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J C Winter

Publications and source records attributed to J C Winter.

At least 19 recordsLinked to original sources
PubMed1992

Reversal of testosterone-induced dominance by the serotonergic agonist quipazine.

Anabolic steroids and other androgens, such as testosterone propionate (TP), have a facilitatory role in the expression of aggressive behavior. Based upon literature indicating an inverse relationship between aggression and the central neurotransmitter serotonin (5-HT), the present study was undertaken to investigate the role of 5-HT in androgen-induced aggression. In this study, an animal model of aggression involving competition between male rat pairs for sugar pellets was used to investigate the effects of TP. When TP was administered daily (30 mg/kg) to nondominant rats, these animals became dominant. Dominant behavior was found to be stable throughout the study with continued daily administration of TP. To test the serotonergic component of TP-induced aggression, the serotonergic agonist 2-(1-piperazinyl) quinolone dimaleate (quipazine) was administered acutely to TP-dominant rats. Quipazine dose dependently reduced aggressive dominance in TP-dominant rats, as well as in naturally dominant rats. When the serotonergic antagonists pirenpirone or pizotyline were coadministered with quipazine to either group of dominant rats, they blocked the effect of quipazine in reducing dominance. However, when 1-[1H-Indol-4-yloxy]-3-[isopropylamino]-2-propanol (pindolol), a drug that acts at both beta-adrenergic receptors and at 5-HT1A and 5-HT1B receptors, was coadministered with quipazine there was a reversal of the quipazine effect on aggression only in TP-dominant rats. These results indicate that androgen-induced aggression may involve a complex alteration in serotonergic neurotransmission.

Anabolic Agents↗
PubMed1992

Stimulus effects of ibogaine in rats trained with yohimbine, DOM, or LSD.

The stimulus effects of ibogaine were compared with those of yohimbine, an alpha 2-adrenoceptor antagonist, 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-hydroxytryptamine2 (5-HT2) agonist, and lysergic acid diethylamide (LSD), a nonspecific 5-HT agonist. Rats were trained with either yohimbine (6 mg/kg), DOM (0.6 mg/kg), or LSD (0.1 mg/kg) vs. no treatment in a two-lever discrimination task. Tests of generalization were then conducted with ibogaine. In yohimbine-trained animals, 39.7% of responses following ibogaine (15 mg/kg) were on the drug-appropriate lever, but this response level was not significantly different from no treatment-appropriate responding. A response distribution that was significantly different from responding under both drug and no treatment training conditions was observed in DOM-trained rats after administration of 15 mg/kg ibogaine. Pizotyline (BC-105) blocked all DOM-appropriate responding produced by ibogaine. In LSD-trained animals, 20 mg/kg ibogaine mimicked LSD. Pizotyline blocked LSD-appropriate responding produced by ibogaine in five of six animals. The present data suggest the involvement of 5-HT2 receptor activity, and the possibility of a 5-HT1A contribution, in the stimulus properties of ibogaine.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1992

Yohimbine as a serotonergic agent: evidence from receptor binding and drug discrimination.

Stimulus control was established in rats trained to discriminate either 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) (0.2 mg/kg) or yohimbine (3 mg/kg) from saline. Tests of generalization were then conducted with a group of drugs thought to act via the 5-hydroxytryptamine1A (5-HT1A) receptor and a group of drugs thought to act as antagonists at alpha 2 adrenoceptors. In addition, each drug was characterized in terms of its affinity for 5-HT1A and alpha 2 adrenoceptors by means of radioligand binding techniques. It was observed that the stimulus effects of DPAT generalized fully to those of the alpha 2-adrenoceptor antagonists, yohimbine, rauwolscine and L-657,743, but not to idazoxan or atipamezole. The dissociation constants (Kd, nM) of the alpha 2-adrenoceptor antagonists at the 5-HT1A receptor were 74, 52, 80, 199 and 13,000, respectively. Thus, the discrimination data are explicable in terms of a direct action of yohimbine and some other alpha 2 adrenoceptor antagonists upon 5-HT1A receptors. In yohimbine-trained rats, full generalization to DPAT, flesinoxan and tandospirone was observed. In light of the negligible affinity of flesinoxan and tandospirone for the alpha 2 adrenoceptor (9000 and 8800 nM, respectively), and high affinity for the 5-HT1A receptor (0.3 and 43 nM, respectively), a mechanism mediated by the latter site is suggested. We would emphasize two implications of the present study. First, the present data suggest that rats trained with yohimbine as a discriminative stimulus generalize to drugs with minimal affinity for the alpha 2 adrenoceptor but with high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Phencyclidine/SKF-10,047 binding sites: evaluation of function.

Results of correlation analyses comparing rank-order affinities with rank-order potencies of (+)SKF-10,047, phencyclidine (PCP), and several PCP analogs support the involvement of [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine binding sites (TCP sites) in mediating both the discriminative stimulus properties of PCP and production of 180 degrees perseveration in a 4-arm radial maze. For the same group of drugs, no significant relationship was found to exist between affinities at haloperidol-sensitive (+)[3H]SKF-10,047 binding sites (H-S-SKF sites) and potencies. Also, H-S-SKF sites were found to lack pharmacological selectivity and to be localized in the microsomal fraction of cells. It is concluded that TCP sites may represent receptors which mediate effects not only of PCP, but also of (+)SKF-10,047. In addition, the possibility that H-S-SKF sites may represent a type of membrane-bound enzyme is discussed.

Animals↗
PubMed1988

A comparison of the discriminative stimulus properties of l-5-hydroxytryptophan in the presence of either citalopram or Ro 4-4602.

The establishment of stimulus control by 5-HTP, the amino acid precursor for serotonin (5-HT), has been reported previously [1-3]. In the present investigation, two groups of rats were trained with 5-HTP versus saline in a 2-lever discrimination procedure. Prior to the administration of 5-HTP, subjects were pretreated with either Ro 4-4602, an inhibitor of peripheral decarboxylase (R-HTP), or citalopram, a specific 5-HT reuptake inhibitor (C-HTP). Neither C-HTP nor R-HTP was antagonized completely by either pirenperone or pizotyline. When C-HTP and R-HTP were tested in a third group of rats trained with LSD, complete generalization was not observed. The results of cross tests in the R-HTP and C-HTP groups with LSD, TFMPP, 8-OH-DPAT, C-HTP, and R-HTP indicate that the stimuli induced by R-HTP and C-HTP are similar but not identical. Taken together, these data suggest that 5-HTP produces a compound stimulus that is not readily explained in terms of either 5-HT1 or 5-HT2 receptors alone.

5-Hydroxytryptophan↗
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↗
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↗