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Biomedical subjects

G Winger

Publications and source records attributed to G Winger.

71 records · Page 4Linked to original sources
PubMed1987

Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties.

Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or beta-dioxadrol in monkeys experienced with ketamine self-administration. The order of potency in displacing bound 1-[1-(2-thienyl)cyclohexyl]piperidine from binding sites in rat brain homogenates was dexoxadrol much greater than levoxadrol = beta-(+/-)-dioxadrol. Viewed in the context of previous studies with stereochemical probes of the PCP receptor, these results extend and confirm the supposition that dexoxadrol and levoxadrol are the stereochemical probes of choice in the study of effects mediated through PCP receptors. The absolute configuration of dexoxadrol was determined to be 4S, 6S by X-ray crystallography, thus defining the optimum chirality necessary for receptor binding and PCP-like activity in the dioxadrol series. Based on these and other considerations, receptor-active conformations of dexoxadrol and PCP are proposed.

Analgesics↗
PubMed1987

Kappa opioids in rhesus monkeys. II. Analysis of the antagonistic actions of quadazocine and beta-funaltrexamine.

In rhesus monkeys, kappa opioid agonists have been shown to increase urinary output, increase tail-withdrawal latencies from warm water and produce distinct discriminative stimulus effects. In order to explore further the relation between these effects and activity at the kappa opioid receptor type, the antagonist activity of quadazocine against several kappa opioid agonists was examined with the tail-withdrawal and drug-discrimination procedures. Quadazocine dose dependently antagonized the increases in tail-withdrawal latency produced by the kappa agonists bremazocine, ethylketazocine and U-50, 488, as well as the discriminative stimulus effects of these drugs. The dose-ratio analysis of Schild revealed apparent pA2 values for quadazocine in combination with bremazocine, ethylketazocine and U-50, 488 of 6.1, 6.4 and 6.4, respectively, with the tail-withdrawal procedure and 6.3, 6.4 and 6.1, respectively, with the drug-discrimination procedure. Quadazocine also antagonized the effects of a mu agonist (morphine) in the tail-withdrawal procedure, and the apparent pA2 value for these data was 8.2. The activity of the mu-selective alkylating agent, beta-funaltrexamine (beta-FNA), was examined alone and in combination with the kappa agonist ethylketazocine in the urinary-output, tail-withdrawal and drug-discrimination procedures. At about 30 to 60 min postinjection, beta-FNA alone produced ethylketazocine-appropriate responding under the drug-discrimination procedure and increased urine output but did not increase tail-withdrawal latencies. At 24 to 48 hr postinjection, beta-FNA did not antagonize effects of ethylketazocine in any of the three procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects.

The effects of the kappa agonists bremazocine, ethylketazocine, tifluadom and U-50,488 were examined in rhesus monkeys with four experimental procedures: urinary output was measured in normally hydrated monkeys; muscle relaxation and stupor were observed; and the time it took monkeys to withdraw their tails from warm water was evaluated. Lastly, the kappa agonists were examined in monkeys trained to respond differentially in the presence or absence of ethylketazocine. For comparison, morphine and another kappa agonist, Mr 2033, were examined under some of the procedures. Kappa agonists produced dose-dependent increases in urine output whereas morphine did not. Morphine, as well as each of the kappa agonists examined, produced dose-dependent increases in tail-withdrawal latencies from both 50 and 55 degrees C water; analgesic doses of kappa agonists produced marked stupor and muscle relaxation. Kappa agonists produced ethylketazocine-appropriate responding in the drug discrimination procedure. Doses of kappa agonists that produced ethylketazocine-appropriate responding were similar to doses that increased urine output and smaller than doses that increased tail-withdrawal latencies. The opioid antagonist quadazocine (WIN 44,441) antagonized the effects of bremazocine, ethylketazocine, tifluadom and U-50,488.

Analgesia↗
PubMed1986

Discriminative and aversive properties of beta-carboline-3-carboxylic acid ethyl ester, a benzodiazepine receptor inverse agonist, in rhesus monkeys.

Rhesus monkeys were trained to discriminate injections of saline from those of beta-carboline-3-carboxylic acid ethyl ester (beta-CCE), a compound that binds to the benzodiazepine receptor, but often has actions opposite to those of the benzodiazepines. A benzodiazepine agonist midazolam and low doses of a specific benzodiazepine antagonist, Ro 15-1788, reversed the discriminative effects of beta-CCE. Higher doses of Ro 15-1788 produced stimulus effects similar to beta-CCE. In a separate experiment, monkeys responded to terminate intravenous infusions of beta-CCE, but not midazolam. This aversive effect of beta-CCE was reversed by Ro 15-1788. The behavioral effects of beta-CCE in these non-human primates are consistent with other data that have shown it to act on benzodiazepine receptors, and support the hypothesis that beta-CCE can be considered an inverse agonist at this receptor.

Animals↗
PubMed1985

Comparison of fixed-ratio and progressive-ratio schedules of maintenance of stimulant drug-reinforced responding.

The effectiveness of doses of i.v. cocaine and nomifensine in maintaining lever-press responding in rhesus monkeys was evaluated under two schedules, fixed- and progressive-ratio (FR, PR). The doses that maintained maximum rates of responding under the fixed-ratio schedule were 0.32 mg/kg per injection cocaine and 0.10 mg/kg per injection nomifensine. The fixed-ratio rates maintained by this dose of nomifensine were slightly lower than those maintained by cocaine. Under the progressive-ratio schedule, the maximum response rates developed with 0.32 mg/kg per injection cocaine and 0.32 mg/kg per injection nomifensine. Maximum performances under the progressive ratio were slightly higher with cocaine than with nomifensine. Taken in conjunction with existing data for other drugs and conditions, these data indicate that progressive-ratio schedules may yield information on the relative reinforcing effects of drugs that differs only slightly from that obtained with fixed-ratio schedules.

Animals↗
PubMed1982

Discriminative stimulus effects of pentobarbital in rhesus monkeys: tests of stimulus generalization and duration of action.

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan, and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20-60, 120-240, and 480-720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.

Animals↗
PubMed1982

A procedure for rapid evaluation of the discriminative stimulus effects of drugs.

Rhesus monkeys were trained in a two-lever drug-discrimination procedure with several discrete trials per session. During training sessions, either a sham injection or a subcutaneous injection of the training drug was administered ten minutes prior to each trial. During each trial, completion of 100 consecutive responses on the lever appropriate for the animal's pharmacological condition (e.g., left for sham, right for drug) resulted in the delivery of three grams of food. Training sessions consisted of from zero to four sham trials that preceded two consecutive drug trials. The number of sham trials varied unsystematically to preclude discrimination of the drug trials on the basis of the number of preceding trials. Discriminations were established with each of the training drugs employed (codeine, methohexital, and ketamine). During dose-effect evaluations of the training drug or other drugs (test sessions), a progressively large dose of drug was injected prior to each trial and 100 consecutive responses on either the sham- or drug-appropriate lever resulted in the delivery of food. Test sessions continued until either drug-lever responding or a marked suppression in the rate of responding occurred. Thus, a cumulative dose-effect curve for each drug was generated within a single session. Preliminary findings suggest that the pattern of cross-drug generalization generated by this cumulative-dosing procedure is similar to that obtained with procedures that evaluate only a single dose of drug per session.

Animals↗
PubMed1981

Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon.

Separate groups of pigeons were trained to discriminate the IM injection of ketamine, cyclazocine, or dextrorphan from saline. Each of the training drugs and phencyclidine produced dose-related, drug-appropriate responding in each group of birds. In contrast, ethylketazocine and nalorphine generally produced responding appropriate for saline. These results indicate that common elements of discriminable effects exist among ketamine, cyclazocine, and dextrorphan, structurally dissimilar compounds that are generally considered to belong to distinct pharmacological classes.

Animals↗
PubMed1981

Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons.

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.

Animals↗
PubMed1980

Effect of ethanol and of noise on reaction time in the monkey: variation with stimulus level.

To determine whether the latency-increasing effects of ethanol were differential with respect to the intensity of the stimulus that initiated the response, three rhesus monkeys were trained on a behavioral task in which the latency of a simple motor response was measured following the onset of a pure tone stimulus. Following training, the animals were tested at a number of different tone intensities and functions relating latency to tone intensity were constructed. When these were stable, the animals were given ethanol in doses of 1.0-2.5 g/kg and the effects on response latencies to different tone intensities were determined. It was found that for all except the lowest stimulus levels, the effect of ethanol was dose-related, while for a given dose the effect was equal across intensity. These results indicate that the effects of ethanol in this situation are on response execution rather than stimulus detection. The effects of ethanol were compared to those of exposure to high intensity noise. This treatment, which affects primarily the inner ear, resulted in substantial increases in latency to low intensity tones, but little, if any, shift at high intensities.

Acoustic Stimulation↗
PubMed1980

The effects of ethanol, phenobarbital, and baclofen on ethanol withdrawal in the rhesus monkey.

Physical dependence on ethanol was produced in four rhesus monkeys by IV ethanol administration every 8 h. Ethanol was administered on each occasion until the eyeblink reflex was lost. Evidence of physical dependence development, in the form of tremoring 8 h after an infusion, appeared on day 8 of chronic administration. Abrupt cessation of ethanol administration following 16 days of chronic administration was accompanied by moderate to severe tremoring, retching, vomiting, and one or more convulsions. Peak withdrawal occurred between 12 and 32 h after abrupt discontinuation of ethanol administration, and decreased over a period of 64-204 h. Ethanol dependence was then reinstated. Once every 3-4 days, ethanol was withheld for 16 h. Withdrawal signs were scored for the first 12 h of this period, and then a test dose of ethanol, phenobarbital, or baclofen was administered. Withdrawal or intoxication signs were scored over the next 4 h, at which time ethanol administration was resumed. Both ethanol and phenobarbital suppressed ethanol withdrawal signs in a dose-related manner, and produced dose-related intoxication. Baclofen was largely ineffective in reducing withdrawal-induced tremors, although it was capable of producing sedation of a different type than that produced by phenobarbitol and ethanol.

Alcoholism↗
PubMed1976

Comparison of behavior maintained by infusions of eight phenylethylamines in baboons.

Doses of eight phenylethylamines were substituted for cocaine on a drug-maintained behavior baseline in baboons. Intravenous infusions of drug were contingent upon completion of 160 lever presses (a 160-response fixed-ratio schedule; FR 160). A 3-h time-out period followed each infusion, permitting a maximum of 8 infusions per day. Fenfluramine was the only drug that did not maintain self-infusion performance at any dose tested. d-Amphetamine was approximately 10 times more potent than phentermine, phenmetrazine or diethylpropion, and 20 to 30 times more potent than methylenedioxyamphetamine (MDA), clortermine or chlorphentermine, in maintaining self-infusion behavior. Some doses of d-amphetamine and phentermine produced a cyclic pattern of drug intake over days. Increasing self-infused doses of all drugs produced a substantial suppression of concurrent food-maintained behavior. There was no clear relation between the potency of the phenylethylamines in maintaining self-infusion performance and the potency in suppressing food-maintained behavior which indicates that different mechanisms may underlie the two effects. Examination of chemical structures indicates that substitution on the phenyl ring may decrease the potency of phenylethylamines in maintaining self-infusion behavior.

3,4-Methylenedioxyamphetamine↗
PubMed1975

Barbiturate-reinforced responding in rhesus monkeys: comparisons of drugs with different durations of action.

The rate and pattern of pressing a lever was studied in rhesus monkeys under conditions where each press led to the intravenous injection of a barbiturate or of saline. The reinforcing effect of the barbiturate was indicated by higher rates of responding on the lever that delivered drug than on the lever that did not and by lower rates of responding when saline was delivered instead of the barbiturate. Responding increased and was maintained by the following ranges of dose/injection: barbital (2.5-10.0 mg/kg), pentobarbital (0.25-4.0 mg/kg), amobarbital (0.25-4.0 mg/kg), thiopental (0.50-4.0 mg/kg) and methohexital (0.125-2.0 mg/kg). Response rates were inversely related to the dose delivered with each injection for each of the barbiturates over these ranges. Within 3-hour access periods, injections tended to occur in bursts followed by pauses.

Animals↗
PubMed1972

Behavioral maintenance of high concentrations of blood ethanol and physical dependence in the rat.

Rats maintained on an intermittent food schedule with an available ethanol solution drink to excess (13.1 grams of ethanol per kilogram of body weight, daily). Removal of ethanol produces symptoms of physical dependence including death from tonic-clonic seizures. Overindulgence in oral self-administration of an aqueous ethanol solution, resulting in unequivocal physical dependence, approximates a model of human alcoholism.

Alcohol Drinking↗