Biomedical subjects
R W Dunn
Publications and source records attributed to R W Dunn.
Kevorkian: tragic hero.
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Mixed reaction to suicide of terminally ill woman.
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Allow physicians who commit sex offences to work, but away from patients.
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Cognitive and EEG recovery following bolus intravenous administration of anesthetic agents.
Bolus intravenous (IV) administration of commonly used IV anesthetic agents such as fentanyl and the fentanyl analogues, alfentanil, remifentanil, and sufentanil, etomidate and propofol, produced anesthesia in rats as measured by the loss of righting (LOR) with calculated ED150 doses of 0.06, 0.09, 0.037, 0.007, 2.51 and 6.12 mg/kg, respectively. Animals trained in an eight arm radial maze (RAM) were assessed for cognitive recovery, as measured by response efficiency (percentage of correct arm entries within 10 min), immediately, 15 min and 30 min following IV administration of the calculated ED150 dose of each of these agents, and the subsequent return of righting (ROR). Animals administered fentanyl or sufentanil were unable to successfully complete the maze throughout the testing periods. Animals receiving remifentanil showed cognitive recovery within the first testing interval (immediately following the return of righting), while animals receiving alfentanil, etomidate or propofol showed recovery at the 15-min testing interval following ROR. In a separate experiment, bolus IV administration of the ED150 dose of these agents was evaluated in an acute rat EEG model. Following ROR, return to baseline EEG levels occurred at 0.30, 2.88, 5.06, 16.25, 31.29 and 43.98 min for remifentanil, propofol, alfentanil, etomidate, fentanyl and sufentanil, respectively. These data show that the return to efficient cognitive functioning corresponds to the return to normal baseline EEG waveforms.
Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors.
Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.
The alpha-2 antagonists idazoxan and rauwolscine but not yohimbine or piperoxan are anxiolytic in the Vogel lick-shock conflict paradigm following intravenous administration.
The alpha 2 agonist clonidine has been shown to be anxiolytic in a number of preclinical anxiety models. Interestingly, intravenous infusion of the alpha 2 antagonists idazoxan at 10 mg/kg and rauwolscine at 2.24 mg/kg significantly disinhibited lick-shock conflict responding in rats similar to the alpha 2 agonist clonidine (0.022 mg/kg) and the benzodiazepine diazepam (0.5 mg/kg). However, the alpha 2 antagonists yohimbine and piperoxan, the alpha 2 agonists medetomidine, guanfacine, and guanabenz, the non-specific alpha antagonist phentolamine, and the alpha 1 antagonist prazosin did not disinhibit conflict responding in the Vogel lick-shock paradigm. In fact, yohimbine has been shown to be anxiogenic in both animals and man. This may be due to yohimbine's lack of specificity and its ability to inhibit GABAergic release. In addition, all of these agents, except idazoxan, did not increase water consumption in water deprived rats. Idazoxan (10 mg/kg) significantly decreased water consumption by 45%. Therefore, idazoxan increased conflict responding for water reward at a dose (10 mg/kg) which also decreased water consumption in a non-conflict paradigm. These data suggest that agents with selective antagonism at the alpha 2 receptor site may be anxiolytic while agents with less specificity at this site such as yohimbine, piperoxan, and phentolamine are not anxiolytic.
Single versus multiple infusions of fentanyl analogues in a rat EEG model.
Administration of anesthetic agents to rats produces a loss of righting (LOR) which is predictive of clinical anesthesia. Following bolus i.v. administration of fentanyl, sufentanil, alfentanil, and remifentanil, the ED100 doses for LOR were 0.035, 0.003, 0.05, and 0.020 mg/kg, respectively. For the EEG infusion studies, rats were implanted with jugular catheters and 5 cortical electrodes on the surface of the dura mater. Each agent was infused at a rate of 0.02 ml/min such that each animal received the ED100 dose every 60 seconds until LOR was observed and the infusion was stopped. Following a single infusion to LOR, the difference in time from the return of righting (ROR) to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 30.9, 35.3, 14.9, and 1.3 minutes, respectively. Following a three hour washout period, multiple infusions (three successive infusions to LOR) were administered. Following ROR (after the third LOR) the return to baseline EEG for fentanyl, sufentanil, alfentanil, and remifentanil was 56.1, 58.5, 13.6, and 2.9 minutes, respectively. There were no statistically significant differences between the single and multiple infusions for the return to baseline EEG for alfentanil and remifentanil, but there were significant increases in time to return to baseline following multiple infusions of fentanyl and sufentanil. These results show that there was no cumulation of alfentanil and remifentanil with respect to EEG effects but cumulation was observed for fentanyl and sufentanil.
Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats: a potential model for obsessive compulsive disorder.
Schedule-induced polydipsia was used to determine the effects of selective serotonin re-uptake inhibitors on adjunctive water consumption. Polydipsia was induced in food deprived rats by exposure to a fixed time feeding schedule (FT = 60 s) for 150 min per day for 22 days. Selected polydipsic rats consumed 3-4 times greater volume of water compared to food deprived control rats. Chronic administration of the selective serotonin re-uptake inhibitors fluoxetine and clomipramine (CMI) at 5 mg/kg per day and fluvoxamine at 10 mg/kg twice a day significantly decreased schedule-induced polydipsia (SIP) on day 15 and throughout the remainder of the study compared to control rats. The noradrenergic re-uptake inhibitor, desipramine (DMI), only decreased SIP behavior on day 1. The neuroleptic, haloperidol (0.03 and 0.1 mg/kg), and the benzodiazepine, diazepam (2.5 mg/kg), failed to alter SIP behavior. Since obsessive-compulsive disorder (OCD) and polydipsic behavior both involve excessive expression of a normal behavior, the polydipsia model may be relevant for the prediction of compounds useful in the treatment of OCD.
Effects of 5,7 dichlorokynurenic acid on conflict, social interaction and plus maze behaviors.
Antagonists at the N-methyl-D-aspartate (NMDA) receptor site share a number of properties including anticonvulsant and anxiolytic-like behaviors. In the social interaction and elevated plus maze assay, two non-conditioned paradigms predictive of anxiolytic activity, the NMDA antagonists 5,7 DCKA, CPP and MK-801, as well as diazepam, all significantly increased both social interaction time and open arm exploration time, respectively. Likewise, in the Cook and Davidson conditioned conflict paradigm, the NMDA antagonists 5,7 dichlorokynurenic acid (DCKA; 100 and 173 mg/kg), (+-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 10 mg/kg), dizolcipine (MK-801; 0.03 mg/kg) and the benzodiazepine, diazepam (3-30 mg/kg) significantly disinhibited conflict responding. In addition, administration of 5,7 DCKA did not result in a generalization to a MK-801 discriminative cue in a drug discrimination paradigm. In general, antagonism at the NMDA receptor complex results in anxiolytic-like behavior in rodents. In particular, selective antagonism at the strychnine-insensitive glycine modulatory site (5,7 DCKA) may represent a new and novel class of compounds with potential therapeutic efficacy in anxiety without some of the side effects associated with other NMDA antagonists.
Effects of atypical antipsychotic agents on social behavior in rodents.
There are numerous preclinical screening procedures that are predictive of clinical efficacy for the positive symptoms of schizophrenia but no assays for the negative symptoms such as social withdrawal. In the social interaction test in rats, the atypical antipsychotic drug clozapine (10.0 mg/kg) and two putative atypical agents risperidone (0.0625 mg/kg) and HP 873 (0.5 and 1.0 mg/kg) significantly increased social interaction behaviors between pairs of unfamiliar but not familiar rats. The benzodiazepine diazepam (1.25-5.0 mg/kg) increased social behaviors in both paradigms. Haloperidol, chlorpromazine, raclopride, and SCH23390 decreased social behaviors in these assays. In vitro receptor binding studies revealed that only clozapine, risperidone, and HP 873 displayed dopamine to serotonin affinity ratios for both D2/5-hydroxytryptamine2(5-HT2)/ and D1/5-HT1A of greater than or equal to 12.9 and 1.0, respectively. The present study suggests that antipsychotic agents that may be effective in social withdrawal can be identified in this modified social interaction paradigm. Further, our data suggests that a compound's effectiveness for the treatment of social withdrawal is at least in part due to its relative affinity for binding to dopamine D1 and serotonin 5-HT1A receptors.
D-cycloserine attenuates scopolamine-induced learning and memory deficits in rats.
The muscarinic antagonist scopolamine (SCOP; 1.0 mg/kg, ip) impaired both the acquisition of a learning task in the Morris water maze (MWM) and choice accuracy in the T-maze reinforced alternation procedure in rats. Acetylcholinesterase inhibitors (AChEIs) have been shown to attenuate these deficits. D-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, was investigated for its effects on SCOP-induced dementia in the MWM and T-maze paradigms. Combined administration of SCOP and DCS (3.0, 10.0, or 30.0 mg/kg, ip; 30 min pretreat) significantly reversed SCOP-induced deficits in the T-maze as measured by percentage correct choices. In addition, DCS (3.0 or 10.0 mg/kg, ip) significantly attenuated SCOP-induced deficits in the MWM as measured by latency to find the submerged platform. For comparison, the long-acting acetylcholinesterase inhibitor galanthamine (GAL) was tested in the T-maze (1.25, 2.5, or 5.0 mg/kg, ip) and the MWM (2.5 or 5.0 mg/kg, ip). GAL attenuated SCOP-induced deficits in both learning and memory models similar to DCS. These data suggest that the strychnine-insensitive partial glycine agonist, D-cycloserine, may be efficacious in disease states of central cholinergic hypofunction such as Alzheimer's disease.
3-[4-[1-(6-Fluorobenzo[b]thiophen-3-yl)-4-piperazinyl]butyl]- 2,5,5-trimethyl-4-thiazolidinone: a new atypical antipsychotic agent for the treatment of schizophrenia.
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Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents.
Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.
Yohimbine-induced seizures involve NMDA and GABAergic transmission.
The alpha 2-antagonist, yohimbine has been shown to dose-dependently induce clonic seizures in mice. The convulsant effects of yohimbine are not due to alpha 2-antagonism, as other alpha 2-antagonists, such as rauwolscine and idazoxan, did not produce seizures at doses up to 100 mg/kg. Since GABAmimetic and excitatory amino acid antagonist agents attenuate yohimbine-induced seizures, the respective contribution of these systems to the production of yohimbine seizures was investigated. The CD50 dose of yohimbine (dose required to produce clonic seizures in 50% of the mice) was determined to be 25.5 mg/kg (s.c.). The CD15 dose of N-methyl-DL-aspartic acid (NMDLA), bicuculline and methyl-6,7-dimethoxy-4 ethyl-beta carboline-3-carboxylate (DMCM) significantly potentiated the convulsant effects of yohimbine, such that the CD50 dose was decreased from 25.5 mg/kg to 1.6, 10.9 and 9.9 mg/kg, respectively. Furthermore, the potentiation in the presence of NMDLA was significantly greater than either bicuculline or DMCM. These results suggest that yohimbine-induced seizures are not only mediated through the impairment of GABAergic transmission but moreover, by a possible endogenous enhancement of excitatory amino acid transmission. In addition, the effects of GABAmimetic agents, competitive and non-competitive NMDA receptor antagonists and strychnine-insensitive glycine receptor antagonists were compared in the yohimbine-, bicuculline- and NMDLA-induced seizure assays.
3-substituted-1,2-benzisoxazoles: novel antipsychotic agents.
A series of 3-substituted-6-fluoro-1,2-benzisoxazoles (II) was synthesized and evaluated for potential antipsychotic activity. Many of the compounds displayed potent antipsychotic-like activity in the apomorphine induced climbing in mice (CMA) or spiroperidol binding assays, and compound 42 (HRP 392, 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(2-methoxyphenyl) piperazine) was selected for more detailed antipsychotic evaluation in a battery of preclinical assays. The results of these studies suggests that 42 is a potential antipsychotic drug with less propensity for EPS than some standard neuroleptics in monkeys. The compound was advanced for toxicological evaluation.
GABAmimetic agents display anxiolytic-like effects in the social interaction and elevated plus maze procedures.
Benzodiazepine (BZD) anxiolytics, through their activation of the BZD-GABA receptor complex, display robust anxiolytic-like effects following systemic administration in both conditioned and non-conditioned behavioral procedures. The present results show that the GABAA agonists muscimol (0.5-1.0 mg/kg), THIP (2.5-10.0 mg/kg), and isoguvacine (25.0 mg/kg) as well as the GABA transaminase (GABA-T) inhibitor AOAA (aminooxyacetic acid; 5.0-20.0 mg/kg) following intraperitoneal administration exert anxiolytic-like activity of similar magnitude to that of diazepam in two non-conditioned procedures, namely the social interaction and the elevated plus maze tests. We have also extended our original findings that the anti-epileptic drug sodium valproate exerts an anxiolytic-like effect in the Geller conflict paradigm, to show this agent's robust activity in the social interaction and elevated plus maze tests following systemic administration (100-400 mg/kg). These results show that GABAergic agents that facilitate GABA transmission are effective following systemic administration in non-conditioned anxiety procedures and may indicate potential therapeutic efficacy in certain anxiety states.
Synthesis and biological evaluation of a series of substituted N-alkoxyimides and -amides as potential atypical antipsychotic agents.
In a continuing program to discover antipsychotic agents with a reduced propensity toward extrapyramidal side-effects, a series of N-alkoxyimides and -amides was prepared. Evaluation of these compounds in vitro revealed affinities for D2, 5HT2 and 5HT1A receptors. Several members of the series displayed a profile indicative of potential antipsychotic activity in preclinical assays. The most potent compound in these assays, 7, also displayed possible effectiveness for the negative symptoms of schizophrenia. The synthesis of these compounds and details of their structure-activity relationships are described.