Biomedical subjects

J C Winter

Publications and source records attributed to J C Winter.

At least 37 records · Page 2Linked to original sources

PubMed1999

Further investigations of the serotonergic properties of the ibogaine-induced discriminative stimulus.

1. 5-HT3, 5-HT2C, and 5-HT1A receptor ligands were assessed in rats trained to discriminate ibogaine from water. 2. Significant ibogaine-appropriate responding was observed following treatment with the 5-HT2C agonists MK-212 (79.6%) and mCPP (76.4%). This substitution was completely antagonized by metergoline, an agent with 5-HT2C antagonist properties. However, metergoline was ineffective against ibogaine itself. This suggests that although ibogaine may act as an agonist at 5-HT2C receptors, this interaction is not essential to its discriminative cue. 3. Neither the 5-HT3 agonist, mCPBG (44.3%), nor the 5-HT3 antagonist, ondansetron (48.9%) substituted for ibogaine. Likewise, the 5-HT1A agonist 8-OH-DPAT (34.7%) and the 5-HT1A antagonist WAY-100635 (30.1%) failed to substitute. Furthermore, WAY-100635 failed to antagonize the ibogaine cue. 4. Unlike 5-HT2C receptors, 5-HT1A and 5-HT3 receptors do not appear to be involved in the ibogaine stimulus.

Animals↗

PubMed1998

The effects of beta-carbolines in rats trained with ibogaine as a discriminative stimulus.

The structural features and hallucinogenic properties shared by ibogaine and certain beta-carbolines prompted the evaluation of several representative beta-carbolines in rats trained with ibogaine as a discriminative stimulus. In a previous report from our laboratory harmaline completely substituted for ibogaine (83.5%). In the present study, only 6-methoxyharmalan completely substituted (86.3%). However, partial substitution was observed with harmine, harmane, harmalol, and tetrahydro-beta-carboline (THBC). Norharmane and 6,7-dimethoxy-4-ethyl-carboline-3-carboxylate (DMCM) failed to produce appreciable substitution. These results provide evidence for an ibogaine-like ether this extends to the previously reported anti-addictive effects of ibogaine remains to be established.

Animals↗

PubMed1998

The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat.

Extracts of the leaves of the Ginkgo biloba tree are widely used throughout the world for their purportedly beneficial effects on brain function. In the present investigation, a standardized extract, EGb 761, was self-administered orally by male Fischer 344 rats that were then tested in an eight-arm radial maze. The tasks employed were a) continuous learning and b) delayed nonmatching to position. Chronic postsession administration of EGb 761 at a dose of 50 mg/kg had no effect on continuous learning but the same dose given presession resulted in a trend toward fewer sessions to reach criterion performance as well as fewer errors. In addition, it was observed that rats chronically treated with EGb 761 lived significantly longer than vehicle-treated subjects. In a delayed nonmatching to position task using a 30-min delay in 20-month-old rats. EGb 761 administered presession produced a dose-related decrease in total, retroactive, and proactive errors; a repeated-measures design was used, with subjects serving as their own controls. Following the dose-response determination, the group, now 26 months of age, was divided in two with half receiving EGb 761 at a dose of 200 mg/kg presession and the other half vehicle (sweetened condensed milk). A statistically significant positive effect of treatment with EGb-761 was observed. The present data are consistent with the beneficial effects on cognitive performance which have been widely reported in human subjects. In addition, the data suggest that the methods employed, i.e., continuous learning and delayed nonmatching to position tasks in aged rats, are capable of detecting drugs of possible value in the treatment of human cognitive impairment. Finally, the present results encourage a search for the pharmacologically active principles of EGb 761 and for their mechanisms of action.

Animals↗

PubMed1998

Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus.

In the present investigation, the ability of two known hallucinogens, lysergic acid dimethylamide (LSD) and (-)-2,5-dimethoxy-4-methyl-amphetamine (DOM), to substitute for the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) was assessed in Fischer-344 rats. In these subjects, intermediate levels of generalization were observed to both agents (LSD, 63%; DOM, 66.4%). This intermediate generalization was completely blocked by pretreatment with the 5-HT2A antagonist pirenpirone, suggesting that the ibogaine-like effects of these agents are mediated by the 5-HT2A receptor. However, pirenpirone did not antagonize ibogaine itself, nor did it antagonize the ibogaine-like effects of harmaline and 12-hydroxyibogamine (noribogaine). To further evaluate the serotonergic properties of ibogaine, in vivo protection assays and in vitro binding assays were employed. Micromolar 5-HT2A affinity was observed with ibogaine (92.5 microM), 12-hydroxyibogamine (34.5 microM), and harmaline (42.5 microM). Despite the apparently low affinity of these agents, both ibogaine and harmaline, but not 12-hydroxyibogamine, produced significant protection from receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) when given 60 min prior to this alkylating agent. The results of these studies suggest that although ibogaine may produce some of its effects via interactions with 5-HT2A receptors, these do not appear to be essential to the ibogaine-induced discriminative stimulus.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1998

The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the sigma1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for sigma2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (-)-SKF 10,047 (78.9%), (+/-)-pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) indicating a potential role for opiate receptors in the ibogaine stimulus. Partial substitution was also observed with naltrexone (55.6%) but not with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of the ibogaine cue, although naloxone produced a moderate but statistically significant antagonism (69.8%). In addition, naloxone produced complete antagonism of the ibogaine-appropriate responding elicited by both (-)-SKF 10,047 (19.7%) and nalorphine (25.8%), whereas the ibogaine-appropriate responding produced by diprenorphine was only partially antagonized (44.4%). The latter observations taken together with the finding that both nalorphine (>100 microM) and diprenorphine (30 microM) have extremely low affinity for sigma2 receptors, suggest that the ibogaine-appropriate responding produced by these agents is not mediated by sigma2 receptors. These findings imply that opiate effects may be involved in the ibogaine stimulus. In contrast to sigma2 and opiate receptors, ibogaine's reported interactions with NMDA receptors do not appear to be involved in its discriminative stimulus, as neither PCP nor MK-801 produced a significant level of ibogaine-appropriate responding. Thus, the present study offers evidence that unlike NMDA receptors, both sigma2 and opiate receptors may be involved in the ibogaine discriminative stimulus.

Animals↗

PubMed1998

The discriminative stimulus effects of KA 672, a putative cognitive enhancer: evidence for a 5-HT1A component.

Stimulus control was established in a group of seven rats using a dose of KA 672 [7-methoxy-6-[3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]3,4-dimethyl-2H-1-benzopyran-2-one HCl] of 1.0 mg/kg, administered i.p., 15 min before training. A two-lever operant task using a fixed-ratio 10 schedule of sweetened milk reinforcement was used. Based upon a criterion for the presence of stimulus control of five consecutive sessions during which 83% or more of all responses were on the appropriate lever, a mean of 23 sessions was required to reach criterion performance. Subsequently, it was observed that KA 672-induced stimulus control is partially but significantly antagonized by the selective 5-HT1A antagonist, WAY-100635. Furthermore, KA 672 generalized to the selective 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin [8-OH-DPAT], and this generalization was blocked by WAY-100635. Other tests of generalization were conducted with the structural analogs, scoparone, CD-127, and OMPP, as well as with the receptor-selective ligands ketamine, PCP, dizocilpine, prazosin, urapidil, apomorphine, and DTG. Of these drugs only dizocilpine met the criteria for full substitution while an intermediate level of generalization was observed to ketamine, PCP, urapidil, and apomorphine. The present results indicate that KA 672-induced stimulus control is mediated in part by activity at the 5-HT1A receptor and that behaviorally significant interactions occur as well at PCP/NMDA, dopaminergic, and adrenergic receptors.

Animals↗

PubMed1998

A comparison of N,N-dimethyltryptamine, harmaline, and selected congeners in rats trained with LSD as a discriminative stimulus.

1. A series of N-substituted tryptamines was compared with a series of beta-carbolines in rats trained to discriminate LSD (0.1 mg/kg) from saline. 2. Intermediate levels of substitution were elicited by MDMT (76.4%), DMT (77.9%), and DET (48.7%). 6-F-DET produced 41.3% LSD-appropriate responding at a dose of 6.0 mg/kg but only 4 of 8 subjects completed the test session thus precluding statistical analysis. Bufotenine (25.8%) also failed to substitute. Although none of the tryptamines substituted completely for LSD, the pattern of substitution is consonant with what is known of their activity in humans. MDMT, DMT, and DET are well established in the literature as hallucinogens but the same cannot be said for 6-F-DET and bufotenine. 3. Of the beta-carbolines tested, none substituted for LSD completely and only harmane elicited intermediate substitution (49.5%). No significant generalization of the LSD stimulus to 6-methoxyharmalan, harmaline, or THBC was observed. Thus, in contrast to the tryptamines, scant ability to substitute for LSD was observed in the beta-carbolines tested. 4. Taken together, the present data indicate that the representative tryptamines employed in the present study exhibit greater similarity to the LSD stimulus than do representative beta-carbolines. The receptor interactions responsible for these differences remain to be determined.

Animals↗

PubMed1998

WAY-100635 reverses 8-OH-DPAT-induced performance impairment in the radial maze.

1. The effects of the 5-HT1A receptor agonist, (8-OH-DPAT), alone and in combination with the selective 5-HT1A antagonist, WAY-100635, were assessed in Fischer-344 rats in an 8-arm radial maze. 2. At a dose of 1.0 mg/kg, 8-OH-DPAT significantly reduced both efficiency of performance (% correct arm entries) and response rate (arms/min) compared with the saline condition. 3. These effects were completely blocked by WAY-100635 which by itself had no effect on efficiency or response rate. 4. WAY-100635 inhibits 8-OH-DPAT-induced impairment in radial maze performance.

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

PubMed1997

[3H]8-OH-DPAT labels a 5-HT site coupled to inhibition of phosphoinositide hydrolysis in the dorsal raphe.

The present study was undertaken to compare the properties of the [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) binding site in the dorsal raphe nucleus with the hippocampal 5-HT1A receptor. In both tissues inclusion of 1 mM Mg2+ enhanced specific [3H]8-OH-DPAT binding, while 1 mM GTP decreased radioligand binding. [3H]8-OH-DPAT appears to bind to a single population of binding sites in both the hippocampus and the dorsal raphe nucleus, although the K(d) for the radioligand at the dorsal raphe site was five times that observed at the hippocampal 5-HT1A receptor. Similarly, although 5-HT and selective 5-HT1A receptor ligands displayed high affinity for the [3H]8-OH-DPAT binding site in the dorsal raphe nucleus, the affinity at the dorsal raphe site was less than that observed at the hippocampal 5-HT1A receptor. 8-OH-DPAT inhibited forskolin-stimulated adenylyl cyclase activity in the hippocampus, but did not alter enzyme activity in the dorsal raphe nucleus. Conversely, 8-OH-DPAT inhibited the accumulation of [3H]inositol phosphates in the dorsal raphe nucleus, but not in the hippocampus. An inhibition of phosphoinositide hydrolysis in the dorsal raphe nucleus also was found with the putative 5-HT1A receptor selective ligands, flesinoxan and gepirone. However, addition of another putative 5HT1A receptor selective ligand, buspirone, did not alter the generation of [3H]inositol phosphates, but blocked the inhibitory effect of 8-OH-DPAT on phosphoinositide hydrolysis. These studies demonstrate that the 8-OH-DPAT binding site in the dorsal raphe nucleus displays a binding profile which is similar to the hippocampal 5-HT1A receptor, but unlike this 5-HT1A receptor the binding site in the dorsal raphe nucleus is negatively coupled to phosphoinositide turnover.

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

PubMed1997

Effects of chronic ibogaine treatment on cerebellar Purkinje cells in the rat.

The present investigation assessed the chronic toxicity of ibogaine on cerebellar Purkinje cells in male Fischer 344 rats. A behaviorally active dose of ibogaine (10 mg/kg, i.p.) was administered to a group of six subjects every other day for 60 days while the control group received an equivalent volume of saline (1 ml/kg). Estimates of Purkinje cell number were determined using the optical dissector/fractionator technique. No significant differences in Purkinje cell number were observed between the ibogaine (243764[+/-32766]) and control groups (230813[+/-16670]).

Animals↗

PubMed1997

The effects of noribogaine and harmaline in rats trained with ibogaine as a discriminative stimulus.

In the present investigation, Fischer-344 rats were trained to discriminate 10.0 mg/kg of ibogaine from water using a pretreatment time of 60 minutes. Analysis of dose response data generated an ED50 of 4.6 mg/kg. The time course of the ibogaine (10.0 mg/kg) cue was also determined. The stimulus reached a maximum level of 94% ibogaine-appropriate responding at the 60-min pretreatment time. This was followed by a time-dependent decrease in ibogaine-appropriate responding. At a pretreatment time of 8 hrs only 6.4% drug-appropriate responding was observed. In substitution experiments, intermediate generalization was observed with a metabolite of ibogaine, 12-hydroxyibogamine [noribogaine] (71.6%) whereas complete generalization was seen with harmaline (83.5%).

Animals↗

PubMed1997

Further investigations of the interactions of antipsychotics with the (-)2,5-dimethoxy-4-methylamphetamine (DOM) discriminative stimulus.

Stimulus control induced by (-)-2,5-dimethoxy-4-methylamphetamine (DOM) is believed to be mediated by agonism at 5-HT2A receptors. We hypothesized that blockade of (-) DOM-induced stimulus control may thus prove useful in the pre-clinical characterization of novel antipsychotic agents by providing an in vivo index of antagonism at that receptor. A previous study (Fiorella et al., 1995a) observed no antagonism by typical agents such as haloperidol and thioridazine, partial antagonism by the atypical agent, clozapine, and full antagonism by risperidone, a second atypical antipsychotic. The present investigation extends these observations to include seven additional drugs: SCH 23390, sulpiride, amperozide, melperone, octoclothepin, tiospirone and ritanserin. Of the drugs tested in rats in which (-) DOM-induced stimulus control had reliably been established, only tiospirone and ritanserin produced complete antagonism of the (-) DOM stimulus. Intermediate levels of antagonism were observed following treatment with amperozide, melperone, and octoclothepin. Finally, SCH 23390 and sulpiride yielded no evidence of antagonistic activity in (-) DOM-trained animals. Because clozapine and risperidone are both classified as atypical antipsychotics yet yield different degrees of antagonism of (-) DOM-induced stimulus control, we tested the substitution of risperidone for clozapine in rats trained with clozapine as a discriminative stimulus. No significant substitution was observed. In conclusion it appears that complete or partial antagonism of the (-) DOM stimulus serves as an effective pre-clinical means of identifying antipsychotics with significant 5-HT2A antagonist properties. However, the failure of risperidone to substitute for clozapine in pigeons (Hoenicke et al., 1992) and in rats (present study) suggests that despite their shared 5-HT2A antagonist properties, clozapine and risperidone differ with respect to their stimulus effects.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1997

The effects of age on continuous learning in the radial maze.

Two groups of male Fischer 344 rats were trained in 1 session per day on a series of tasks in a food-reinforced radial maze. The younger group (n = 10) was 3 months old at the start of these experiments; the older group (n = 10) was 21 months old at the start. Following acclimation to the maze, subjects were trained successively on an 8-arm task (8A1) in which entry into all arms was reinforced and a 4-arm task (141) in which only entry into arms 1 through 4 was reinforced. The 8-arm task was then repeated (8A2) and followed by a second 4-arm task (581) in which only entry into arms 5 through 8 was reinforced. The criterion for moving from one task to the next in the sequence was 3 consecutive sessions in which no more than 1 error was made. Comparison of the groups revealed that the younger rats required significantly fewer sessions and made fewer errors before reaching criterion performance in tasks 141, 8A2, and 581. The 2 groups did not differ in their mean rate of responding. The present data indicate that the use of a series of tasks that require continuous learning in a positively reinforced radial maze will permit continued differentiation of young and old rats. This approach may prove useful in the assessment of interventions in the process of age-related cognitive decline.

Age Factors↗

PubMed1997

Effects of ibogaine on performance in the 8-arm radial maze.

The effects of ibogaine were studied in 12 rats trained to perform in an 8-arm radial maze. In Phase I, the mean number of sessions to criterion and cumulative errors to criterion, as well as mean response rate, were determined for two groups of six animals in a task where only four arms were baited. Group 1 received a potentially neurotoxic dose of ibogaine (50 mg/kg IP administered twice, with approximately 8 h between injections), and group 2 received vehicle. Both groups had similar levels of performance, but ibogaine-treated subjects had a significantly lower rate of responding in the maze. During Phase II, subjects were given a range of doses of ibogaine 20 min prior to working in the maze. Ibogaine produced a dose-dependent decrease in response rate, but efficiency (% arms correct) was not affected. In Phase III, subjects were divided into the same groups as they had been in Phase I. Ibogaine (30 mg/kg, IP) or vehicle was administered immediately following daily sessions in the maze. Ibogaine-treated rats committed significantly fewer errors than those in the vehicle treated group. Thus, in the present study, ibogaine failed to produce any deleterious effects on either acquisition of a novel task or efficiency in a previously learned task.

Animals↗

PubMed1996

Ibogaine and noribogaine potentiate the inhibition of adenylyl cyclase activity by opioid and 5-HT receptors.

The effects of the putative anti-addictive compound ibogaine and its principal metabolite, noribogaine, on adenylyl cyclase activity were determined in various areas of the rat brain. Neither compound altered either basal or forskolin-stimulated adenylyl cyclase activities in the frontal cortex, midbrain or striatum. However, in all three brain areas the addition of ibogaine and noribogaine significantly enhanced inhibition of adenylyl cyclase activity by a maximally effective concentration of morphine. Similarly, both compounds also potentiated the inhibition of hippocampal adenylyl cyclase activity by a maximally effective concentration of 5-hydroxytryptamine (5-HT). Although ibogaine appears to be more potent than noribogaine in augmenting opioid- and 5-HT-mediated inhibition of adenylyl cyclase activity, both compounds appear to be of comparable efficacy. Neither compound, however, modified the inhibitory action of the muscarinic acetylcholine agonist, carbachol, on adenylyl cyclase activity. The present data indicate that ibogaine and noribogaine cause a selective increase in receptor-mediated inhibition of adenylyl cyclase activity. This potentiation may be involved in the pharmacological actions of these compounds.

Adenylyl Cyclases↗

PubMed1996

Effects of ibogaine and noribogaine on phosphoinositide hydrolysis.

The effects of the antiaddictive compound, ibogaine, and its primary metabolite, noribogaine (12-hydroxyibogamine), on phosphoinositide hydrolysis were investigated. Although ibogaine did not alter phosphoinositide turnover in either striatal or hippocampal slices, noribogaine elicited a concentration-dependent increase in the generation of [3H]inositol phosphates. This stimulation was not altered by inclusion of tetrodotoxin, cadmium or omega-conotoxin indicating that the increased production of [3H]inositol phosphates was not secondary to a release of one or more neurotransmitters. The present study indicates a stimulation of phosphoinositide hydrolysis by noribogaine may be involved in the behavioral effects of ibogaine.

Animals↗

PubMed1996

The interaction of clozapine with the meta-chlorophenylpiperazine (mCPP) discriminative stimulus.

The psychotropic effects of the 5-HT2C agonist mCPP in human subjects are blocked by the atypical antipsychotic clozapine, but not by typical antipsychotics. An understanding of the mechanistic basis for the interaction of clozapine and mCPP would provide further insight into the basis for its unique therapeutic effects in humans. Drug-induced stimulus control provides an animal model for the subjective effects of psychotropic agents in humans. In the present study, the interaction of the atypical antipsychotic clozapine and the typical antipsychotic fluphenazine with the mCPP-stimulus were defined. Neither drug antagonized the stimulus effects of mCPP in vivo. In contrast, clozapine fully antagonized the mCPP-stimulated phosphoinositide turnover at the 5-HT2C receptor in vitro. The present data indicate that the paradigm of mCPP-induced stimulus control does not facilitate the differentiation of atypical and typical antipsychotic activities.

Animals↗

PubMed1996

Potentiation of LSD-induced stimulus control by fluoxetine in the rat.

The present investigation examined the interaction between fluoxetine enantiomers and LSD in rats trained with LSD as a discriminative stimulus. The dose response relationships for LSD alone and in combination with either (+)- or (-)-fluoxetine were determined. In both instances, the LSD dose response relationship was shifted to the left. However, statistical significance was observed only for the (+)- enantiomer. It is concluded that the effects of LSD as a discriminative stimulus are potentiated by the acute administration of fluoxetine. These results are consistent with anecdotal reports of interactions between LSD and acutely administered SSRIs in humans.

Animals↗