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Biomedical subjects

J C Winter

Publications and source records attributed to J C Winter.

At least 73 records · Page 4Linked to original sources
PubMed1988

Interactions between serotonergic agonists and antagonists in rats trained with LSD as a discriminative stimulus.

Drugs purported to have selective affinities for 5-HT1A, 5-HT1B, and 5-HT2 receptors were tested in rats trained with 0.1 mg LSD versus saline. Included were 5-methoxy-dimethyltryptamine (MDMT), 2,5-dimethoxy-4-methyl-amphetamine (DOM), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), m-trifluoromethylphenyl-piperazine (TFMPP), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969). Tests were then repeated in the presence of either pizotyline or pirenperone. DOM substituted for LSD and both were blocked by pizotyline and pirenperone. MDMT, 8-OH-DPAT, TFMPP, and RU-24969 substituted less completely and were variably affected by the antagonists. An unexpected result was potentiation of the stimulus or disruptive effects of certain doses of 8-OH-DPAT and TFMPP by pizotyline and pirenperone. The present findings suggest more complex interactions between these drugs than has previously been assumed.

Animals↗
PubMed1988

Generalization of the discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone to yohimbine.

Rats were trained with either 8-OH-DPAT (0.2 mg/kg) or ipsapirone (10 mg/kg) versus saline in a 2-lever discrimination task. Tests of generalization were then conducted with yohimbine. All drugs were administered IP 15 min before testing. In 8-OH-DPAT-trained subjects, 85% of the responses following yohimbine (3 mg/kg) were on the drug-appropriate lever. Likewise, yohimbine (6 mg/kg) yielded 86% drug-appropriate responses in ipsapirone-trained rats. Previous studies have provided evidence that both 8-OH-DPAT and ipsapirone have high affinity for 5-HT1A receptors and the anxiolytic-like activity of the latter drug has been attributed to its activity at those receptors. In contrast, yohimbine is an alpha 2 adrenergic antagonist, has negligible affinity for the 5-HT1A receptor, and is generally regarded as being anxiogenic. The present data, which indicate a high degree of similarity between the stimuli induced by yohimbine, 8-OH-DPAT, and ipsapirone, suggest that a re-evaluation of the presumed mechanisms of actions of these drugs is in order.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Use of the radial maze in studies of phencyclidine and other drugs of abuse.

Effects of drugs known to disrupt performance in an 8-arm radial maze are reported in terms of changes caused in the pattern of arm entry. Phencyclidine (PCP) and N-allyl-N-normetazocine (SKF-10,047) alter the pattern of arm entry in a way which distinguishes their actions from those of scopolamine and certain serotonergic agonists. The apparent rank order of potencies for causing this effect is (+)SKF-10,047 greater than PCP greater than (-)SKF-10,047. Results of previous radial maze studies evaluating the interactions of clonidine and verapamil with PCP are summarized. Data are reported which indicate that the ability of verapamil to potentiate PCP's behavioral effects stems from an alteration of the pharmacokinetics of PCP; when verapamil (20 mg/kg, IP) was administered 15 minutes before [3H]PCP (40 microCi/kg, IP), brain levels of tritium were increased by 154 to 225 percent. Finally, possible advantages of using a 4-arm radial maze in studies of PCP and related drugs are discussed.

Animals↗
PubMed1987

The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory.

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Interactions of clonidine with phencyclidine and ketamine: studies of radial maze performance and righting reflex in rats.

Rats were trained to obtain food pellets in an 8-arm radial maze until a criterion of 89% efficiency, i.e., all arms entered within 9 arm entries, was reached in 5 consecutive sessions. Decreases in efficiency caused by phencyclidine (PCP; 4 to 9 mg/kg, IP, 15 min before testing) or ketamine (25 mg/kg, IP, 5 min) were attenuated when subjects were pretreated with clonidine (0.05 mg/kg, IP, 30 min). However, significant improvements in performance in the maze were not observed when clonidine (0.05 to 0.4 mg/kg, IP) was administered 15 min after PCP (9 mg/kg, IP, 45 min). Subsequent studies of righting reflex demonstrated an increased frequency and duration of anesthesia when clonidine (0.05 mg/kg, IP) was administered 15 minutes before PCP (12.5 to 50 mg/, IP) or ketamine (50 to 100 mg/kg, IP). When clonidine (0.05 mg/kg, IP) was administered 15 minutes before [3H]PCP (40 microCi/kg, IP), brain levels of tritium were reduced by 42 to 55%. The present findings do not support the suggestion that clonidine may be useful in the treatment of PCP intoxication. The data does indicate that pretreatment of surgical patients with clonidine may reduce the dose of ketamine required for anesthesia.

Anesthesia↗
PubMed1986

Verapamil does not antagonize LSD-induced stimulus control.

Discriminative stimulus control was established in rats (N = 6) with LSD (100 microg/kg) and saline using a 2-lever response choice task and an FR10 schedule of food reinforcement. Subjects were then tested once per week with either pizotyline (BC-105) or verapamil alone or in combinations with LSD. In In agreement with previous reports, pizotyline antagonized LSD and, when tested alone, exhibited modest agonistic effects (18% LSD-appropriate). In contrast, verapamil failed to block LSD at any dose tested. Verapamil alone appeared to have somewhat greater agonistic activity (35% LSD-appropriate) than did pizotyline but neither drug substituted completely for LSD. These data suggest that calcium channel antagonism by pizotyline is not essential to its anti-LSD effects.

Animals↗
PubMed1986

Effects of phencyclidine, N-allyl-N-normetazocine (SKF-10,047), and verapamil on performance in a radial maze.

Two groups of eight rats were trained to obtain food pellets in an 8-arm radial maze. Stable performance was assumed to be present when a criterion of 89% efficiency, i.e., all arms entered within 9 arm entries, was reached in 5 consecutive sessions. The effects of phencyclidine (PCP) and N-allyl-N-normetazocine (SKF-10,047) were then evaluated in Group 1. The interaction between verapamil and PCP was examined in Group II. Both PCP (6 mg/kg, IP, 15 min before testing) and SKF-10,047 (30 mg/kg, IP, 30 min) decreased efficiency but only PCP caused a concurrent increase in rate of arm entry. Significant effects of PCP on rate and efficiency lasted for greater than 6 hours and less than 40 minutes, respectively. Verapamil (20 mg/kg, IP, 30 minutes) was found to selectively potentiate the effect of PCP on efficiency. This finding does not support the suggestion that verapamil may be useful in the treatment of PCP intoxication. It is concluded that the radial maze may provide an interesting method for the study of PCP and other psychoactive drugs.

Animals↗
PubMed1985

Sedation and the stimulus properties of antihistamines.

A group of six rats was trained to discriminate the effects of diphenhydramine (10 mg/kg; 30 min pretreatment time) and saline in a two-lever choice task using a fixed ratio schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. Diphenhydramine established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 26 (standard error = 7). A second group of six rats was similarly trained with chlorpheniramine (10 mg/kg; 30 min pretreatment time) and saline. Four of the group reached criterion performance in a mean of 56 sessions (SE = 7). The diphenhydramine stimulus generalized completely to promethazine, azatidine, and chlorpheniramine. In rats trained with chlorpheniramine, only promethazine and azatidine substituted completely while diphenhydramine yielded intermediate results, i.e., significantly different from both training conditions. It is concluded that the relative propensity of antihistamines to induce sedation in humans is not correlated with distinctive stimulus properties in the rat.

Animals↗
PubMed1984

The stimulus properties of para-methoxyamphetamine: a nonessential serotonergic component.

A group of six rats was trained to discriminate the effects of para-methoxyamphetamine (PMA; 3 mg/kg, 15 min pretreatment time) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. PMA established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 19 (SE = 2, range = 14-24). A second group of ten rats was similarly trained with lysergic acid diethylamide (LSD; 0.1 mg/kg, 15 min pretreatment time) and saline. In rats trained with PMA, LSD yielded intermediate results, i.e., significantly different from both training conditions. Likewise, the response distribution was intermediate in nature when LSD-trained subjects were tested with PMA. Pizotyline did not antagonize PMA-induced stimulus control in rats trained with PMA and saline but did antagonize the intermediate responding produced by PMA in LSD-trained subjects. It is concluded that PMA-induced stimulus control does not depend upon activation of serotonergic receptors but that PMA does possess some LSD-like effects which are mediated serotonergically.

Amphetamines↗
PubMed1981

The stimulus properties of gamma-hydroxybutyrate.

Fourteen rats were trained to discriminate the effects of gamma-hydroxybutyrate (GHB) (sodium salt, 200 mg/kg) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Intermediate responding, i.e., responding not fully appropriate for either training condition was observed in tests following morphine, lysergic acid diethylamide, chlordiazepoxide, and the presumed GABA-mimetics muscimol, gamma-butyrolactone, baclofen, and 3-aminopropane sulfonic acid. Naloxone blocked the intermediate results following morphine, but had no effect on GBH-induced stimulus control. The GABA antagonist bicuculline partially blocked GHB, but pizotyline, phentolamine, and butaclamol were without effect. It is concluded that the compound stimulus produced by GHB is most closely associated with GABAergic systems, but that minor opiate and serotonergic components are present as well.

Animals↗
PubMed1981

Drug-induced stimulus control and the concept of breaking point: LSD and quipazine.

Discriminative stimulus control was established in rats (N = 12) with LSD (100 microgram/kg) and saline using a two-lever response choice task and an FR10 schedule of water reinforcement. Subjects were then tested once per week with either LSD or quipazine (3 mg/kg) and every other week the test ratio was doubled, i.e., each drug was tested at ratios of 10, 20, 40, and 80. In contrast with LSD, which maintained stimulus control at all ratios, LSD-appropriate responding following quipazine declined significantly at FR80. In addition, five of eight subjects tested with quipazine failed to complete the FR80 in 15 min. In subsequent experiments, the breaking point, here defined as the number of LSD-appropriate responses prior to emission of ten responses on the saline-appropriate lever, was determined for LSD and for quipazine. Mean values (N = 12) for LSD and quipazine were 161 +/- 28 and 65 +/- 19, respectively.

Animals↗
PubMed1981

Caffeine-induced stimulus control.

Six rats were trained to discriminate the effects of caffeine (60 mg/kg, pretreatment time: 1 hour) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. The mean number of sessions prior to the onset of criterion performance was 22 (SE = 3; range = 11--32). In trained subjects, doses of caffeine of 30, 10, and 3 mg/kg were followed by a progressively smaller proportion of responses on the caffeine-appropriate lever. Stimulus control by caffeine began to diminish about four hours after administration and was completely absent after 24 hours. The caffeine cue generalized partially to d-amphetamine and completely to aminophylline. Neither pizotyline nor spiperone antagonized stimulus control induced by caffeine.

Aminophylline↗
PubMed1980

Effects of the phenethylamine derivatives, BL-3912, fenfluramine, and Sch-12679, in rats trained with LSD as a discriminative stimulus.

Six rats were trained to discriminate the effects of LSD (100 micrograms/kg) and saline in a two-lever choice task. They were then tested with each of three phenethylamine derivatives, BL-3912 (2,5-dimethoxy-4-methyl-alpha-ethyl-phenethylamine), fenfluramine (N-ethyl-alpha-methyl-m-(trifluoro-methyl)phenethylamine), and Sch-12679 (N-methyl-1-phenyl-7,8-dimethoxy-2,3,4,5-tetra-hydro-3-benzazepine maleate). Fenfluramine and Sch-12679 yielded intermediate results, i.e., responding was not fully appropriate for either training condition while BL-3912 substituted completely for LSD. The LSD-like effects of each of the drugs were antagonized by pretreatment with BC-105, a serotonergic antagonist known to block the stimulus effects of indole and phenethylamine hallucinogens. The present data together with consideration of the known clinical effects of BL-3912, fenfluramine, and Sch-12679 are consistent with the following conclusions: (1) a variety of drugs may substitute in whole or in part for LSD in LSD-trained rats, and (2) even complete substitution of a drug for LSD in the rat is not necessarily associated with the production by that drug of hallucinations in man.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1979

Comparison of the discriminative stimulus properties of nefopam and morphine.

Separate groups of rats were trained to discriminate nefopam or morphine from saline in a two-lever operant task. Nefopam produced saline-appropriate responding in morphine-trained rats. The highest dose of morphine tested in nefopam-trained rats produced responding appropriate for neither training treatment. This intermediate morphine responding was antagonized by a naloxone treatment that had no effect on the nefopam discrimination. These results suggest that the stimulus properties of nefopam and morphine are qualitatively different but also that morphine produces effects related to those that result in stimulus control by nefopam.

Animals↗
PubMed1979

Discriminative stimulus properties of intravenous morphine in the rat.

Using a single-lever operant task, rats were trained to discriminate between the effects of 1 mg/kg morphine and saline administered intravenously 15 min prior to sessions. Tests of stimulus control indicated that responding appropriate to the morphine training treatment was present at 5 min and persisted for at least 60 min following intravenous administration. Morphine administered intraperitoneally 15 min prior to sessions resulted in dose-related responding with 6 mg/kg producing stimulus control not significantly different from the intravenous training treatment. These results suggest that the discriminative stimulus properties of morphine in the rat are qualitatively similar following intraperitoneal and intravenous administration.

Animals↗