DA, potentiating NE‐induced eating or carbachol‐induced drinking. C5a has been shown to act presynaptically to modulate endogenous catecholamine function. In this study 125‐C3a binding to a refined synaptosome preparation reveals a C3a binding site which is completely inhibited by C3ai. We also show that the psychopharmacological action of C3a is also antagonized by C3ai. These studies demonstrate the presence of anaphylatoxin‐sensitive sites in the perisynaptic membrane systems of the rat CNS. They also suggest that the anaphylatoxins could mediate or contribute to the neuropsychiatric disorders often seen in immune complex disease.
Neocortical anomalies in autoimmune mice: A model for the developmental neuropathology seen in the dyslexic brain
Authors: Sherman Gordon F. , Rosen Glenn D. , Galaburda Albert M. 
Published: January 2005

AbstractDevelopmental ectopias (nests of neurons) in the molecular layer of the cerebral neocortex and associated dysplasias of underlying layers have been seen in two strains of mice (New Zealand Black and BXSB) that spontaneously develop autoimmune disorders. The ectopias are usually unilateral and males are more often affected than females. The emerging situation is comparable to that of male dyslexics who in addition to their language problems show similar developmental brain anomalies. These anomalies are through to have their origin during the last stages of neuronal migration. We believe that maternal autoantibodies passing through the placenta and blood‐brain barrier may damage the important structural components of the cerebral cortex affecting the final positions of migrating neurons. The autoimmune mice are a useful experimental animal model for understanding the development of neuropathology in dyslexics.
α‐Flupenthixyl chloride: Binding profile to dopaminergic, serotonergic, adrenergic, and cholinergic neuro‐receptors
Authors: Murphy Randall B. , Einstein Richard , Schuster David I. , Narula A. P. S. , Meyerson Laurence R. 
Published: January 2005

AbstractThe binding of the putative affinity ligand α‐flupenthixyl chloride (FPT‐Cl), a derivative of the neuroleptic α‐flupenthixol (FPT), to rat striatal dopamine, α1‐adrenergic, and muscarinic cholinergic recognition sites, as well as to serotonin (5‐HT) receptors and to the presynaptic 5‐HT transport complex, was examined in vitro. FPT and FPT‐Cl were relatively potent at inhibiting the binding of [3H]‐flupenthixol and [3H]‐spiroperidol in striatal tissue preparations as well as [3H]/spiroperidol and [3H]‐WB‐4101 in cortex with Ki values in the 10–20 nM range. With the exception of the muscarinic cholinergic sites (3H‐quinuclidinyl‐benzilate [3H‐QNB]), where FPT‐Cl was more potent than FPT, the Ki values for FPT‐Cl were, in general, slightly greater than those for FPT for other neuro‐receptors tested. FPT‐Cl was found to be essentially inactive at 5‐HT binding sites labeled with [3H]‐LSD and at the 5‐HT transport complex labeled with [3H]‐imipramine, with lC50 values for both exceeding 5μM. It is concluded that the transformation of FPT to FPT‐Cl is not severely detrimental to its dopamine receptor binding characteristics, suggesting that in the presence of appropriate antagonists for masking other receptors, FPT‐Cl may represent a useful affinity ligand to label dopamine receptors.
Comparison of the effects of clonidine, rilmenidine, and guanfacine in the holeboard and elevated plus‐maze
Authors: Johnston Amanda L. , Koening‐Berard Elisabeth , Cooper Teresa A. , File Sandra E. 
Published: January 2005

AbstractThe effects of clonidine, rilmenidine, and guanfacine were studied in the holeboard and elevated‐plus maze tests in rats. In the holeboard test, clonidine had a profound effect on locomotor activity, significantly (P < 0.05) reducing this measure at all but one of the doses tested (0.005–0.25 mg/kg). In contrast, rilmenidine and guanfacine only markedly affected locomotor activity at 2.5 mg/kg or higher. The ED50<apos;s for locomotor activity were as follows: clonidine, 0.024 mg/kg; rilmenidine, 1.92 mg/kg; and guanfacine 1.65 mg/kg. All three compounds also caused significant decreases in the number of head dips and time spent head‐dipping. The effects of clonidine (0.005–0.25 mg/kg)and rilmenidine (0.25–10 mg/kg)on the number of head‐dips were significant (P < 0.01) at all doses and were dose dependent. The actions of guanfacine were similar, with all doses (0.125–5 mg/kg) differing significantly (P < 0.05) from the controls, except 1 mg/kg. However, the time spent head‐dipping was only decreased significantly (P < 0.05) by clonidine (0.005–0.25 mg/kg), rilmenidine (1,5, and 10 mg/kg), and guanfacine (0.5–5.0 mg/kg). In the elevated plus‐maze, clonidine had no significant effect on the % number of entries made onto open arms, or the % of time spent on the open arms; rilmenidine reduced the % time spent on the open arms, but this decrease was secondary to the drop in total activity; in contrast, guanfacine reduced both the % number of entries made onto open arms and the % time spent on the open arms, and this was independent of the drop in total arm entries, thus indicating an anxiogenic‐like effect. The results show that all three compounds are sedative (as judged by reductions in locomotor activity in the holeboard), with clonidine being much more potent on this measure. Guanfacine differed from the other two compounds in its apparent anxiogenic‐like effects in the plus maze.
Effects of loperamide‐oxide on fentanyl drug discrimination in rats
Authors: Meert Theo F. , Niemegeers Carlos J. E. 
Published: January 2005

AbstractThe effects of loperamide and loperamide‐oxide were studied in rats trained to discriminate 0.04 mg/kg, fentanyl from saline. After oral pretreatment with the doses of 0.63, 2.50, 10.0, and 40.0 mg/kg, neither loperamide nor loperamide‐oxide produced any generalization with fentanyl. Both compounds depressed the response rate at 10 and 40 mg/kg. These results indicate that loperamide and loperamide‐oxide produce no fentanyl generalization in rats up to doses at least 250 times their antidiarrheal dose and that both drugs are expected to be devoid of an opiate‐like addiction liability in man.
Graphic assessment of statistical significance and clinical‐biological relevance
Authors: Lewi Paul J. 
Published: January 2005

AbstractA diagram is presented that evaluates results from clinical and biological studies in which two treatments are compared. In the case of all‐or‐none observations (such as symptoms), the diagram presents the overall rate of occurrence (Prevalence), the difference of the rates of occurrence in the two treatment groups (contrast), and the statistical significance of the result. The prevalence‐contrast (p‐c) diagram can also be applied to other variables (such as scores, temperature, blood pressure, etc.). Accumulation of p‐c diagrams from related studies adds clinical‐biological relevance to statistical significance.
Rimcazole (BW234U) in the maintenance treatment of outpatients with schizophrenia
Authors: Munetz Mark R. , Schulz S. Charles , Bellin Marvin , Harty Irma 
Published: January 2005

AbstractRimcazole (BW234U), a substituted carbazole compound, has been reported to be effective in treating acutely ill schizophrenic patients without significant extrapyramidal side effects. A two‐phase study was done to assess the efficacy and safety of rimcazole in the maintenance treatment of schizophrenia. Study I was a double‐blind comparison of rimcazole (50–300 mg daily) with haloperidol (5–30 mg daily) with ten stable schizophrenic outpatients. Three of six patients relapsed on rimcazole, while there were no relapses on haloperidol. One patient dropped out of each group. Extrapyramidal side effects were minimal in the rimcazole group, and two patients with tardive dyskinesia showed marked improvement in AIMS Scores. Study II was an open label trial of rimcazole using a higher maximum dose of 450 mg daily in seven schizophrenic outpatients. Four of the seven patients relapsed, at a mean of 7 weeks, one dropped out, and two patients remained stable. While the drug was generally well tolerated, both of the nonrelapsing patients developed transient elevations in liver transaminases. The small sample size in these studies prevents definitive conclusions to be drawn. There may be subgroups of schizophrenic patients who can be successfully maintained on rimcazole with less morbidity than from standard neuroleptic drugs.
Comments on method and theory in drug discrimination: A potpourri of problems, perplexities, and possibilities
Authors: Holloway Frank A. , Gauvin David V. 
Published: January 2005

AbstractThis paper focuses on how selected training variables may affect the nature of drug discrimination (DD) during generalization tests, specifically addressing the following issues: (1) the production and interpretation of intermediate drug‐lever responding in drug‐saline tasks, (2) how the complexity of the interoceptive stimulus and the nature of the reinforcing event may interact to influence generalization functions, and (3) the ways in which DD history can influence the pattern of generalization results. The analysis of these issues suggests that knowledge of the behavioral factors that are operative in DD tasks may be as critical as knowledge of the pharmacological action of the drugs themselves. First, the issue of quantal vs. continuous response distribution in DD experiments may be partially resolved by attending to how the response class alternates are defined and to whether the reinforcement schedule biases the animal toward an “all‐or‐none”, or maximization, strategy or toward a response mixing or matching strategy. Both strategies appear equivalently to map the drug stimulus dimension. Second, the baseline motivational state defined by the nature of the reinforcing event (e.g., appetitive or aversive) may influence the pattern or profile of drug‐stimuli generalization tests by altering the saliency of one set of effects produced by a given drug over other effects produced by that same drug. In essence, basal conditions can exert selective influence over which stimulus features acquire stimulus control. Finally, the applicability of the paradigms of latent inhibition, overshadowing, and blocking to DD may provide some useful insights into how drug stimuli provide information to the organism.
Methods for planning experimental designs that allow measurement of several concurrent drug effects
Authors: Overton Donald A. , Shen C. Frank 
Published: January 2005

AbstractPsychoactive drugs concurrently produce a variety of effects on the formation and retrieval of memories and on performance of learned responses. Experimental designs used in psychopharmacology are usually arranged so that some drug effects do not occur or do not influence the dependent variables of interest and so that the strength and statistical significance of the remaining effects can be concurrently determined. Moderately complex designs are often required to allow the simultaneous evaluation of the several drug effects expected to occur in a preparation. In general, the inclusion of more experimental conditions in a design will allow concurrent measurement of more drug effects, but it is often less than obvious exactly which effects can be measured by any given design. Multiple linear regression provides a method for determining which effects can be measured with certain types of designs and hence provides a method for selecting designs adequate to deal with the drug effects anticipated in any particular experiment. This paper presents illustrative examples of the use of multiple linear regression to evaluate the utility of selected experimental designs. It also describes some new experimental designs more adequate than those previously employed for the study of state‐dependent learning and concurrently occurring drug effects.
Drug discrimination in pentylenetetrazol‐trained baboons: Generalization to buspirone and β‐carboline‐3‐carboxylic acid ethyl ester but not lorazepam or pentobarbital
Authors: Ator Nancy A. , Cook J. M. , Griffiths R. R. 
Published: January 2005

AbstractPentylenetetrazol (PTZ) has been characterized as producing anxiogenic effects in humans and rats, and PTZ drug discrimination procedures in rats have been used to categorize drug effects as anxiogenic. In the present study, baboons trained to discriminate a subconvulsant dose of PTZ from the no‐drug condition showed dose‐dependent generalization to PTZ and to β‐carboline‐3‐carboxylic acid ethyl esther [β‐CCE; a benzodiazepine (BZ)‐receptor inverse agonist] but no generalization to the BZ‐receptor antagonist Ro 15‐1788 (flumazenil). Ro‐1788 produced surmountable antagonism of the β‐CCE discriminative stimulus. The novel anxiolytic buspirone also occasioned 100% drug lever responding in the PTZ‐trained baboons, although lorazepam and pentobarbital did not. Results with the 5HT ligand 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) were mixed. Lorazepam but not buspirone antagonized PTZ. Observations of baboons after PTZ, buspirone, and β‐CCE at doses occasioning PTZ lever responding showed that tremors and agitation occurred after buspirone but not after β‐CCE or PTZ.
CGS 9896 blocks the pentylenetetrazol‐like effect of withdrawal from chronic ethanol
Authors: Harris Cynthia M. , Elkhayat Ibrahim S. , Benjamin Dan , Bhadra Samiran , Lal Harbans 
Published: January 2005

AbstractTermination of chronic ethanol produces a withdrawal syndrome characterized not only by physical signs but also by subjective symptoms. One such subjective effect is an interoceptive discriminative stimulus similar to that of the anxiogenic drug pentylenetetrazol (PTZ). In the present study, the pyrazoloquinoline CGS 9896, a nonsedating anxiolytic of low abuse liability, was tested for its ability to reduce the PTZ‐like stimulus effect of ethanol withdrawal. Rats were trained with food reward in a two‐lever choice task to discriminate between PTZ, 20 mg/kg, and saline. Training was then suspended, and the rats were given ethanol for 4–6 days in a nutritionally complete liquid diet (dose consumed 11–13 g/kg/day). At selected times after a final dose of ethanol (3 g/kg), given by gavage, they were tested for lever selection. In contrast to their saline‐lever selection in tests with saline prior to chronic ethanol, rats selected the PTZ lever in tests with saline during withdrawal. Although CGS 9896 transiently impaired performance of the lever‐selection task, it decreased the percentage of rats selecting the PTZ lever during withdrawal. Blockade by CGS 9896 of the PTZ‐like withdrawal stimulus was dose‐dependent over the range 5–20 mg/kg and was more effective after orally than after intraperitoneally administered CGS 9896. These data suggest that CGS 9896 may ameliorate some of the unpleasant subjective sequelae of ethanol withdrawal and may be of clinical value in the treatment of alcoholism.
Discrimination between oral amobarbital and diazepam effects in rats
Authors: Henteleff Harvey B. , Barry Herbert 
Published: January 2005

AbstractAmobarbital (40 mg/kg) and diazepam (8 mg/kg) were orally intubated in 8 male and 8 female rats 60 min before the 10‐min discrimination sessions. Presses on different levers, depending on the drug given, were reinforced by food pellets on a 10‐sec fixed interval schedule. Within 27 sessions, divided between the 2 drugs, the rats made reliably more than 50% of their presses on the reinforced lever prior to the first food pellets of the session. Additional training sessions included higher doses of both drugs (60–120 mg/kg amobarbital; 12–32 mg/kg diazepam). The amobarbital choice predominated after the high amobarbital doses (80–120 mg/kg) but was close to 50% after all diazepam doses. Response rates were decreased by the highest doses of amobarbital but not diazepam. In a subgroup of 7 high‐dose discriminators, the reinforced lever was predominantly chosen after high doses of either drug. In a subgroup of 7 high‐dose nondiscriminators, the high diazepam doses induced a majority of amobarbital choices but the high amobarbital doses induced a greater preponderance of amobarbital choices. The discriminative performance by both subgroups indicated qualitatively different effects of the 2 drugs in spite of their similar sedative effects. A low response rate by both subgroups after a lower dose of both drugs and in nondrug tests indicated that both drug effects were distinctively different from the nondrug condition.
Generalization of cocaine to the isomers of 3,4‐Methylenedioxyamphetamine and 3,4‐methylenedioxyamethamphetamine: Effects of training dose
Authors: Broadbent Julie , Michael Elizabeth K. , Appel James B. 
Published: January 2005

AbstractMDA and MDMA are popular recreational drugs which have considerable abuse potential and may be neurotoxic. Because these compounds have sometimes been reported to have behavioral effects that resemble those of d‐amphetamine, the stimulus properties of all of the enantiomers of both MDA and MDMA were analyzed in animals trained to discriminate another abused stimulant, cocaine, from saline. Since the extent of generalization of any drug depends on training dose, separate groups of rats were trained to detect 3.5, 10.0, or 20.0 mg/kg of this compound. The results indicate that all of these doses of cocaine maintain discrimination behavior reliably and consistently and that the three cues are qualitatively similar. Among all the individual enantiomers of MDA and MDMA, only d‐MDA mimicked cocaine; however, this effect occurred consistently only in the group trained to detect the lowest dose (3.5 mg/kg).
Interaction of haloperidol and risperidone (R 64 766) with amphetamine‐induced motility changes in rats
Authors: Megens Anton A. H. P. , Awouters Frans H. L. , Niemegeers Carlos J. E. 
Published: January 2005

AbstractThe interaction of the new antipsychotic risperidone (RIS) and haloperidol (HAL) with amphetamine (AMP) was studied in rats using an activity meter which measured horizontal, vertical, and stationary components of motility. All three components increased markedly and progressively after AMP doses between 0.63 and 5.00 mg/kg (hyperactivity dose range). At still higher doses of 10.0 to 80.0 mg/kg, stationary movements (reflecting stereotypy) further increased, whereas horizontal activity was much reduced and vertical activity virtually abolished. Both HAL and RIS were potent AMP antagonists. Doses on the order of 0.02 to 0.04 mg/kg significantly reduced hyperactivity and reversed stereotypy to a motility pattern equivalent to that of a lower AMP dose. Both compounds were able to restore normal motility at any dose level of AMP stimulation. At the lowest dose of AMP (0.63 mg/kg), the required normalization doses were comparable for HAL (0.022–0.046 mg/kg) and RIS (0.034–0.16 mg/kg). In order to normalize motility induced by higher AMP doses up to 5.00 mg/kg, however, a relatively small dose increment of HAL (to 0.045–0.071 mg/kg), but a large dose increment of RIS (to 0.50–0.96 mg/kg) was required. In other words, the dose‐normalization curves of RIS and HAL diverged at low doses of AMP (0.63–5.0 mg/kg). At higher doses of AMP (10–80 mg/kg), however, this difference disappeared, and the slopes of the dose‐normalization curves became comparable for the two antagonists. It is suggested from these experiments that RIS and HAL are equipotent in controlling a low level of dopaminergic overactivity by partially occupying dopamine‐D2 receptors. Higher levels of functional dopamine antagonism up to saturation of the D2 receptors require a much higher dose of RIS than of HAL. Therefore, the risk of dopaminergic overblockade (and induction of EPS) is considered to be much smaller with RIS than with HAL.
Dopamine receptor agonist activity of U‐66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties
Authors: von Voigtlander Philip F. , Althaus John S. , Ochoa Marlene Camacho , Neff Gary L. 
Published: January 2005

AbstractInvestigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, and d‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be therapeutically useful.